SP-SAP References

SP-SAP (Cat. #IT-07)discontinued

see also: SSP-SAP (Cat. #IT-11)

92 entries found for : it-07

Chronic pain in dogs (Dolor crónico en el perro)

Puente BR (2021) Chronic pain in dogs (Dolor crónico en el perro). Zaragoza Spain: Gruppo Asis Biomedia, S. L..

Summary: The author presents a thorough overview of aspects of canine chronic pain. He includes SP-SAP (Substance P-Saporin) as an experimental drug, “its use as an adjuvant analgesic in dogs with bone cancer has been studied,”

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Featured Article: SP-SAP human clinical trial for cancer pain – an anesthesiologist’s point of view

Noe C, McDermott E (2015) Featured Article: SP-SAP human clinical trial for cancer pain – an anesthesiologist’s point of view. Targeting Trends 16(3)

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Read the featured article in Targeting Trends.

Treatment considerations for cancer pain: A global perspective.

Pergolizzi J, Gharibo C, Ho K (2015) Treatment considerations for cancer pain: A global perspective. Pain Pract 15:778-792. doi: 10.1111/papr.12253

Summary: This review discusses the treatment of cancer pain, addressing various aspects of the overall picture, such as early pain treatment to reduce central sensitization and chronic pain, pain assessment tools, and guidelines for treating specific populations of patients. Some of the current tools for pain management are discussed, including SP-SAP, which is currently in clinical trials as a cancer pain therapeutic.

Related Products: SP-SAP (Cat. #IT-07)

Preliminary results from a phase I study of substance P-saporin in terminal cancer patients with intractable pain.

Frankel AE, Nymeyer H, Lappi DA, Higgins D, Ahn C, Noe C (2014) Preliminary results from a phase I study of substance P-saporin in terminal cancer patients with intractable pain. Journal of Clinical Oncology 32:191. doi: 10.1200/jco.2014.32.31_suppl.191

Summary: Existing pain therapies are insufficient to control cancer pain in 10-15% of patients. Substance P (SP) and its receptor, neurokinin-1 (NK-1r) have been determined to play a major role in spinal transmission of chronic pain. Animal studies have demonstrated that disruption of the NK-1r pathway alleviates chronic pain caused by a variety of stimuli. The authors are conducting a Phase I clinical trial in humans (NCT02036281) assessing the ability of SP-SAP (Cat. #IT-07) to treat intractable chronic pain due to cancer. Patients have received intrathecal injections of 1, 2, or 4 µg of SP-SAP with no evidence of toxicity or neurological or cardiac abnormalities. Doses will escalate up to 90 µg.

Related Products: SP-SAP (Cat. #IT-07)

Intrathecal substance p-saporin in the dog: distribution, safety, and spinal neurokinin-1 receptor ablation.

Wiese AJ, Rathbun M, Butt MT, Malkmus SA, Richter PJ, Osborn KG, Xu Q, Veesart SL, Steinauer JJ, Higgins D, Lappi DA, Russell B, Yaksh TL (2013) Intrathecal substance p-saporin in the dog: distribution, safety, and spinal neurokinin-1 receptor ablation. Anesthesiology 119(5):1163-1177. doi: 10.1097/ALN.0b013e3182a95164

Summary: Here the authors investigate the safety parameters of SP-SAP on purpose-bred beagles (currently in human clinical trials). The dogs received 1.5, 15, or 150 μg intrathecal injections of the conjugate. SP-SAP pharmacology and physiological effects were assessed by behavioral and functional observations, immunohistochemistry, ELISA, blood and urine analysis, histopathology, and in situ hybridization. The general conclusions include that neurokinin-1 receptor (NK1r) positive neuron loss is detectable as soon as 7 days after administration of SP-SAP, the neuron loss is permanent, toxicity is specific to NK1r-positive neurons, and, other than the 150 μg dose, NK1r neuron loss was restricted to the superficial dorsal horn.

Related Products: SP-SAP (Cat. #IT-07), SP-SAP (Cat. #IT-07)

Read the featured article in Targeting Trends.

Intrathecal substance p-saporin in the dog: efficacy in bone cancer pain.

Brown DC, Agnello K (2013) Intrathecal substance p-saporin in the dog: efficacy in bone cancer pain. Anesthesiology 119(5):1178-1185. doi: 10.1097/ALN.0b013e3182a95188

Summary: This work demonstrates the use of naturally occurring bone cancer in dogs as a model for pain therapy. Companion dogs with bone cancer received 20-60 μg intrathecal injections of SP-SAP (currently in human clinical trials) depending on the size of the dog. Significantly more dogs in the control group required unblinding and adjustment of pain care than in the SP-SAP group, indicating the efficacy of SP-SAP in pain control. This study also demonstrates the validity of the dog model for testing analgesic protocols.

Related Products: SP-SAP (Cat. #IT-07)

Read the featured article in Targeting Trends.

Substance P-saporin for bone cancer pain in dogs: Can man’s best friend solve the lost in translation problem in analgesic development?

Hayashida K (2013) Substance P-saporin for bone cancer pain in dogs: Can man’s best friend solve the lost in translation problem in analgesic development?. Anesthesiology 119(5):999-1000. doi: 10.1097/ALN.0b013e3182a951a2

Summary: This editorial describes the SP-SAP papers in this latest issue of Anesthesiology. The results of the paper are discussed, and the potential in using companion dogs for pain models is emphasized. While most pain models have been rodent-based, companion dogs provide models for chronic pain due to natural causes such as cancer and arthritis, along with frequent opportunity for behavioral assessments by the owner. Such assessments can be done without stress to the animal.

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Lamina I NK1 expressing projection neurones are functional in early postnatal rats and contribute to the setting up of adult mechanical sensory thresholds.

Man SH, Geranton SM, Hunt SP (2012) Lamina I NK1 expressing projection neurones are functional in early postnatal rats and contribute to the setting up of adult mechanical sensory thresholds. Mol Pain 8(1):35. doi: 10.1186/1744-8069-8-35

Summary: Projections from lamina I neurons regulate mechanical and thermal sensitivity due to injury. Little is known about how these pathways develop immediately after birth. Rats at postnatal day 3 were treated with 2 μl of 5 μM SP-SAP (Cat. #IT-07) injected into the intrathecal space. Blank-SAP (Cat. #IT-21) was used as a control. The data show that neurokinin-1 positive neurons project to the parabrachial nucleus in the hindbrain, and that these neurons and lamina I neurons were responsive to noxious stimulation at postnatal day 3. Treated animals also displayed increased mechanical sensitivity from postnatal day 45 on.

Related Products: SP-SAP (Cat. #IT-07), Blank-SAP (Cat. #IT-21)

Role of neurokinin-1 expressing neurons in the locus coeruleus on ventilatory and cardiovascular responses to hypercapnia.

de Carvalho D, Bicego KC, de Castro OW, da Silva GS, Garcia-Cairasco N, Gargaglioni LH (2010) Role of neurokinin-1 expressing neurons in the locus coeruleus on ventilatory and cardiovascular responses to hypercapnia. Respir Physiol Neurobiol 172(1-2):24-31. doi: 10.1016/j.resp.2010.04.016

Summary: NK-1 receptors (NK1R) play an important role in cardiorespiratory responses to hypercapnia. In order to paint a clearer picture of the systems involved the authors injected 0.4 µl of 2 µM SP-SAP (Cat. #IT-07) into the locus coeruleus (LC) of rats. Mouse IgG-SAP (Cat. #IT-18) was used as a control. The data suggest that several subpopulations of neurons express NK1R in the LC, and that these subpopulations play different roles in the modulation of cardiorespiratory reponses to hypercapnia.

Related Products: SP-SAP (Cat. #IT-07), Mouse IgG-SAP (Cat. #IT-18)

Synaptic plasticity and pain: role of ionotropic glutamate receptors.

Larsson M, Broman J (2011) Synaptic plasticity and pain: role of ionotropic glutamate receptors. Neuroscientist 17(3):256-73. doi: 10.1177/1073858409349913

Summary: This review discusses the role of glutaminergic sensory synapses in pain hypersensitivity caused by tissue or nerve injury. The focus is on the roles of ionotrophic glutamate receptors, and how they are involved in dorsal horn synaptic plasticity. The role of substance P in such mechanisms is briefly discussed, as elucidated by the use of SP-SAP (Cat. #IT-07).

Related Products: SP-SAP (Cat. #IT-07)

Dorsal horn neurons expressing NK-1 receptors mediate scratching in rats.

Carstens EE, Carstens MI, Simons CT, Jinks SL (2010) Dorsal horn neurons expressing NK-1 receptors mediate scratching in rats. Neuroreport 21:303-308. doi: 10.1097/WNR.0b013e328337310a

Summary: The itch signal is passed through the superficial dorsal horn. The authors investigated whether ablation of NK-1 receptor-expressing neurons in this area would affect itch-related scratching behavior. Rats received 20 µl of 2.27-µM SP-SAP (Cat. #IT-07) as an intracisternal injection. The reduction in itch response to intradermal 5-hydroxytryptamine indicates that NK-1 receptor-expressing superficial dorsal horn neurons are important for spinal itch transmission.

Related Products: SP-SAP (Cat. #IT-07)

Substance P neurotransmission and violent aggression: the role of tachykinin NK(1) receptors in the hypothalamic attack area.

Halasz J, Zelena D, Toth M, Tulogdi A, Mikics E, Haller J (2009) Substance P neurotransmission and violent aggression: the role of tachykinin NK(1) receptors in the hypothalamic attack area. Eur J Pharmacol 611:35-43. doi: 10.1016/j.ejphar.2009.03.050

Summary: Stimulation of the hypothalamic attack area elicits biting attacks in rats. The authors eliminated NK1 receptor-expressing neurons in this area with bilateral 6.25-ng injections of SP-SAP (Cat. #IT-07). Violent attacks were dramatically reduced while milder forms of aggression remained unchanged, indicating that these two forms of aggression are controlled via different pathways. Lesioned animals also displayed reduced anxiety-like behavior in the elevated plus-maze, suggesting a connection between the hypothalamic attack area and brain areas controlling anxiety.

Related Products: SP-SAP (Cat. #IT-07)

Spinal NK-1 receptor-expressing neurons and descending pathways support fentanyl-induced pain hypersensitivity in a rat model of postoperative pain.

Rivat C, Vera-Portocarrero LP, Ibrahim MM, Mata HP, Stagg NJ, De Felice M, Porreca F, Malan TP (2009) Spinal NK-1 receptor-expressing neurons and descending pathways support fentanyl-induced pain hypersensitivity in a rat model of postoperative pain. Eur J Neurosci 29:727-737. doi: 10.1111/j.1460-9568.2009.06616.x

Summary: Opioids activate hyperalgesia and allodynia. The authors test the hypothesis that NK-1 receptor-containing ascending pathways play a role in sensitivity to fentanyl. Rats received an intrathecal injection of SP-SAP (Cat. #IT-07), and controls received saporin (Cat. #PR-01). The data indicate that these ascending pathways have a role in fentanyl-induced hyperalgesia.

Related Products: SP-SAP (Cat. #IT-07), Saporin (Cat. #PR-01)

Unilateral ablation of preBotzinger Complex disrupts breathing during sleep but not wakefulness.

McKay LC, Feldman JL (2008) Unilateral ablation of preBotzinger Complex disrupts breathing during sleep but not wakefulness. Am J Respir Crit Care Med 178(1):89-95. doi: 10.1164/rccm.200712-1901OC

Summary: Previous data has shown that ablation of preBötzinger complex (preBötC) neurokinin 1 expressing (NK1R) neurons disrupts breathing patterns in both sleep and wakefulness. The initial disruption is during sleep, with the eventual onset of ataxic breathing while the animals are awake. Here rats received a unilateral injection of SP-SAP (Cat. #IT-07, 6.7 ng) into the left preBötC. SP plus unconjugated saporin (Cat. #PR-01) was used as a control. Unilaterally treated rats did not develop disrupted breathing patterns during wakefulness.

Related Products: SP-SAP (Cat. #IT-07), Saporin (Cat. #PR-01)

The neonatal injury-induced spinal learning deficit in adult rats: central mechanisms.

Young EE, Baumbauer KM, Hillyer JE, Patterson AM, Hoy KC, Jr., Mintz EM, Joynes RL (2008) The neonatal injury-induced spinal learning deficit in adult rats: central mechanisms. Behav Neurosci 122:589-600. doi: 10.1037/0735-7044.122.3.589

Summary: This report examined whether neonatal injuries had any contralateral effects in adult life, and evaluated the role of the NK1 receptor of adult animals that had been subjected to neonatal trauma. Rats were injected with 5 µl of SP-SAP (Cat. #IT-07, 30 ng/µl, 100 ng/µl, or 300 ng/µl) into the intrathecal space. Blank-SAP (Cat. #IT-21) was used as a control. The results indicate both that injury effects are isolated in the injured limb, and NK1 receptor-expressing cells are involved in processing this pain.

Related Products: SP-SAP (Cat. #IT-07), Blank-SAP (Cat. #IT-21)

Selective ablation of dorsal horn NK(1) expressing cells reveals a modulation of spinal alpha2-adrenergic inhibition of dorsal horn neurones.

Rahman W, Suzuki R, Hunt SP, Dickenson AH (2008) Selective ablation of dorsal horn NK(1) expressing cells reveals a modulation of spinal alpha2-adrenergic inhibition of dorsal horn neurones. Neuropharmacology 54:1208-1214. doi: 10.1016/j.neuropharm.2008.03.014

Summary: In this work the spinal origin of the major descending noradrenergic inhibitory pathway is examined with the help of SP-SAP (Cat. #IT-07). Rats received a 10-µl infusion of 1-mM SP-SAP (saporin, Cat. #PR-01, was used as a control) into the sub-arachnoid space terminating in the L4-5 region. Results from examining neuronal responses under the influence of the alpha2-adrenoceptor antagonist atipamezole suggest that NK1 expressing cells are involved with activity in noradrenergic pathways and descending facilitation.

Related Products: SP-SAP (Cat. #IT-07), Saporin (Cat. #PR-01)

Substance P receptor-expressing dorsal horn neurons: Lessons from the targeted cytotoxin, substance P-saporin.

Wiley RG (2008) Substance P receptor-expressing dorsal horn neurons: Lessons from the targeted cytotoxin, substance P-saporin. Pain 136:7-10. doi: 10.1016/j.pain.2008.03.010

Summary: This review covers some of the more recent work utilizing SP-SAP (Cat. #IT-07) and SSP-SAP (Cat. #IT-11) in the dorsal horn. Specific answers to experimental questions are discussed, as well as some of the questions generated by the research. The potential of SP-SAP and SSP-SAP as pain therapeutics is also explored, along with potential clinical applications of other targeted toxins in pain therapy.

Related Products: SP-SAP (Cat. #IT-07), SSP-SAP (Cat. #IT-11)

Molecular basis of violent behavior: The role of NK1 receptors

Haller J, Toth M, Zelena D, Halasz J (2007) Molecular basis of violent behavior: The role of NK1 receptors. Neuroscience 2007 Abstracts 531.22/GGG24. Society for Neuroscience, San Diego, CA.

Summary: Background. Neurons expressing Neurokinin1 receptor (NK1 or Substance P receptor) are abundant in limbic areas crucial for different emotional behaviors. In recent years, NK1 receptor blockers were proposed for the treatment of anxiety and depression. Moreover, in two different laboratory models, NK1 receptor blockade was successfully used to decrease violent components of aggression related behaviors in Wistar rats (Biol. Psychiatry, 2007, in press). In the above study, the NK1 receptor blockade reduced the number of more violent hard bites, while the number of soft bites was unaltered. Aggressive encounters were accompanied by a marked activation of neurons expressing NK1 receptors in the medial amygdala and in the hypothalamic attack area, where the highest number and proportion of activated NK1 positive neurons were found. Aim / Methods. We evaluated the precise role of neurons expressing NK1 receptors in the hypothalamic attack area during resident/intruder test. These neurons were selectively eliminated by a Substance P conjugated saporin bilateral microinjection into the hypothalamic attack area. After a week recovery, lesioned and vehicle treated control residents were faced with a smaller untreated opponent in their home cages for 20 min. The brains of the residents were later removed to assess the site of injection and the extent of the lesion. Results. In lesioned Wistars, the bilateral microinjection resulted in a complete and selective disruption of NK1 positive neurons in the hypothalamic attack area. Compared to vehicle injected controls, the number of hard bites toward unfamiliar residents showed a marked decrease (almost a complete abolition) in the lesioned group. The latency of hard bites was significantly increased compared to vehicle injected controls. The number of bite attacks was also reduced, but this reduction was mainly secondary to the dramatic reduction in the number of hard bites. Conclusions. Our data show that hypothalamic neurons expressing NK1 receptors are involved in the control of aggressiveness, especially in the expression of violent attacks. These data confirm and support earlier results that NK1 antagonists - beyond anxiety and depression - may also be useful in the treatment of aggressiveness and violence.

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Effects of systemic bicuculline on the formalin-induced nociceptive response in the lip and c-Fos expression in the SP-Saporin-treated rats

Masawaki A, Sugiyo S, Shimoda T, Sakai Y, Ohyamaguchi A, Uehashi D, Moritani M, Yoshida A, Niwa H, Takemura M (2007) Effects of systemic bicuculline on the formalin-induced nociceptive response in the lip and c-Fos expression in the SP-Saporin-treated rats. Neuroscience 2007 Abstracts 186.16/RR16. Society for Neuroscience, San Diego, CA.

Summary: This study examines the effect of systemic bicuculline (2 mg/kg, ip) on formalin-induced pain-related behavior in the lip (PRB; face scrubbing behavior) and c-Fos expression in the trigeminal nucleus caudalis (SpVc) 2hrs after formalin injection and 2-4 weeks after intra cisterna magna (i.c.m.) injection of substance P (SP) conjugated to neurotoxin, saporin (SP-Sap; 3 µM, 5 µl), blank-Sap- or saline-treatment. In SP-Sap-treated rats, the number of NK-1- immunoreactive (NK-1-IR) neurons in lamina I of the SpVc decreased compared with that of saline- or blank-Sap-treated rats. In SP-Sap-treated rats, PRB at phase 2 decreased compared with that of saline- or blank-Sap-treated rats. In SP-Sap-treated rats, the number of c-Fos-IR cells in the VcI/II decreased compared with that in the saline- or blank-Sap-treated rats. In saline- and blank-Sap- treated rats but not SP-Sap-treated rats, systemic bicuculline decreased the number of PRB at phase 2. These results indicate that i.c.m. injection of SP-Sap eliminates NK-1-bearing neurons in L1 of SpVc, and that NK-1-bearing neurons in the SpVc have pivotal role in formalin-induced PRB at phase 2 and c-Fos expression in the SpVc. The decremental effects of systemic bicuculline on the formalin-induced nociceptive responses at phase 2 and c-Fos expression in the VcI/II are secure in the presence of NK-1 receptor bearing neurons in the Vc.

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Elimination of rat spinal substance P receptor bearing neurons dissociates cardiovascular and nocifensive responses to nicotinic agonists.

Khan IM, Wart CV, Singletary EA, Stanislaus S, Deerinck T, Yaksh TL, Printz MP (2008) Elimination of rat spinal substance P receptor bearing neurons dissociates cardiovascular and nocifensive responses to nicotinic agonists. Neuropharmacology 54(2):269-279. doi: 10.1016/j.neuropharm.2007.09.014

Summary: Nocifensive behavior and cardiovascular responses due to nicotinic agonists may be sustained by substance P-positive primary afferents. Rats received 10-µl intrathecal injections of 10 µM SP-SAP (Cat. #IT-07); unconjugated saporin (Cat. #PR-01) was used as a control. Lesioned animals displayed reduced nocifensive response to nicotinic agonists. Tachycardia and pressor responses were enhanced upon administration of cytisine and epibatidine.

Related Products: Saporin (Cat. #PR-01), SP-SAP (Cat. #IT-07)

Respiratory plasticity in response to changes in oxygen supply and demand

Bavis RW, Powell FL, Bradford A, Hsia CCW, Peltonen JE, Soliz J, Zeis B, Fergusson ED, Fu Z, Gassmann M, Kim CB, Maurer J, McGuire M, Miller BM, O’Halloran KD, Paul RJ, Reid SG, Rusko HK, Tikkanen HO, Wilkinson KA (2007) Respiratory plasticity in response to changes in oxygen supply and demand. Integ and Comp Biol 47(4):532-551. doi: 10.1093/icb/icm070

Summary: This paper covers data presented at the First Annual Congress of Respiratory Biology. One of the subjects discussed is the use of SP-SAP (Cat. #IT-07) to elucidate the role of central chemoreceptors in the nucleus tractus solitarius during ventilatory acclimatization to hypoxia.

Related Products: SP-SAP (Cat. #IT-07)

Superficial NK1 expressing spinal dorsal horn neurones modulate inhibitory neurotransmission mediated by spinal GABA(A) receptors.

Rahman W, Sikander S, Suzuki R, Hunt SP, Dickenson AH (2007) Superficial NK1 expressing spinal dorsal horn neurones modulate inhibitory neurotransmission mediated by spinal GABA(A) receptors. Neurosci Lett 419:278-283. doi: 10.1016/j.neulet.2007.04.039

Summary: It has been shown that elimination of lamina 1 NK1 receptor-expressing neurons affects pain behaviors. The authors investigated whether eliminating these neurons would alter GABAergic spinal inhibitory systems. Rats received 10-µl injections of 10-µM SP-SAP (Cat. #IT-07) into the L4-5 regions. Data generated by electrical and mechanical stimuli suggest that although GABAergic transmission is dependent on NK1 receptor-expressing neurons, loss of these cells results in a decrease in spinal cord excitability.

Related Products: SP-SAP (Cat. #IT-07)

Anti-nociceptive effects of selectively destroying substance P receptor-expressing dorsal horn neurons using [Sar(9),Met(O(2))(11)]-substance P-saporin: Behavioral and anatomical analyses.

Wiley RG, Kline IV RH, Vierck Jr CJ (2007) Anti-nociceptive effects of selectively destroying substance P receptor-expressing dorsal horn neurons using [Sar(9),Met(O(2))(11)]-substance P-saporin: Behavioral and anatomical analyses. Neuroscience 146:1333-1345. doi: 10.1016/j.neuroscience.2007.01.066

Summary: While lumbar injections of SP-SAP (Cat. #IT-07) produce specific lesions, use of this targeted conjugate in the forebrain has been problematic. The authors investigated the use of SSP-SAP (Cat. #IT-11), a conjugate of saporin with a stable analog of substance P. The greater stability of SSP-SAP resulted in increased potency as well as better specificity. SSP-SAP is shown to be a highly effective reagent for the removal of NK1 receptor-expressing neurons in the brain and spinal cord.

Related Products: SP-SAP (Cat. #IT-07), SSP-SAP (Cat. #IT-11)

Targeted deletion of neurokinin-1 receptor expressing nucleus tractus solitarii neurons precludes somatosensory depression of arterial baroreceptor-heart rate reflex.

Potts JT, Fong AY, Anguelov PI, Lee S, McGovern D, Grias I (2007) Targeted deletion of neurokinin-1 receptor expressing nucleus tractus solitarii neurons precludes somatosensory depression of arterial baroreceptor-heart rate reflex. Neuroscience 145(3):1168-1181. doi: 10.1016/j.neuroscience.2007.01.001

Summary: Previous work by these authors examined the role of substance P in arterial baroreflex. Here, 1.5 ng bilateral injections of SP-SAP (Cat. #IT-07) into the caudal nucleus tractus solitarii of rats were used to further elucidate the fundamental role of substance P in this system. The depressive effect of somatosensory input by neurokinin-1 receptor-expressing neurons on arterial baroreceptor-heart rate reflex was abolished in lesioned animals.

Related Products: SP-SAP (Cat. #IT-07)

Read the featured article in Targeting Trends.

Substance P-saporin down-regulates substance P receptor immunoreactive sensory dorsal root ganglion neurons innervating the lumbar intervertebral discs in rats.

Ohtori S, Inoue G, Koshi T, Ito T, Doya H, Moriya H, Takahashi K (2006) Substance P-saporin down-regulates substance P receptor immunoreactive sensory dorsal root ganglion neurons innervating the lumbar intervertebral discs in rats. Spine 31:2987-2991. doi: 10.1097/01.brs.0000250306.12996.fa

Summary: Neurokinin-1 (NK-1) receptor expressing neurons that innervate lumbar intervertebral discs may be involved in lower back pain. Here the authors investigate the basic effect of SP-SAP (Cat. #IT-07) on neurons innervating the L5/6 intervertebral disc. Rats were injected with 175 ng of SP-SAP. The number of NK-1 receptor expressing neurons was reduced by over 75% in the treated animals, demonstrating SP-SAP as a useful tool to investigate the mechanism of discogenic low back pain, particulary for investigating behavioral impacts.

Related Products: SP-SAP (Cat. #IT-07)

Spinal NK-1 receptor expressing neurons mediate opioid-induced hyperalgesia and antinociceptive tolerance via activation of descending pathways.

Vera-Portocarrero LP, Zhang ET, King T, Ossipov MH, Vanderah TW, Lai J, Porreca F (2007) Spinal NK-1 receptor expressing neurons mediate opioid-induced hyperalgesia and antinociceptive tolerance via activation of descending pathways. Pain 129:35-45. doi: 10.1016/j.pain.2006.09.033

Summary: Administration of opioids can induce hyperalgesia in humans and other mammals. In this work the authors examined the role of NK-1 receptor-expressing neurons in the spinal dorsal horn during a hyperalgesic condition not induced by tissue injury. 5 µl of 10 µM SP-SAP (Cat. #IT-07) was injected into the intrathecal space of rats. Saporin (Cat. #PR-01) was used as a control. Osmotic pumps then delivered morphine. Data from the lesioned animals indicate that NK-1 receptor-expressing neurons play a critical role in this hyperalgesic circuit.

Related Products: SP-SAP (Cat. #IT-07), Saporin (Cat. #PR-01)

Ablation of NK(1) receptor bearing neurons in the nucleus of the solitary tract blunts cardiovascular reflexes in awake rats.

Abdala AP, Schoorlemmer GH, Colombari E (2006) Ablation of NK(1) receptor bearing neurons in the nucleus of the solitary tract blunts cardiovascular reflexes in awake rats. Brain Res 1119(1):165-173. doi: 10.1016/j.brainres.2006.08.059

Summary: Cardiovascular function is largely controlled by the nucleus of the tractus solitarius (NTS). This work focuses on the baroreflex, cardiopulmonary chemoreflex, and arterial chemoreflex. Rats were injected with either 20 nl of 2 µM SP-SAP (Cat. #IT-07) into the subpostremal NTS, or 200 nl into the subpostremal and commissural NTS. Saporin (Cat. #PR-01) was used as a control. Using various testing methods it was established that NK-1 receptor-expressing neurons in the NTS are critical for these reflexes.

Related Products: SP-SAP (Cat. #IT-07), Saporin (Cat. #PR-01)

Ascending and descending pathways support fentanyl-induced pain hypersensitivity with and without a surgical incision

Rivat C, Vera-Portocarrero LP, Ibrahim MM, Mata HP, Stagg NJ, De Felice M, Porreca F, Malan TP (2006) Ascending and descending pathways support fentanyl-induced pain hypersensitivity with and without a surgical incision. Neuroscience 2006 Abstracts 248.10. Society for Neuroscience, Atlanta, GA.

Summary: Acutely administered the analgesic opioid fentanyl has been shown to enhance mechanical hypersensitivity in a model of surgical pain induced by hindpaw incision in the rat. Recent evidence showed the importance of descending pathways originating from the rostral ventromedial medulla (RVM) in opioid-induced hyperalgesia after sustained morphine administration. Such hyperalgesia is also associated with numerous neurochemical changes in primary afferent fibers and spinal dorsal horn, such as increased spinal dynorphin expression. These changes may activate ascending pathways, mediated in part by NK-1 neurotransmission. Here, we examined the roles of ascending and descending pathways in sensory hypersensitivity after acute fentanyl administration. Male Sprague-Dawley rats received 4 fentanyl (4x100 μg/kg, s.c.) or saline injections administered at 15 min intervals. Some animals also received an incision in the plantar hindpaw. Thermal hyperalgesia and tactile allodynia were measured daily. In control rats, fentanyl induced analgesia followed by an immediate and long-lasting hyperalgesia, as previously described. Fentanyl also enhanced pain sensitivity induced by plantar incision. In SP-saporin pretreated rats, fentanyl induced analgesia and a moderate long-lasting hyperalgesia. The SP-saporin pretreatment slightly reduced both hyperalgesia and allodynia in postoperative rats and, to a larger extent, in fentanyl treated rats. Lidocaine injection in the RVM completely reversed fentanyl-induced sensory hypersensitivity and fentanyl enhancement of incision-induced hyperalgesia and allodynia. A slight reduction of incision-induced sensory hypersensitivity was observed after lidocaine injection in rats without fentanyl pretreatment. Spinal dynorphin content increased by 30 ± 7% and 71 ± 33% in fentanyl and fentanyl/incision treated rats, respectively. These data support the crucial role of the descending pathways from the RVM in the fentanyl-induced hyperalgesia and the partial implication of the NK-1 receptor containing ascending pathways.

Related Products: SP-SAP (Cat. #IT-07)

Formalin-induced pain-related responses in rat lacking neurokinin-1 receptor neurons in the trigeminal nucleus caudalis

Masawaki A, Sugiyo S, Shimoda T, Sakai Y, Watanabe M, Moritani M, Yoshida A, Niwa H, Takemura M (2006) Formalin-induced pain-related responses in rat lacking neurokinin-1 receptor neurons in the trigeminal nucleus caudalis. Neuroscience 2006 Abstracts 50.8. Society for Neuroscience, Atlanta, GA.

Summary: This study examines the effect of intra cisterna magna injection of substance P (SP) conjugated to saporin (SP-Sap; 5µM, 5µl) on formalin-induced pain-related behavior (PRB; face scrubbing behavior ) and c-Fos expression in the trigeminal nucleus caudalis (SpVc). In SP-Sap-treated rats, the numbers of NK-1-immunoreactive neurons in lamina I of the SpVc decreased compared with those in saline- or blank Sap-treated rats. The mean numbers ±SEM of PRB /5 min at the first phase (0-5 min after For injection) were 58.2±19.2 in the SP-Sap-treated rats, 115.6±14.0 in the saline treated rats and 86.9±45.7 in the blank-Sap-treated rats. The numbers at the quiescent period (5-10 min) were 45.2±26.3 in the SP-Sap- treated rats, 93.6±26.5 in the saline treated rats and 69.4±16.3 in the blank-Sap-treated rats. These at the former second phase (10-50 min) were 58.1±22.3 in the SP-Sap-treated rats, 133.6±26.1 in the saline treated rats and 95.8±29.6in the blank-Sap-treated rats. These at the latter second phase (55-90 min) were 7.0±5.6 in the SP-Sap-treated rats,13.7±12.4 in the saline treated rats and 10.4±22.5 in the blank-Sap-treated rats. These results indicate that formalin-induced nociceptive responses in the SP-Sap-treated rats are reduced.

Related Products: SP-SAP (Cat. #IT-07), Blank-SAP (Cat. #IT-21)

Secondary hyperalgesia in the monoarthritic rat is mediated by GABA(B) and NK1 receptors of spinal dorsal horn neurons: A behavior and c-fos study.

Castro AR, Pinto M, Lima D, Tavares I (2006) Secondary hyperalgesia in the monoarthritic rat is mediated by GABA(B) and NK1 receptors of spinal dorsal horn neurons: A behavior and c-fos study. Neuroscience 141(4):2087-2095. doi: 10.1016/j.neuroscience.2006.05.048

Summary: Hallmarks of secondary hyperalgesia in a rat model of monoarthritic pain are: decreased activation of GABA(B) neurons, and increased activation of NK1r neurons. Using 10-µl injections of 1-µM SP-SAP (Cat. #IT-07) into T(13)-L(1) the workers looked at the role of each receptor. Pain thresholds increased after treatment with SP-SAP or baclofen, a selective GABA(B) receptor agonist. Fos immunoreactivity was also decreased in treated animals, indicating that both GABA(B) and NK1r are involved in secondary hyperalgesia.

Related Products: SP-SAP (Cat. #IT-07)

Local and descending circuits regulate long-term potentiation and zif268 expression in spinal neurons.

Rygh LJ, Suzuki R, Rahman W, Wong Y, Vonsy JL, Sandhu H, Webber M, Hunt S, Dickenson AH (2006) Local and descending circuits regulate long-term potentiation and zif268 expression in spinal neurons. Eur J Neurosci 24(3):761-772. doi: 10.1111/j.1460-9568.2006.04968.x

Summary: Long-term potentiation (LTP) has been shown to occur in sensory areas of the spinal cord. This modification of synaptic strength may be one of the mechanisms by which acute pain is transformed into chronic pain. 10 µl of 1-µM SP-SAP (Cat. #IT-07) or control saporin (Cat. #PR-01) was injected into the subarachnoid space (L4-L5) of rats. Using electrophysiological recording, immunohistochemistry, behavioral assessment, and antisense experiments, the authors demonstrate that dorsal horn neuron generation of LTP may transform acute pain into chronic pain.

Related Products: SP-SAP (Cat. #IT-07), Saporin (Cat. #PR-01)

Toward better pain control.

Basbaum AI, Julius D (2006) Toward better pain control. Sci Am 294(6):60-67. doi: 10.1038/scientificamerican0606-60

Summary: The authors discuss some of the advances in understanding and treating different types of pain, and specifically outline circuits, receptors, and ligands involved in pain pathways. Several treatments are described, one of which is the use of SP-SAP (Cat. #IT-07) to disrupt the chronic pain pathway in the spinal cord.

Related Products: SP-SAP (Cat. #IT-07)

Safety evaluation of Intrathecal Substance P-Saporin, a targeted neurotoxin, in dogs.

Allen JW, Mantyh PW, Horais K, Tozier N, Rogers SD, Ghilardi JR, Cizkova D, Grafe MR, Richter P, Lappi DA, Yaksh TL (2006) Safety evaluation of Intrathecal Substance P-Saporin, a targeted neurotoxin, in dogs. Toxicol Sci 91(1):286-298. doi: 10.1093/toxsci/kfj143

Summary: SP-SAP (Cat. #IT-07) has been shown to reverse neuropathic pain behavior in rodents and prevent the formation of hyperalgesia. A safety study was done in beagles to further the use of this molecule as a human therapeutic. Animals received doses from 1.5-150 µg of SP-SAP as bolus intrathecal lumbar injections. Doses of 15 µg and above displayed significant loss of NK1r-expressing cells in lumbar Laminae II and I, but no adverse toxicity was observed at any dose.

Related Products: SP-SAP (Cat. #IT-07)

Read the featured article in Targeting Trends.

Spinal-supraspinal serotonergic circuits regulating neuropathic pain and its treatment with gabapentin.

Suzuki R, Rahman W, Rygh LJ, Webber M, Hunt SP, Dickenson AH (2005) Spinal-supraspinal serotonergic circuits regulating neuropathic pain and its treatment with gabapentin. Pain 117(3):292-303. doi: 10.1016/j.pain.2005.06.015

Summary: The anticonvulsant, gabapentin, is thought to modulate calcium channel function. In animals, it also affects abnormal pain function. 10 µl of 1 µM SP-SAP (Cat. #IT-07) was injected into the subarachnoid space of rats. It was found that the effects of gabapentin were blocked when NK-1r expressing neurons in the dorsal horn were eliminated. The results suggest that not only is the NK-1r pathway a determinant of neuronal and behavioral manifestations of neuropathy, it is also involved in the action of gabapentin.

Related Products: SP-SAP (Cat. #IT-07)

Sleep-disordered breathing after targeted ablation of preBotzinger complex neurons.

McKay LC, Janczewski WA, Feldman JL (2005) Sleep-disordered breathing after targeted ablation of preBotzinger complex neurons. Nat Neurosci 8(9):1142-1144. doi: 10.1038/nn1517

Summary: Sleep-disordered breathing is common in elderly humans as well as patients with neurodegenerative disease. The authors investigated the role of preBötzinger complex neurons of rats in respiratory rhythm generation. Using the fact that preBötzinger complex neurons in the ventrolateral medulla express the neurokinin-1 receptor, animals were given bilateral injections of SP-SAP (Cat. #IT-07). Beginning 7 days post-injection, lesioned animals displayed marked respiratory disturbances during both sleep and wakeful periods.

Related Products: SP-SAP (Cat. #IT-07)

Elimination of neurokinin-1 receptor neurons in caudal nucleus reverses the effects of systemic bicuculline on c-Fos expression in rat trigeminal sensory nucleus: I. High intensity electrical stimulation of the trigeminal ganglion.

Abe T, Ohshita N, Sugiyo S, Moritani M, Kobayashi M, Takemura M (2005) Elimination of neurokinin-1 receptor neurons in caudal nucleus reverses the effects of systemic bicuculline on c-Fos expression in rat trigeminal sensory nucleus: I. High intensity electrical stimulation of the trigeminal ganglion. Neuroscience 133(3):739-747. doi: 10.1016/j.neuroscience.2005.03.021

Summary: The authors investigated the role of NK-1r + neurons in lamina 1 of the trigeminal caudal nucleus (Vc) for ora-facial nociception. After a 5 µl injection of 5 µM SP-SAP (Cat. #IT-07) into the cisterna magna, c-fos expression in the Vc was evaluated. SP-SAP treatment, along with use of bicuculline, a GABAA receptor antagonist, showed that NK-1r+ neurons in laminae I and III of the Vc are involved in nociceptive processing in the trigeminal sensory nucleus.

Related Products: SP-SAP (Cat. #IT-07)

Impairment of skilled forelimb use after ablation of striatal interneurons expressing substance P receptors in rats: an analysis using a pasta matrix reaching task.

Chiken S, Tokuno H (2005) Impairment of skilled forelimb use after ablation of striatal interneurons expressing substance P receptors in rats: an analysis using a pasta matrix reaching task. Exp Brain Res 162(4):532-536. doi: 10.1007/s00221-004-2189-2

Summary: The substance P receptor is expressed by two types of interneurons in the striatum. The authors investigated whether elimination of these neurons would impair motor control by the basal ganglia. Rats were treated with 7.5 ng injections of SP-SAP (Cat. #IT-07) into the dorsolateral part of the striatum. Lesioned animals did not perform as well as controls in a test measuring accurate reaching with the forepaw. The data show that striatal interneurons expressing the substance P receptor are necessary for accurate reaching.

Related Products: SP-SAP (Cat. #IT-07)

Ablation of a population of neurons in the dorsal horn of the spinal cord is insufficient to induce sprouting of touch responsive myelinated afferents into the innervation territory of pain sensitive unmyelinated afferents.

Whiteside GT, Woods ME, Pearson MS, Pomonis JD, Turchin PI, Walker K (2005) Ablation of a population of neurons in the dorsal horn of the spinal cord is insufficient to induce sprouting of touch responsive myelinated afferents into the innervation territory of pain sensitive unmyelinated afferents. Med Hypotheses Res 2:275-282.

Related Products: SP-SAP (Cat. #IT-07)

Spinal neurons that express NK-1 receptors modulate descending controls that project through the dorsolateral funiculus.

Khasabov SG, Ghilardi JR, Mantyh PW, Simone DA (2005) Spinal neurons that express NK-1 receptors modulate descending controls that project through the dorsolateral funiculus. J Neurophysiol 93(2):998-1006. doi: 10.1152/jn.01160.2003

Summary: The involvement of neurokinin-1 receptor-expressing neurons in the spinal cord with the ascending systems of hyperalgesia and central sensitization has been well established. The authors used 10 µl injections of 5 µM SP-SAP (Cat. #IT-07) into the intrathecal space of rats, and examined the descending systems that travel via the dorsolateral funiculus (DLF). While SP-SAP alone had no effect, administration of SP-SAP in conjunction with a DLF transection enhanced neuronal responses to mechanical and heat stimuli.

Related Products: SP-SAP (Cat. #IT-07)

Transient attenuation of CO2 sensitivity after neurotoxic lesions in the medullary raphe-area in awake goats.

Hodges MR, Opansky C, Qian B, Davis S, Bonis J, Bastasic J, Leekley T, Pan LG, Forster HV (2004) Transient attenuation of CO2 sensitivity after neurotoxic lesions in the medullary raphe-area in awake goats. J Appl Physiol 97(6):2236-2247. doi: 10.1152/japplphysiol.00584.2004

Summary: The authors wished to investigate the influence medullary raphe-area neurons have on breathing. This control may be through CO2/H+ chemoreceptors and/or through non-chemoreceptor modulation. 1 or 10 µl of 50 pM SP-SAP (Cat. #IT-07) or Saporin (Cat. #PR-01) was injected into the raphe of goats. Breathing and CO2 sensitivity were evaluated during different physiologic conditions. The data suggest that SP receptor- and glutamate receptor-expressing neurons in the medullary raphe both influence CO2 sensitivity, but not altered breathing periods.

Related Products: SP-SAP (Cat. #IT-07), Saporin (Cat. #PR-01)

Small reduction of neurokinin-1 receptor-expressing neurons in the pre-Botzinger complex area induces abnormal breathing periods in awake goats.

Wenninger JM, Pan LG, Klum L, Leekley T, Bastastic J, Hodges MR, Feroah T, Davis S, Forster HV (2004) Small reduction of neurokinin-1 receptor-expressing neurons in the pre-Botzinger complex area induces abnormal breathing periods in awake goats. J Appl Physiol 97(5):1620-1628. doi: 10.1152/japplphysiol.00952.2003

Summary: Previous work has shown that lesion of the pre-Bötzinger Complex (pre-BötzC) of rats with SP-SAP (Cat. #IT-07) results in hypoventilation and an abnormal breathing pattern. The authors used 1 or 10 µl of 50 pM SP-SAP bilaterally injected into the pre-BötzC area to further investigate this system in goats. The results show transient changes in respiratory rhythm and respiratory muscle activation patterns, indicating that SP receptor-expressing neurons in the pre-BötzC are involved in the regulation of respiration.

Related Products: SP-SAP (Cat. #IT-07)

Large lesions in the pre-Botzinger complex area eliminate eupneic respiratory rhythm in awake goats.

Wenninger JM, Pan LG, Klum L, Leekley T, Bastastic J, Hodges MR, Feroah TR, Davis S, Forster HV (2004) Large lesions in the pre-Botzinger complex area eliminate eupneic respiratory rhythm in awake goats. J Appl Physiol 97(5):1629-1636. doi: 10.1152/japplphysiol.00953.2003

Summary: Previously the authors demonstrated that lesioning the pre-Bötzinger Complex (pre-BötzC) with SP-SAP (Cat. #IT-07) resulted in transient disruptions of normal respiratory muscle activation in goats. The purpose of this study was to examine the effects of a more complete lesion of the pre-BötzC area. The authors treated SP-SAP-lesioned goats with ibotenic acid. The results suggest that the pre-BötzC is critical for generating a normal respiratory rhythm during the awake state.

Related Products: SP-SAP (Cat. #IT-07)

Apnea induced by stimulation of bronchopulmonary C-fibers (PCFs) depends on neurons expressing the neurokinin a receptor (NK1R) in the commissural subnucleus of the nucleus tractus solitarius (cNTS).

Xu F, Zhuang J, Hernandez J, Shi S (2004) Apnea induced by stimulation of bronchopulmonary C-fibers (PCFs) depends on neurons expressing the neurokinin a receptor (NK1R) in the commissural subnucleus of the nucleus tractus solitarius (cNTS). Neuroscience 2004 Abstracts 661.13. Society for Neuroscience, San Diego, CA.

Summary: Stimulation of PCFs by right atrial injection of capsaicin (CAP) reflexly produces an apnea and hypotension via stimulating cNTS neurons. Recent evidence indicates that activation of NK1R within the cNTS significantly amplifies this apneic response (Mutoh, et al., Am J Physiol, 2000). We asked whether the cNTS contained the highest density of the neurons responding to PCF stimulation and expressing NK1R, and what the effect of selective destruction of these neurons was on the cardiorespiratory responses to CAP. In the first series of our experiments, double labeling (c-fos and NK1R immunoreactivity) was used to mark the medullary neurons that were activated by right atrial injection of CAP (0.5-1.0 µg) and displayed NK1R. We found that compared to control (vehicle injection), the greatest enhancement of and highest density of Fos expression were observed within the cNTS, and a number of Fos-stained cNTS neurons had expression of NK1R. In the second series of our experiments, bilateral microinjection (100 nl) of substance P-saporin conjugate (SP-SAP) to selectively destroy the local neurons containing NK1R and SAP (control) into the cNTS was performed in two groups of rats, respectively. Our results showed that at 18 days after SP-SAP (rather than SAP) injection, the majority of cNTS NK1R neurons were destroyed. This lesion did not significantly change cardiorespiratory baseline variables, but did eliminate the apnea and reduce the hypotension induced by CAP. In sharp contrast, the lesion failed to affect the cardiorespiratory responses to hypoxia (10% O2 for 1 min). These findings strongly suggest that cNTS neurons with NK1R are necessary for the PCF-mediated cardiorespiratory responses but are not significantly involved in the cardiorespiratory response to acute hypoxia.

Related Products: SP-SAP (Cat. #IT-07)

Behavioral evidence for a capsaicin-sensitive inhibitory pathway (CSIP): A novel modulatory role for substance P

King CD, Baker B, Gu JG, Vierck CJ, Yezierski RP (2004) Behavioral evidence for a capsaicin-sensitive inhibitory pathway (CSIP): A novel modulatory role for substance P. Neuroscience 2004 Abstracts 292.18. Society for Neuroscience, San Diego, CA.

Summary: Exposure to noxious thermal stimulation or application of capsaicin cream causes the release of SP from capsaicin-sensitive primary afferent terminals that activate neurokinin-1 receptor (NK1R) expressing neurons in the superficial dorsal horn. Recent evidence suggests the existence of a capsaicin-sensitive inhibitory pathway (CSIP), a novel inhibitory mechanism that involves NK1R expressing neurons in laminae III-V. To determine the functional significance of these NK1R expressing neurons, substance P-saporin neurotoxin (SP-SAP) was used to ablate NK1R neurons in the superficial laminae. Elimination of the NK1R neurons in this region made it possible to evaluate the modulatory effects of NK1R expressing inhibitory neurons in deeper laminae. Reflexive responses were evaluated in rats during a 10-minute trial at 44.5°C before (pre-) and 14 days after (post-) intrathecal injection of 350ng SP-SAP. Testing conditions included: 1) baseline; 2) hindpaw application of 1% capsaicin cream; and, 3) intrathecal injection of the NK1 antagonist CP-97,345 following hindpaw application of 1% capsaicin cream. In normal rats, hindpaw application of capsaicin produced thermal hyperalgesia. In contrast, application of capsaicin produced a hypoalgesia in the same rats after treatment with SP-SAP. The capsaicin-induced hyperalgesia in normal rats was blocked by CP-97,345. The antagonist also blocked the capsaicin-induced hypoalgesia in SP-SAP rats. In conclusion, it is suggested that substance P activates inhibitory interneurons in the deep dorsal horn. The inhibitory effect initiated by substance P on pain transmission neurons represents a novel role of substance P in the spinal processing of nociceptive information.

Related Products: SP-SAP (Cat. #IT-07)

Altered effects of systemic bicuculline on intensity-dependent c-Fos expression in rats ablated with NK-1 receptor-bearing neurons in the trigeminal caudal nucleus

Abe T, Shimoda T, Sugiyo S, Ohshita N, Takao T, Takemura M (2004) Altered effects of systemic bicuculline on intensity-dependent c-Fos expression in rats ablated with NK-1 receptor-bearing neurons in the trigeminal caudal nucleus. Neuroscience 2004 Abstracts 294.12. Society for Neuroscience, San Diego, CA.

Summary: In rats pretreated with saporin conjugated to substance P (SP-Sap: 5 μM, 5 μl) into cisterna magna, the numbers of neurons-immunoreactive for NK-1 receptor (NK-1R) in laminae I and III of trigeminal caudal nucleus (Vc) were significantly decreased compared with rats similarly treated with saline (Sal; 5 μl) or blank-saporin (Bl-Sap; 5 μM, 5 μl). We examined the effects of selective ablation of NK-1R-bearing neurons and systemic administration of bicuculline (2 mg/kg, i.p.) on the expression of c-Fos induced 2 hr after electrical stimulation (5 Hz, 5 ms) of the trigeminal ganglion (TG) at low (0.1 mA) and high intensities (1.0 mA). In Sal- or Bl-Sap treated rats, 10 min stimulation at 0.1 and 1.0 mA of the TG induced c-Fos-immunoreactive (c-FosIR) cells in the ipsilateral superficial layers of the Vc (VcI/II) in a intensity-dependent manner. In rats treated with SP-Sap, and stimulated at 1.0 mA but not at 0.1 mA, the numbers of c-FosIR cells in the Vc were significantly decreased compared to Sal- or Bl-Sap treated rats. In Sal- or Bl-Sap treated rats preadministed with bicuculline and stimulated at 0.1 mA and 1.0 mA, the numbers of c-FosIR cells in VcI/II were significantly increased and decreased, respectively. However, in SP-Sap treated rats preadministered with bicuculline and stimulated at 0.1 mA and 1.0 mA, the numbers of c-FosIR cells in VcI/II were significantly increased. These results indicate that NK-1R-bearing neurons in the Vc have pivotal role in the modality and/or intensity-dependent sensory (nociceptive) processing in the TSN through GABAA receptors.

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Spinal neurons involved in the generation of at-level pain following spinal injury in the rat.

Yezierski RP, Yu CG, Mantyh PW, Vierck CJ, Lappi DA (2004) Spinal neurons involved in the generation of at-level pain following spinal injury in the rat. Neurosci Lett 361(1-3):232-236. doi: 10.1016/j.neulet.2003.12.035

Summary: The elimination of substance P receptor-expressing neurons in lamina I of the spinal cord using SP-SAP (Cat. #IT-07) has been shown to reduce behavior associated with chronic pain. The authors investigated the effects of 150 or 300 ng SP-SAP treatment during or after intraspinal administration of quisqualic acid in rats. Both treatments resulted in a reduction of pain-associated behavior. These results demonstrate that pain following spinal cord injury involves a population of spinal neurons expressing the substance P receptor.

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Medullary serotonergic neurons and adjacent neurons that express neurokinin-1 receptors are both involved in chemoreception in vivo.

Nattie EE, Li A, Richerson GB, Lappi DA (2004) Medullary serotonergic neurons and adjacent neurons that express neurokinin-1 receptors are both involved in chemoreception in vivo. J Physiol 556(1):235-253. doi: 10.1113/jphysiol.2003.059766

Summary: The retrotrapezoid nucleus contains neurokinin-1 receptor (NK-1r)-expressing neurons that are involved in chemoreception. NK-1r-expressing neurons are also present in areas that contain medullary serotonergic neurons. These serotonergic neurons have been shown to be chemosensitive in vitro. With two 100-nl injections of 1 µM SP-SAP (Cat. #IT-07), anti-SERT-SAP (Cat. #IT-23), or both, the authors examined whether both cell populations are involved in chemoreception in vivo in rats. The results support that separate populations of serotonergic and NK-1r-expressing neurons are each involved in chemoreception in vivo.

Related Products: SP-SAP (Cat. #IT-07), Anti-SERT-SAP (Cat. #IT-23), Antibody to Serotonin Transporter (SERT, Cat. #AB-N09)

Cytochrome oxidase activity in the monkey globus pallidus and subthalamic nucleus after ablation of striatal interneurons expressing substance P receptors.

Chiken S, Hatanaka N, Tokuno H (2003) Cytochrome oxidase activity in the monkey globus pallidus and subthalamic nucleus after ablation of striatal interneurons expressing substance P receptors. Neurosci Lett 353(2):103-106. doi: 10.1016/j.neulet.2003.09.026

Summary: 1-6 µl of 15-20 ng/µl SP-SAP (Cat. #IT-07) was injected into the forelimb representation of the putamen. Animals were examined for the loss of interneurons as well as regional metabolic changes. The results indicate that substance P receptor-expressing neurons do not modulate inhibitory influences on the GP.

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Substance P-saporin lesions of NK1-receptor expressing neurons in the medullary raphe reduce central chemoreception in sleep and wakefulness

Nattie EE, Li A (2003) Substance P-saporin lesions of NK1-receptor expressing neurons in the medullary raphe reduce central chemoreception in sleep and wakefulness. Neuroscience 2003 Abstracts 826.7. Society for Neuroscience, New Orleans, LA.

Summary: Breathing, especially in sleep, depends on a CO2-related drive that comes from central chemoreceptors. Many brainstem chemoreceptor sites contain NK1-receptor expressing neurons and cell specific killing of them at one site, the retrotrapezoid nucleus, by injection of substance P-saporin (SP-SAP)produces hypoventilation and reduced chemosensitivity (J. Physiol. 544.2: 603-616, 2002). Here we focus on the medullary raphe, a putative chemoreceptor site rich in NK1-receptor expressing neurons. We studied rats, instrumented with EEG and EMG electrodes for sleep determination, before and during the two weeks after placing two injections (0.1 pmole in 100 nl of SP-SAP) 1 mm apart in the medullary raphe. SP-SAP injections reduced the number of NK1 receptor expressing neurons by 53% compared to controls injected with IgG-SAP (P< 0.01, two-way ANOVA). Room air breathing was unaffected in sleep or wakefulness. The level of breathing during inhalation of 7% CO2 at 7 and 14 days was reduced by 13 and 22%, respectively, in NREM sleep (P < 0.01, two way ANOVA) and by 19 and 24%, respectively, in wakefulness (P < 0.01, two way ANOVA). Body temperature, resting metabolic rate, and sleep cycling were not significantly affected. These SP-SAP injections did not significantly reduce the number of medullary raphe serotonergic neurons as determined by TPOH immunoreactivity. We conclude that, as in the retrotrapezoid nucleus, NK1 receptor expressing neurons in the medullary raphe are involved in central chemoreception.

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Reduced scratching in rats receiving intracisternal substance-saporin to ablate cervical superficial dorsal horn neurons that express NK-1 receptors

Carstens EE, Iodi-Carstens M, Simons CT (2003) Reduced scratching in rats receiving intracisternal substance-saporin to ablate cervical superficial dorsal horn neurons that express NK-1 receptors. Neuroscience 2003 Abstracts 908.2. Society for Neuroscience, New Orleans, LA.

Summary: While glutamate and the neuropeptide substance P (SP) are involved in the spinal neurotransmission of nociceptive signals, little is known about transmitters involved in itch. We investigated a role for SP in itch by determining if scratching behavior is affected by selective neurotoxic destruction of cervical superficial dorsal neurons that express NK-1 receptors for SP. Sprague-Dawley rats received intracisternal microinjection of SP conjugated to saporin (SP-SAP; 2.27 μM/ 20 μl). Controls received saporin (SAP) only. At least 2 wk post-surgery, rats were tested for dose-related hindlimb scratching directed toward the site of intradermal microinjection of serotonin (5-HT; 50, 100 or 200 μg/10 μl) or saline (control) into the nape of the neck, with at least 1 wk between sessions for each dose. After the intradermal injection, rats were videotaped for 44 min. The numbers and durations of individual scratching bouts were counted and averaged for each dose. Rats receiving SAP exhibited a dose-related increase in scratching bouts similar to naïve rats. Rats receiving SP-SAP exhibited significantly reduced scratching (to ~38%) at all 5-HT doses. Individual bout durations (~2 s) did not vary significantly between groups or by dose of 5-HT. After behavioral testing, rats were perfused with fixative and caudal medullary and cervical spinal cord sections processed immunohistochemically for NK-1 receptors. Tissue from SAP-treated rats exhibited a normal distribution of pronounced NK-1 immunoreactivity in superficial layers of the dorsal horn at caudal medullary through C5 levels, while in SP-SAP-treated rats there was a complete absence of NK-1 immunoreactivity at these levels. These results indicate that SP plays an important role in neurotransmission from itch-signaling primary afferent fibers to second-order neurons in the superficial dorsal horn.

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Spinal neurons that possess the substance P receptor (SPR) modulate descending systems that control excitability of spinal nociceptive neurons

Khasabov SG, Ghilardi JR, Mantyh PW, Simone DA (2003) Spinal neurons that possess the substance P receptor (SPR) modulate descending systems that control excitability of spinal nociceptive neurons. Neuroscience 2003 Abstracts 13.3. Society for Neuroscience, New Orleans, LA.

Summary: We have recently shown that ablation of spinal SPR-expressing spinal neurons by intrathecal application of the cytotoxin conjugate substance P-saporin (SP-SAP) prevents the development of sensitization produced by intraplantar injection of capsaicin (Khasabov et al., 2002) and reduced hyperalgesia produced by inflammation and nerve injury (Mantyh et al., 1997; Nichols et al., 1999). Since the majority of spinal SPR-expressing neurons project to the brain, it is possible that these neurons are an integral part of ascendingdescending circuitry that modulates excitability of spinal nociceptive neurons. Here we studied the contribution of ascending SPR positive neurons in the regulation of brain stem descending pathways that pass through the dorsolateral funiculus (DLF) and modulate spinal cord excitability and sensitization. Rats were given an intrathecal injection of vehicle (0.9% NaCl, 10μl) or SP-SAP (5·10-6M, 10μl) at the lumbar enlargement 30 days prior to electrophysiological recording from lumbar spinal neurons. Spontaneous activity and evoked responses of nociceptive neurons to heat (35-51.°C) and mechanical stimuli (von Frey monofilaments) were obtained before and 1 hour after ipsilateral DLF transection. In vehicle-treated animals, DLF transection produced a 183% increase spontaneous activity, a leftward shift in the temperature-response curve, and a 60% increase in the number of impulses evoked by mechanical stimuli (n=25). In contrast, neurons in the SP-SAP group did not show any changes in spontaneous or evoked activity after DLF transaction (n=29). We conclude that ascending spinal SPR-possessing neurons modulate activity of descending inhibitory systems that pass through the DLF.

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Ablation of a population of NK-1 expressing neurons in the dorsal horn of the spinal cord does not induce αβ sprouting into lamina II

Woods M, Whiteside G, Pearson M, Pomonis J, Turchin P, Walker K (2003) Ablation of a population of NK-1 expressing neurons in the dorsal horn of the spinal cord does not induce αβ sprouting into lamina II. Neuroscience 2003 Abstracts 64.11. Society for Neuroscience, New Orleans, LA.

Summary: Peripheral nerve injury results in hyperalgesia and allodynia. It has been proposed that sprouting of myelinated touch responsive Aβ-fibers into the innervation territory of pain sensitive C fibers in the spinal cord contributes to these abnormal behaviors. In has further been postulated that excitatory cell death of spinal cord neurons may result in “vacant synapses” that induce sprouting (Woolf et al., 1992). We have investigated whether selectively ablating a population of cells in laminae I and II, using intrathecal (i.t.) SP-saporin (SP-SAP), will induce sprouting from deeper laminae. Male Sprague-Dawley rats were either injected i.t. at the lumbar region with SP-SAP (1 μl, 5 μM) or the sciatic nerve was axotomised at the mid-thigh level. Two weeks later the sciatic nerve was injected with the retrograde tracer, cholera toxin-β subunit (CTB) (2 μl, 2%) which selectively traces Aβ-fibers. Three days post CTB the animals were perfused, the lumbar ganglia and spinal cord harvested, sectioned and stained immunohistochemically for NK-1 and CTB. As previously described axotomy resulted in considerable CTB immunostaining in laminae I, II and III compared to non-axotomised controls in which it was present only in I and III. SP-SAP i.t. resulted in a substantial reduction of NK-1 like immunostaining in the spinal cord compared to saline injected controls. CTB was not detected in lamina II of spinal cords from animals with an ablation of NK-1 expressing cells. These results suggest that the death of dorsal horn neurons does not induce sprouting of Aβ-fibers into lamina II.

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Neurokinin-1 receptor-expressing neurons in the amygdala modulate morphine reward and anxiety behaviors in the mouse.

Gadd CA, Murtra P, De Felipe C, Hunt SP (2003) Neurokinin-1 receptor-expressing neurons in the amygdala modulate morphine reward and anxiety behaviors in the mouse. J Neurosci 23(23):8271-8280. doi: 10.1523/JNEUROSCI.23-23-08271.2003

Summary: Mice lacking the neurokinin-1 (NK-1) receptor are insensitive to opiates in models of drug abuse. To assess what areas of the brain may be involved in this process, the authors used 1.0-µl injections of 1.0 µM SP-SAP (Cat. #IT-07) to eliminate NK-1 receptor-positive neurons in the nucleus accumbens, dorsomedial caudate putamen or amygdala of mice. Only mice with amygdala lesions displayed behavior comparable to NK-1 receptor knockout mice—increase in anxiety-like behavior, reduction in stimulant effect of morphine. These data suggest that the amygdala plays an important role in anxiety behaviors and the response to opiates.

Related Products: SP-SAP (Cat. #IT-07)

Targeted toxins in pain.

Wiley RG, Lappi DA (2003) Targeted toxins in pain. Adv Drug Deliv Rev 55(8):1043-1054. doi: 10.1016/s0169-409x(03)00102-9

Summary: The authors discuss the use of 'molecular neurosurgery' in the study of nociception. Applications using targeted toxins, which include immunotoxins, protein-toxin conjugates, or peptide-toxin conjugates, are illustrated. The authors describe the use of these molecules as research tools, as well as their potential for therapeutics. A helpful table is included that lists neuronal surface markers and class of cells targeted for each targeted toxin. Reagents discussed: CTB-SAP (Cat. #IT-14), IB4-SAP (Cat. #IT-10), OX7-SAP (Cat. #IT-02), 192-Saporin (Cat. #IT-01), ME20.4-SAP (Cat. #IT-15), Anti-DBH-SAP (Cat. #IT-03), Anti-DAT-SAP (Cat. #IT-25), SP-SAP (Cat. #IT-07), Dermorphin-SAP (Cat. #IT-12), Orexin-SAP (Cat. #IT-20), CRF-SAP (Cat. #IT-13), and acetylated LDL-SAP (Cat. #IT-08).

Related Products: CTB-SAP (Cat. #IT-14), IB4-SAP (Cat. #IT-10), OX7-SAP (Cat. #IT-02), 192-IgG-SAP (Cat. #IT-01), ME20.4-SAP (Cat. #IT-15), Anti-DBH-SAP (Cat. #IT-03), Anti-DAT-SAP (Cat. #IT-25), SP-SAP (Cat. #IT-07), Dermorphin-SAP / MOR-SAP (Cat. #IT-12), Orexin-B-SAP (Cat. #IT-20), CRF-SAP (Cat. #IT-13), Acetylated LDL-SAP (Cat. #IT-08)

Subtypes of substance P receptor immunoreactive interneurons in the rat basolateral amygdala.

Levita L, Mania I, Rainnie DG (2003) Subtypes of substance P receptor immunoreactive interneurons in the rat basolateral amygdala. Brain Res 981(1-2):41-51. doi: 10.1016/s0006-8993(03)02870-1

Summary: SP-SAP (Cat. #IT-07) has been used to lesion substance P receptor (SPr)-expressing neurons in the basolateral amygdala (BLA), but the interneuron subgroups targeted by SP-SAP in the BLA have not yet been defined. The authors used dual-labeling immunofluorescence to examine SPr colocalization with calbindin-D28K, parvalbumin, calretinin, somatostatin, and neuropeptide Y (NPY). All neurons in the BLA that express NPY also express the SPr and therefore SP-SAP, which specifically eliminates SP receptor-positive neurons is a useful tool to study the role of NPY in the BLA.

Related Products: SP-SAP (Cat. #IT-07)

Intrathecal substance p-saporin attenuates operant escape from nociceptive thermal stimuli.

Vierck CJ, Kline RH, Wiley RG (2003) Intrathecal substance p-saporin attenuates operant escape from nociceptive thermal stimuli. Neuroscience 119(1):223-232. doi: 10.1016/s0306-4522(03)00125-8

Summary: Administration of SP-SAP (Cat. #IT-07) eliminates sensitization of nocifensive reflexes. The authors investigate whether SP-SAP elimination of neurokinin-1 receptor-expressing neurons in the lumbar spinal cord affects nociceptive sensitivity in general, or preferentially affects nociception dependent on spinal and brainstem, or cerebral processing. Rats treated with spinal intrathecal injections of 175 ng of SP-SAP showed attenuated thermal hyperalgesia, and no secondary hyperalgesia, while innate reflexes were unaffected by SP-SAP treatment.

Related Products: SP-SAP (Cat. #IT-07)

Ablation of striatal interneurons influences activities of entopeduncular neurons.

Chiken S, Tokuno H (2003) Ablation of striatal interneurons influences activities of entopeduncular neurons. Neuroreport 14(5):675-678. doi: 10.1097/00001756-200304150-00003

Summary: To investigate the role of the basal ganglia in informational processing of voluntary movement, the authors used SP-SAP (Cat. #IT-07) to lesion SP receptor-expressing neurons in the striatum. A 0.5 µl injection of 40 ng/µl SP-SAP into the dorsolateral portion of the striatum decreased the spontaneous discharge of entopeduncular neurons. These data indicate that SP receptor-positive striatal interneurons indirectly regulate activity of basal ganglia output neurons.

Related Products: SP-SAP (Cat. #IT-07)

Breathing: Rhythmicity, Plasticity, Chemosensitivity.

Feldman JL, Mitchell GS, Nattie EE (2003) Breathing: Rhythmicity, Plasticity, Chemosensitivity. Annu Rev Neurosci 26:239-266. doi: 10.1146/annurev.neuro.26.041002.131103

Summary: Recent research has indicated that specific areas of the brain exert control over several aspects of breathing, such as rhythm generation, reaction to hypoxia, and regulation of carbon dioxide levels and pH. This review covers many of the latest advances, some of which utilize SP-SAP (Cat. #IT-07) and anti-SERT-SAP (Cat. #IT-23). The use of these targeted toxins allows altered breathing behavior through elimination of very specific cell populations.

Related Products: SP-SAP (Cat. #IT-07), Anti-SERT-SAP (Cat. #IT-23)

Ablation of NK1 receptors in rat nucleus tractus solitarii blocks baroreflexes.

Riley J, Lin LH, Chianca DA, Talman WT (2002) Ablation of NK1 receptors in rat nucleus tractus solitarii blocks baroreflexes. Hypertension 40(6):823-826. doi: 10.1161/01.hyp.0000042089.34004.cf

Summary: Stimulation of arterial baroreflexes releases the neuropeptide substance P (SP) from vagal afferent nerves within the nucleus tractus solitarii. To ascertain whether the neurons taking up this SP are critical to baroreflex transmission, the authors injected 18 ng SP-SAP (Cat. #IT-07) into the nucleus tractus solitarii of rats. In animals that received bilateral injections, baroreflex gain was significantly reduced, indicating that neurons expressing SP receptors play a critical role in mediation of this process.

Related Products: SP-SAP (Cat. #IT-07)

Subtypes of substance P receptor immunoreactive interneurons in the basolateral amygdala

Mania I, Levita L, Rainnie DG (2002) Subtypes of substance P receptor immunoreactive interneurons in the basolateral amygdala. Neuroscience 2002 Abstracts 637.8. Society for Neuroscience, Orlando, FL.

Summary: Neurotoxic lesions of substance P receptor immunoreactive (SPR-IR) interneurons in the basolateral amygdala (BLA) using SP-saporin reduce anxiety related behavior. These lesions might provide a way to study how specific interneuron populations regulate neuronal activity in the BLA. In the hippocampus, SP-saporin lesions result in an ablation of PV-, CCK-, and SOM-IR interneurons, while sparing CB-IR interneurons. However, limited information is available about the type of neurons affected by this lesion in the BLA. In this study SPR-IR interneurons were characterized immunocytochemically using dual-labeling immunofluorescence. SPR-IR interneurons were examined for their colocalization with calcium-binding proteins and NPY in the rat BLA. The majority of SPR-IR (74%) neurons had a small round or multipolar somata that emanated 3-4 thin aspiny dendrites consistent with them being local interneurones. Interestingly, none of the SPR-IR cells colocalized PV, and they represent only 3–6 % of the CB expressing interneuron population. However, those SPR-IR neurons that do colocalize CB represent 25-45% of the total SPR-IR population. In contrast, 94% of the NPY-IR neurons colocalized with SPR-IR. However, only 51% of SPR-IR cells also co-express NPY-IR. These data suggest that SPR-IR cells represent a heterogeneous population comprising of roughly equal proportions of CB and NPY neurons. Moreover, in the rat BLA SPR-IR cells form a distinct and dissociable group from the PV-IR interneuron population, which should remain intact after SP-saporin lesions.

Related Products: SP-SAP (Cat. #IT-07)

Neurobiology of substance P and the NK1 receptor.

Mantyh PW (2002) Neurobiology of substance P and the NK1 receptor. J Clin Psychiatry 63(Suppl 11):6-10.

Summary: The NK-1 receptor system is somewhat unusual in that it is expressed on only 5-7% of neurons in the central nervous system. Dr. Patrick Mantyh reviews how tools such as SP-SAP (Cat. #IT-07) have been used to begin defining the roles of substance P and the NK-1 receptor in affective behavior.

Related Products: SP-SAP (Cat. #IT-07)

Effects of lesions in the medullary raphe nucleus on sleep and breathing in adult goats

Hodges MR, Forster HV, Wenninger JM, Brozoski DT, Leekley T, Klum L, Feroah TR, Pan LG, Sengupta J (2002) Effects of lesions in the medullary raphe nucleus on sleep and breathing in adult goats. Neuroscience 2002 Abstracts 321.8. Society for Neuroscience, Orlando, FL.

Summary: The medullary raphe nucleus (MRN) contains populations of both neurokinin-1 and glutamate receptor positive neurons (NK1R+, GluR+). The MRN is also thought to influence breathing during wakefulness and sleep. Therefore, to test the MRN influence on breathing during sleep, adult goats (n=4) were chronically instrumented with microtubules into the MRN and allowed >3 weeks to recover. Sleep was monitored during a period of 6 hours (9pm-3am) prior to and 6-8 days after injection of saporin-substance P (SAP-SP), and the night of and 10-14 days after injection of ibotenic acid (IA). During sleep, EEG, EOG, diaphragm EMG, heart rate and blood pressure were monitored, and arterial blood was sampled. We found no significant effect of neurotoxic lesions on relative percentages of time spent in NREM and REM sleep compared to the post-implant control studies. We also found no evidence of ataxic breathing patterns during awake, NREM or REM states after injection of SAP-SP or IA into the MRN. However, evidence of central apnea was present in 3 of 4 goats. The apneustic events were most frequent during NREM, and less frequent or absent during wakefulness and REM sleep. These apneas were 6-20 seconds in duration and resulted in marked variations in PCO2 and PO2. There was also a tendency for hyperventilation during sleep after IA injections. We conclude that lesions in the MRN by loss of NK1R+ and GluR+ neurons can affect breathing during sleep without affecting sleep itself.

Related Products: SP-SAP (Cat. #IT-07)

Breathing of awake goats after neurotoxic lesions in the medullary raphe

Forster HV, Hodges MR, Wenninger JM, Pan LG, Klum L, Leekley T, Feroah TR, Brozoski DT (2002) Breathing of awake goats after neurotoxic lesions in the medullary raphe. Neuroscience 2002 Abstracts 321.9. Society for Neuroscience, Orlando, FL.

Summary: Neurokinin I immunoreactive neurons are abundantly present in the medullary raphe of adult goats. We therefore wished to determine the effect on breathing of destroying such neurons using the neurotoxin saporin (SAP) conjugated to substance P (SP). Injections (1 to 10 µl) of SAP-SP were made at one or two sites in the raphe pallidus and/or raphe obscurus of 4 awake goats. Over the subsequent 5 hours, breathing remained near control levels. Within a few days, there was mild to marked hypoventilation in 2 goats and an attenuated CO2 sensitivity in 3 goats but breathing did not become irregular or ataxic in any goat. The attenuated CO2 sensitivity was associated with evidence of airway constriction. Eight to 14 days later, we injected (1 to 10 µl) at the same sites 50mM ibotenic acid (neurotoxic through glutamate receptors). In the awake state, this injection caused a further marked hypoventilation in one goat who became terminally apneic when anesthetized. After this injection, in the other 3 goats, eupneic PaCO2 was stable and CO2. sensitivity was normal or below normal. We conclude that in awake goats, normal eupneic breathing and CO2 sensitivity are dependent on medullary raphe neurokinin and glutamate receptor activity which apparently includes but is not limited to regulation of airway diameter.

Related Products: SP-SAP (Cat. #IT-07)

Superficial NK1-expressing neurons control spinal excitability through activation of descending pathways.

Suzuki R, Morcuende S, Webber M, Hunt SP, Dickenson AH (2002) Superficial NK1-expressing neurons control spinal excitability through activation of descending pathways. Nat Neurosci 5(12):1319-1326. doi: 10.1038/nn966

Related Products: SP-SAP (Cat. #IT-07)

Spinal neurons that possess the substance P receptor are required for the development of central sensitization.

Khasabov SG, Rogers SD, Ghilardi JR, Peters CM, Mantyh PW, Simone DA (2002) Spinal neurons that possess the substance P receptor are required for the development of central sensitization. J Neurosci 22(20):9086-9098. doi: 10.1523/JNEUROSCI.22-20-09086.2002

Summary: Using 5 x 10-5 M intrathecal injections of SP-SAP (Cat. #IT-07) the authors examined the role of SPR-expressing neurons in modulation of pain and hyperalgesia. Treated animals exhibited highly attenuated sensitization to stimuli after capsaicin treatment as compared to controls, but normal responses in the absence of capsaicin

Related Products: SP-SAP (Cat. #IT-07)

Substance P-saporin lesion of neurons with NK1 receptors in one chemoreceptor site in rats decreases ventilation and chemosensitivity.

Nattie EE, Li A (2002) Substance P-saporin lesion of neurons with NK1 receptors in one chemoreceptor site in rats decreases ventilation and chemosensitivity. J Physiol 544(Pt 2):603-616. doi: 10.1113/jphysiol.2002.020032

Summary: The authors injected 0.1 pmol SP-SAP (Cat. #IT-07) into the retrotrapezoid nucleus/parapyramidal region of rats. The lesioned animals demonstrated hypoventilation while at rest, decreased response to high CO2 levels, and a tendency to sleep less.

Related Products: SP-SAP (Cat. #IT-07)

Plasticity of wide dynamic range neurones following site-selective ablation of NK-1 receptor expressing lamina I neurones in rat spinal cord.

Suzuki R, Morcuende S, Webber M, Hunt SP, Dickenson AH (2002) Plasticity of wide dynamic range neurones following site-selective ablation of NK-1 receptor expressing lamina I neurones in rat spinal cord. IASP 2002 Abstracts International Association for the Study of Pain, San Diego, CA.

Related Products: SP-SAP (Cat. #IT-07)

Reduced aversion to oral capsaicin following neurotoxic destruction of superficial medullary neurons expressing NK-1 receptors.

Simons CT, Gogineni AG, Iodi Carstens M, Carstens E (2002) Reduced aversion to oral capsaicin following neurotoxic destruction of superficial medullary neurons expressing NK-1 receptors. Brain Res 945:139-143. doi: 10.1016/s0006-8993(02)02913-x

Summary: Capsaicin-induced irritation of the dorsal anterior tongue is mediated by nociceptors expressing VR-1 receptors. The role of NK-1 receptor-expressing neurons during the ingestion of capsaicin was examined by injecting 20 µl of 2.27 µM SP-SAP (Cat. #IT-07) into the cisterna magna of rats. Lesioned rats consumed significantly more water containing high concentrations of capsaicin than control animals.

Related Products: SP-SAP (Cat. #IT-07)

Destruction by SP-SAP of rat retrotrapezoid nucleus (RTN) neurons expressing the neurokinin 1 receptor (NK1R) decreases breathing at rest and in response to hypercapnia.

Nattie EE, Li A (2001) Destruction by SP-SAP of rat retrotrapezoid nucleus (RTN) neurons expressing the neurokinin 1 receptor (NK1R) decreases breathing at rest and in response to hypercapnia. Neuroscience 2001 Abstracts 573.1. Society for Neuroscience, San Diego, CA.

Summary: Neurons in the RTN are hypothesized to provide both a tonic excitation for breathing and one location for central chemoreception (see Nattie, E., Prog. Neurobiol.1999). Lesions in anesthetized animals support the former while both lesions and focal acidification in unanesthetized animals support the latter. Application of substance P (SP) in the RTN increases respiratory output and immunohistochemistry for the SP (NK1) receptor shows extensive staining in the RTN. To destroy specifically these RTN neurons with NK1Rs we injected unilaterally in the RTN of the rat SP conjugated to the ribosomal toxin, saporin (SP-SAP; 100 nl; 1 uM; Advanced Targeting Systems). We measured ventilation by whole body plethysmography in the unanesthetized rat. At 6 to 15 days following SP-SAP injection, ventilation during air breathing was reduced by 19 to 24% and the response to 7% CO2 inhalation was reduced by 22 to 30%. Subsequent immunohistochemistry showed dramatically reduced NK1R staining in the area of the SP-SAP injection, which is difficult to quantify given the small number of RTN neurons and the extensive NK1R distribution along neuronal processes. RTN neurons with NK1Rs provide both a tonic excitation for breathing and a portion of the response to systemic hypercapnia.

Related Products: SP-SAP (Cat. #IT-07)

DL-homocysteic (DLH)-induced tachypnea is eliminated by ablation of neurokinin-1 receptor immunoreactive (NK1R-ir) neurons of the preBötzinger complex (preBötc).

Wang H, Guyenet PG (2001) DL-homocysteic (DLH)-induced tachypnea is eliminated by ablation of neurokinin-1 receptor immunoreactive (NK1R-ir) neurons of the preBötzinger complex (preBötc). Neuroscience 2001 Abstracts 633.4. Society for Neuroscience, San Diego, CA.

Summary: We identified a hot spot of the ventrolateral medulla (VLM) where tachypnea is produced by small injections of the excitatory amino acid DLH in urethane-anesthetized vagotomized rats. We sought to determine its anatomical location relative to a group of NK1R-ir cells that may be a marker of the preBötC. We also determined the location of the hot spot relative to VLM pressor and depressor sites. The VRG was located by recording respiratory units and then 5-10 nl of 10 mM DLH were injected into the VRG at 200 mm interval from Bregma -12.1 to -13.3 mm. DLH produced site-specific changes in respiratory rate and mean arterial blood pressure (MAP). At rostral levels (Bregma -12.1 mm) PND rate decreased and MAP increased (-57 ± 11% and 9.4 ± 0.9%; N= 4-6). At more caudal levels these effects gradually reversed (cross-over point at -12.4 mm). Tachypneic responses were restricted between Bregma -12.5 and -13.1 mm with a sharp peak (88.7 ± 12.8% increase in rate) at -12.7 mm. The hot spot corresponded to where most pre-inspiratory neurons are found. It overlapped with VRG NK1R-ir cells but was more restricted than the distribution of these cells. Depressor responses were maximal at -12.7 mm and stable at more caudal levels. After unilateral ablation of the NK1R-ir cells (N=3) with a saporin-NK1R agonist conjugate, the DLH-induced tachypnea disappeared bilaterally. In conclusion, the tachypnea hot spot corresponds to the defined preBötC. It overlaps with the rostral end of the VLM depressor area and the NK1R-ir neurons of the preBötC may be responsible for DLH-induced tachypnea.

Related Products: SP-SAP (Cat. #IT-07)

Central origin of ataxic breathing after lesion of preBötzinger complex (preBötc) neurokinin 1 receptor expressing (NK1R+) neurons.

Janczewski WA, Gray PA, Feldman JL (2001) Central origin of ataxic breathing after lesion of preBötzinger complex (preBötc) neurokinin 1 receptor expressing (NK1R+) neurons. Neuroscience 2001 Abstracts 243.2. Society for Neuroscience, San Diego, CA.

Summary: Pathological breathing results from near complete lesions of preBötC NK1R+ neurons in awake adult rats (Gray et al., FASEB J.,15, 2001). To determine whether this ataxic pattern is central in origin, we examined the breathing pattern of rats using combined diaphragmatic EMG (diaEMG) and whole body plethysmography (WBP). Under anesthesia, substance P conjugated to saporin was injected bilaterally into the preBötC (n=7) and EMG electrodes were implanted into the diaphragm (n=10). Up to four days postinjection, all rats breathed normally. DiaEMG postinpiratory activity was evident in all rats and accentuated during brief apnea following spontaneous sighs. After postinjection day 5, injected rats showed a transformation in breathing pattern from normal to ataxic characterized by high frequency breaths of varying amplitude separated by periods of tonic diaphragmatic discharge. There was no lag between the WBP output and diaphragmatic activity (WBP measures virtually paralleled the moving average of diaEMG activity), suggesting the absence of significant flow limitations. During apnea, nonrespiratory movement produced artifacts on WBP signal but did not affect diaEMG. We conclude that ablation of preBötC NK1R+ neurons leads to hypoventilation and apneas of purely central origin without upper airway obstruction or bronchoconstriction.

Related Products: SP-SAP (Cat. #IT-07)

Intrathecal infusion of substance P-saporin ablates substance p receptor expressing neurons in the dorsal horn of the spinal cord and attenuates bone cancer pain.

Luger NM, Sabino MC, Schwei MJ, Rogers SD, Pomonis JD, Keyser CP, Mach DB, Salak-Johnson J, Clohisy DR, Mantyh PW (2001) Intrathecal infusion of substance P-saporin ablates substance p receptor expressing neurons in the dorsal horn of the spinal cord and attenuates bone cancer pain. Neuroscience 2001 Abstracts 55.4. Society for Neuroscience, San Diego, CA.

Summary: Over 75% of advanced cancer patients must cope with chronic cancer pain. Interestingly, bone cancer pain is the most common and difficult to control. While current therapies are effective in alleviating many aspects of bone cancer pain, they are often accompanied by significant unwanted side effects. To better understand the population of spinal cord neurons that are involved in conveying bone cancer pain and to determine the efficacy of a novel therapeutic modality, we ablated substance P receptor (SPR)+ neurons in the spinal cord using intrathecal infusion of substance P-Saporin (SP-SAP). SP-SAP is a suicide ligand which consists of the ribosomal inactivating factor saporin conjugated to substance P, a peptidergic neurotransmitter involved in nociception. SP-SAP selectively ablates SPR+ neurons located in lamina I and III-V of the spinal cord. C3H male mice received intrathecal SP-SAP treatment 30 days prior to injection of 2472 osteosarcoma cells into the intramedulary space of a femur. Following injection, osteolytic sarcoma cells were confined within the femur by an amalgam plug. Mice were behaviorally tested 17 days post-tumor implantation and both ongoing and movement-evoked pain assessed. Ablation of SPR+ neurons in the dorsal spinal cord coincided with attenuation of both spontaneous and movement-evoked pain behaviors. These results suggest that SPR expressing neurons are involved in the development and progression of the bone cancer pain state and SP-SAP may serve as a useful therapy to treat this debilitating condition. Supported by NIH & VA.

Related Products: SP-SAP (Cat. #IT-07)

NK1-expressing neurons critical for morphine reward behaviors in mice: C-fos expression and ablation of NK1-expressing neurons.

Gadd CA, Murtra P, Hall CN, Gana M, Webber MJ, De Felipe C, Hunt SP (2001) NK1-expressing neurons critical for morphine reward behaviors in mice: C-fos expression and ablation of NK1-expressing neurons. Neuroscience 2001 Abstracts 224.13. Society for Neuroscience, San Diego, CA.

Summary: We have previously shown using conditioned place preference (CPP) that mice lacking the preferred receptor for substance P (NK1) show an absence of the rewarding response to morphine as well as reduced conditioned place aversion and physical withdrawal signs following chronic opiate treatment (Nature 405, 180-183). To locate those regions of the brain in which NK1-expressing neurons are crucial for opiate-mediated reward behavior, we examined the expression of c-Fos following acute (10 mg/kg IP) and chronic (increasing doses from 10 to 100 mg/kg IP) morphine administration, and following CPP to morphine (7.5 mg/kg) in wild-type and NK1 knockout mice. The expression of c-Fos in the brains of mice treated with chronic or acute morphine treatment was similar in both genotypes. Moreover, NK1-expressing neurons in the striatum and nucleus accumbens (NAc) were never seen to co-express c-Fos immunoreactivity. In contrast, the expression of c-Fos following the CPP protocol was significantly different between genotypes with a reduced number of c-Fos positive neurons in NK1 knockout mice in the amygdala and hippocampus but not in the NAc or dorsomedial striatum (DMS). We next investigated the effects of selective ablation of NK1 expressing neurons by injecting substance P-saporin into these regions. Our results suggest that destruction of these cells in the amygdala but not in the NAc or DMS causes a reduction in CPP to morphine without affecting anxiety levels or locomotor activity.

Related Products: SP-SAP (Cat. #IT-07)

Normal breathing requires preBotzinger complex neurokinin-1 receptor-expressing neurons.

Gray PA, Janczewski WA, Mellen N, McCrimmon DR, Feldman JL (2001) Normal breathing requires preBotzinger complex neurokinin-1 receptor-expressing neurons. Nat Neurosci 4(9):927-930. doi: 10.1038/nn0901-927

Summary: SP-SAP was effective in eliminating preBötC NK1R neurons in adult rats. Unilateral SP-SAP injection transiently produced sighs (large inspiratory efforts followed by prolonged expiration).

Usage: Injections of 0.1–0.2 pmol of SP-SAP or 0.3 pmol each of unconjugated Saporin and Substance P were made in the pre-BötC.

Related Products: SP-SAP (Cat. #IT-07)

The molecular dynamics of pain control.

Hunt SP, Mantyh PW (2001) The molecular dynamics of pain control. Nature Rev Neurosci 2:83-91. doi: 10.1038/35053509

Summary: Over the last twenty years a great deal of progress has been made in the understanding of how pain is processed and transmitted by the CNS. The authors of this review highlight advances in systems neurobiology, behavioral analysis, genetics, and cell and molecular techniques. One method discussed is the use of the targeted toxin substance P-saporin (SP-SAP, Cat. #IT-07, also available with a more stable analog of substance P, SSP-SAP, Cat. #IT-11). This targeted toxin selectively lesions neurons expressing the NK1 receptor. Injection of SP-SAP into the spinal cord of rats dramatically attenuates the response to chronic pain stimuli, yet leaves acute pain response intact.

Related Products: SP-SAP (Cat. #IT-07), SSP-SAP (Cat. #IT-11)

Neuronal lesioning with axonally transported toxins.

Wiley RG, Kline IV RH (2000) Neuronal lesioning with axonally transported toxins. J Neurosci Methods 103:73-82. doi: 10.1016/S0165-0270(00)00297-1

Summary: Functional neuroanatomy studies have long utilized lesioning. Given the complexity of heterogeneous neuron populations conventional lesioning methods have proved relatively crude, and have provided limited information. Wiley and Kline detail some of the immunotoxins utilizing saporin as well as neuropeptide-saporin conjugates that have found use in recent neurological research. These products include SP-SAP (Cat. #IT-07), which eliminates neurons expressing the neurokinin 1 receptor, 192-Saporin (Cat. #IT-01), which eliminates neurons expressing the p75 receptor in rats, anti-DBH-SAP (Cat #IT-03), which destroys noradrenergic and adrenergic neurons, and OX7-SAP (Cat. #IT-02), which is a suicide transport agent targeting all rat neurons. The authors also discuss some of the protocols and methods utilized with these compounds.

Related Products: 192-IgG-SAP (Cat. #IT-01), OX7-SAP (Cat. #IT-02), Anti-DBH-SAP (Cat. #IT-03), SP-SAP (Cat. #IT-07)

Responses of spinal dorsal horn neurons to capsaicin following intrathecal pretreatment with substance p-saporin toxin.

Khasabov SG, Rogers SD, Mantyh PW, Simone DA (2000) Responses of spinal dorsal horn neurons to capsaicin following intrathecal pretreatment with substance p-saporin toxin. Neuroscience 2000 Abstracts 635.13. Society for Neuroscience, New Orleans, LA.

Summary: Intrathecal (i.t.) application of the cytotoxic substance P-saporin (SP-SAP) conjugate is internalized by dorsal horn neurons expressing the SP receptor (SPR) and results in loss of SPR-expressing neurons. Loss of SPR+ neurons attenuates the nocifensive behavior and hyperalgesia produced by intraplantar injection of capsaicin (CAP). Here we determined the effect of SP-SAP on CAP-evoked excitation and sensitization of dorsal horn neurons to heat and mechanical stimuli. Separate groups of rats were given i.t. injection of vehicle (VEH) or SP-SAP (5´10-6mM in 10ml) 10 or 30 days prior to electrophysiological experiments. Extracellular recordings were obtained from nociceptive dorsal horn neurons classed as high threshold (HT) or wide dynamic range (WDR). Responses to mechanical (von Frey monofilaments) and heat (35°C-51°C) stimuli were obtained before and after injection of 10 mg CAP into the receptive field. In VEH-treated animals, CAP produced an intense activation of HT and WDR neurons with a mean peak discharge rate of 52.2±11.2 Hz. In addition, the mean number of impulses evoked by mechanical stimuli increased 267±33% following CAP and mean heat thresholds decreased from 44.7±1.6°C to 37.7±0.7°C. In SP-SAP treated animals, however, the peak response evoked by CAP was decreased by 61±11% as compared to control. Moreover, CAP did not significantly alter responses to mechanical or heat stimuli. These data suggest that dorsal horn neurons that possess the SPR play a critical role in the development of sensitization to mechanical and heat stimuli following CAP.

Related Products: SP-SAP (Cat. #IT-07)

Reduced anxiety related behavior following ablation of amygdala neurons expressing substance P receptor.

Rogers SD, Salak-Johnson JL, Schwei MJ, Pomonis JD, Mantyh PW (2000) Reduced anxiety related behavior following ablation of amygdala neurons expressing substance P receptor. Neuroscience 2000 Abstracts 571.2. Society for Neuroscience, New Orleans, LA.

Summary: The neurokinin substance P (SP) is localized in brain regions that coordinate stress response and may play a role in modulating anxiety. Effects of ablation of substance P receptor (SPR)-expressing neurons by administration of a substance P-toxin conjugate, substance P-saporin (SP-SAP), in the amygdala (a brain region known to modulate stress and anxiety responses) were examined immunohistochemically and behaviorally thirty days following SP-SAP treatments. Rats were bilaterally injected in basolateral amygdala nuclei with 5μl of sterile saline, 1 μM saporin (SAP), or 1 μM SP-SAP. SPR-immunofluoresence levels and number of SPR-IR positive neurons in amygdalar subnuclei decreased following SP-SAP treatment. SP-SAP did not induce significant gliosis or non-specific neuronal death. Interestingly, after SP-SAP treatment, the number of NPY-IR neurons were also decreased, and combined SPR and NPY immunofluorescence demonstrated a large number of NPY-IR neurons colocalize with SPR-IR neurons in the amygdala. Thirty days following SP-SAP treatment, rats were tested in elevated plus maze (EPM) and open field (OF). Anxiety level and exploratory behavior displayed by SP-SAP treated rats were altered; they had significantly more entries into and spent more time in EPM open arms than did saline- or SAP-injected rats. In the OF, SP-SAP treated rats spent less time frozen than saline or SAP treated rats. These results suggest that SPR expressing neurons in the amygdala plays a pivotal role in generation of anxiety behaviors and that SP may play a modulatory role in stress-induced anxiety behavior.

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Intrathecal injections of saporin conjugated substance-P alter the development of renal hypertension.

Ciriello J, Rosas-Arellano MP, Solano-Flores LP (2000) Intrathecal injections of saporin conjugated substance-P alter the development of renal hypertension. Neuroscience 2000 Abstracts 310.2. Society for Neuroscience, New Orleans, LA.

Summary: We have recently shown that there is an up-regulation of mRNA encoding Substance-P (SP) in dorsal root ganglia in the two kidney, one clip (2K1C) model of renal hypertension. In this study, the effect of intrathecal injections of the toxin saporin conjugated to SP (SAP; 5 x 10-6 M) on the development of 2K1C hypertension was investigated in male Wistar rats. Rats were randomly assigned to 2 groups and instrumented with an intrathecal cannula that ended at the T10-T12 spinal level. Arterial pressure (AP) and heart rate (HR) were recorded using the indirect tail-cuff method. After a 1 week control period, one group of animals received a single 10 µl injection of SAP and the other an equal volume of the saline vehicle (control). Two weeks later a clip was placed on the left renal artery in all animals. Injections of either SAP or the vehicle did not alter AP and HR compared to pre-injection levels. In addition, AP and HR were not altered in the SAP group compared to controls for the 2 week period prior to the renal clip. However, during the 4 weeks after the renal clip, AP and HR in the SAP group were significantly lower compared to the control animals. These data suggest that dorsal horn neurons containing SP receptors and that receive afferent renal nerve inputs are involved in renal hypertension.

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Neuropeptide-toxin conjugates in pain research and treatment. (Review)

Wiley RG (2000) Neuropeptide-toxin conjugates in pain research and treatment. (Review). Reg Anesth Pain Med 25(5):546-548. doi: 10.1053/rapm.2000.8457

Summary: Several lines of evidence indicate dorsal horn neurons that respond to substance P (SP) play a role in nociception. Wiley discusses the attributes of SP-SAP (Cat. #IT-07), a targeted toxin that eliminates cells expressing the neurokinin-1 receptor. Animals treated with this material using a lumbar intrathecal injection show a decrease in both hyperalgesia and allodynia in several pain models. The success of SP-SAP indicates that other neuropeptides, hormones, and growth factors would be useful as targeted toxins.

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Pain control: breaking the circuit.

Hunt SP (2000) Pain control: breaking the circuit. Trends Pharmacol Sci 21:284-287. doi: 10.1016/s0165-6147(00)01496-6

Summary: Review and analysis of the value of SP-SAP in research and as a therapeutic.

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Loss of nerve: a molecular approach to better treatment of chronic pain.

Friedrich MJ (2000) Loss of nerve: a molecular approach to better treatment of chronic pain. JAMA 283(2):187-188. doi: 10.1001/jama.283.2.187

Summary: The use of SP-SAP (Cat. #IT-07) as a promising new method for chronic pain relief is discussed in this review article. Chronic pain has classically been treated in ways that frequently have adverse effects on the patient's quality of life. Friedrich touches on recently developed toxins that are useful in techniques of molecular neurosurgery. These techniques allow the dissection of pain pathways in the brain and spinal cord which will provide not only a greater understanding of these pathways but also potential therapies for chronic pain and other pain conditions.

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Transmission of chronic nociception by spinal neurons expressing the substance P receptor.

Nichols ML, Allen BJ, Rogers SD, Ghilardi JR, Honore P, Luger NM, Finke MP, Li J, Lappi DA, Simone DA, Mantyh PW (1999) Transmission of chronic nociception by spinal neurons expressing the substance P receptor. Science 286:1558-1561. doi: 10.1126/science.286.5444.1558

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Selective immunolesion of substance P receptor expressing interneurons in the hippocampus.

Borhegyi ZS, Wiley RG, Lappi DA, Morrell J, Buzsáki G (1999) Selective immunolesion of substance P receptor expressing interneurons in the hippocampus. Neuroscience 1999 Abstracts 561.15. Society for Neuroscience, Miami, FL.

Summary: A ribosome inactivating protein, saporin, conjugated to substance P (SP-SAP) was used to selectively damage substance P receptor expressing interneurons in the dentate gyrus of the rat hippocampus. Three different doses (50ng, 25ng and 5ng) were tested in animals surviving 1, 2, 3, 5 and 10 weeks. Immunohistochemistry (parvalbumin, calbindin, calretinin, SPR, GluR2 and mGluRl1α) was carried out to examine specific or non-specific damage. The results were examined at light and electronmicroscopic level. The highest (50ng) dose eliminated SPR elements in an approximately 3mm area, but it also caused nonspecific damage around the center. In rats injected with 5ng nonspecific damage to granule cells and mossy cells was not observed and SPR interneurons were selectively eliminated a far as 0.7mm from the center of the injection. The loss of SPR immunoreactive cells was clearly visible after two weeks. The selective lesion of a well-defined subgroup of hippocampal interneurons can reveal their physiological role in normal function. Furthermore, the permament and selective absence of interneurons may be an effective tool for creating focal epilepsy. This work was supported by NIH, NIMH and Eötvös fellowship.

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Inhibition of mustard oil-induced thermal hyperalgesia in an operant escape task by substance P-saporin.

Wiley RG, Lappi DA, Vierck CJ (1999) Inhibition of mustard oil-induced thermal hyperalgesia in an operant escape task by substance P-saporin. Neuroscience 1999 Abstracts 271.1. Society for Neuroscience, Miami, FL.

Summary: Substance P (SP) armed with the ribosome inactivating protein, saporin (SAP), selectively destroys neurons expressing the NK-1 receptor, attenuates withdrawal responses after capsaicin injection, after a Chung lesion or CFA and blocks phase 2 of the formalin test. These tests rely on innate “reflex” behaviors (withdrawal or licking) and the primary effects were to mechanical stimuli. In the present study, we sought to determine the effects of lumbar i.t. SP-SAP on reflexes and operant escape responses to thermal stimuli. Rats received lumbar i.t. injections of 175 ng SP-SAP (N=7), 25 ng of [Sar8MetOH11]-SP-SAP (N=8) or PBS with 1 mg/ml BSA (N=8). Nine rats served as naive controls. After recovery from surgery, all rats were adapted to thermal reflex testing and separately trained to escape to a brightly lit room temperature shelf from a dark surface at 47°C, 44°C and 0.3°C. There were no differences between groups at baseline on the escape task or reflex tests at any of the 3 temperatures. When tested at 44°C 3 hours after application of mustard oil to the dorsal surface of both hindpaws, controls spent significantly more time on the escape shelf whereas SP-SAP treated rats did not. In contrast, when tested 3 hrs after mustard oil at 44°C, all rats showed similar reflex responses with decreased latency to licking, more licking and guarding. These results indicate that the SP-SAP lesion of lamina I neurons expressing NK-1 receptor in the spinal dorsal horn prevents enhanced operant escape behavior, but not enhanced reflex responses. That is, the aversive quality of mustard oil-induced thermal hyperalgesia was blocked without interfering with nocifensive reflexes. Also, the anti-hyperalgesia effects ofl umbar intrathecal SP-sap include thermal hyperalgesia. This approach may prove valuable in the treatment of chronic, intractable pain. (This work supported by the NIH and the Department of Veterans Affairs).

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Inhibition of hyperalgesia by ablation of lamina I spinal neurons expressing the substance P receptor.

Mantyh PW, Rogers SD, Honore P, Allen BJ, Ghilardi JR, Li J, Daughters RS, Lappi DA, Wiley RG, Simone DA (1997) Inhibition of hyperalgesia by ablation of lamina I spinal neurons expressing the substance P receptor. Science 278:275-279. doi: 10.1126/science.278.5336.275

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Destruction of neurokinin-1 receptor expressing cells in vitro and in vivo using substance P-saporin.

Wiley RG, Lappi DA (1997) Destruction of neurokinin-1 receptor expressing cells in vitro and in vivo using substance P-saporin. Neurosci Lett 230:97-100. doi: 10.1016/s0304-3940(97)00490-4

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