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Time-dependent descending facilitation from the rostral ventromedial medulla maintains, but does not initiate, neuropathic pain.
Burgess SE, Gardell LR, Ossipov MH, Malan Jr TP, Vanderah TW, Lai J, Porreca F (2002) Time-dependent descending facilitation from the rostral ventromedial medulla maintains, but does not initiate, neuropathic pain. J Neurosci 22(12):5129-5136. doi: 10.1523/JNEUROSCI.22-12-05129.2002
Summary: Various indications, such as declining afferent discharge over time, suggest that the mechanisms involved in persistent neuropathic pain are different than those that initiate the pain. The authors have previously shown that cells expressing the mu-opioid receptor are involved in the descending pain pathway. In this work, the authors lesioned the rostral ventromedial medulla (RVM) in rats using 1.5 pmol in 0.5 µl of dermorphin-SAP (Cat. #IT-12) administered to each side of the RVM. Measurements of pain-related behavior show that mu-opioid receptor-expressing cells in the RVM are involved in the maintenance of heightened sensitivity to stimuli seen in neuropathic pain.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12)
Spinal noradrenergic activation mediates allodynia reduction from an allosteric adenosine modulator in a rat model of neuropathic pain.
Li X, Conklin D, Ma W, Zhu X, Eisenach JC (2002) Spinal noradrenergic activation mediates allodynia reduction from an allosteric adenosine modulator in a rat model of neuropathic pain. Pain 97:117-125. doi: 10.1016/s0304-3959(02)00011-8
Summary: T62 is a thiobene compound that enhances adenosine agonist binding to the A1 receptor. Activation of the adenosine receptor has been effective in several different pain models. The authors used a spinal nerve ligation model for mechanical allodynia to assess T62 efficacy and mode of action. Rats treated with anti-DBH-SAP (4 µg in 5 µl, Cat. #IT-03) experienced no anti-allodynia effects from T62 administration, indicating that modulation of mechanical allodynia by T62 utilizes the spinal noradrenergic system.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Colocalization of mu-opioid receptors and activated G-proteins in rat cingulate cortex.
Vogt LJ, Sim-Selley LJ, Childers SR, Wiley RG, Vogt BA (2001) Colocalization of mu-opioid receptors and activated G-proteins in rat cingulate cortex. J Pharmacol Exper Ther 299:840-848.
Summary: The anterior cingulate cortex (ACC) is a primary site of opiate drug action, and much of this activity is associated with the m-opioid receptor (MOR). The mechanisms by which MOR regulates pain in the ACC are not well understood. Using anti-DBH-SAP (7 µg into left lateral ventricle in rat; Cat. #IT-03) the authors mapped MOR activity in the ACC and evaluated the histochemical and behavioral relationships between MOR binding and mu-receptor-activated G-proteins after lesioning.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Cytotoxic targeting of isolectin IB4-binding sensory neurons.
Vulchanova L, Olson TH, Stone LS, Riedl MS, Elde R, Honda CN (2001) Cytotoxic targeting of isolectin IB4-binding sensory neurons. Neuroscience 108(1):143-155. doi: 10.1016/s0306-4522(01)00377-3 PMID: 11738138
Summary: Vulchanova et al. examine the role of IB4-binding neurons in nociception. IB4-SAP (Cat. #IT-10) was injected into rats (2 µg in left sciatic nerve). The resulting ablation of IB4-binding neurons provides evidence for their role in nociceptive processing and demonstrates a rapid compensatory response to signalling of acute pain.
Related Products: IB4-SAP (Cat. #IT-10), Saporin Goat Polyclonal (Cat. #AB-15), Saporin Goat Polyclonal, HRP-labeled (Cat. #AB-15HRP)
Dermorphin-saporin conjugate relieves inflammatory pain after peripheral application.
Palecek J, Paleckova V, Willis WD (2001) Dermorphin-saporin conjugate relieves inflammatory pain after peripheral application. Neuroscience 2001 Abstracts 508.10. Society for Neuroscience, San Diego, CA.
Summary: Opioid receptors have been shown to exist in specific population of DRG neurons signaling nociceptive information from peripheral tissues. In our study, we attempted to selectively destroy these neurons by using a peripheral application of the mu opioid agonist Dermorphin conjugated to ribosome inactivating toxin Saporin (DERM-SAP, Advanced Targeting Systems) in order to alleviate inflammatory pain. Intraarticular or intraplantar injection of carrageenan or CFA was used to induce inflammation in rats. The DERM-SAP conjugate was injected into the inflamed area 12-48h later. Responses of the animals to mechanical and thermal stimuli were tested before and after the inflammation and up to 21 days after the DERM-SAP application. The rats developed heat hyperalgesia in the affected paw 24 hours after the intraarticular CFA injection. In the saline injected group the hyperalgesia persisted for up to 19 days, but in the DERM-SAP injected group the signs of hyperalgesia were improving from day 7. Also mechanical allodynia tested with a VF filament (1.1g) was alleviated in the DERM-SAP group. In the carrageenan group, the DERM-SAP treatment decreased the heat hyperalgesia and prevented the development of hyperalgesia after repeated carrageenan application, 21days after the DERM-SAP treatment. Postmortem evaluation with a specific antibody showed presence of saporin in the DRG neurons. Our results show that peripheral application of DERM-SAP relieves inflammatory pain and suggest that peripheral application of neuropeptides conjugated to cell toxins or other substances such as antisense probes could be a useful tool for treating pain of peripheral origin. Supported by NIH grants NS09743 and NS11253.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12)
Dose-dependent effects of intrathecal substance P-saporin and SSP-saporin.
Wiley RG, Kline IV RH, Lappi DA (2001) Dose-dependent effects of intrathecal substance P-saporin and SSP-saporin. Neuroscience 2001 Abstracts 281.11. Society for Neuroscience, San Diego, CA.
Summary: Selective destruction of lamina I dorsal horn neurons expressing the neurokinin-1 receptor (NK-1R) can attenuate responses to capsaicin injection and thermal hyperalgesia/mechanical allodynia in models of inflammatory, persistent or neuropathic pain. In the present study, we sought to determine the relationships between spinal intrathecal dose of substance P-saporin or the related toxin, SSP-saporin, the loss of NK-1R neurons and reduction of phase II formalin responses. Rats were injected intrathecally with 10 ul of either vehicle, 175 ng, 350 ng or 700 ng of SP-sap. Others were injected with either vehicle, 25 ng, 50 ng or 100 ng of SSP-sap. After 2 weeks, nocifensive behavior was scored for 90 min after a unilateral hindpaw injection of dilute formaldehyde. The amount of phase II nocifensive behavior from 20-90 min post injection was totaled for each animal. Rats were sacrificed and transverse lumbosacral spinal cord sections were stained for NK-1R using indirect immunoperoxidase technique. Digital micrographs of the superficial dorsal horn were captured and the number of pixels in the darkest intensity values were expressed as percent of the analysis area for each dorsal horn. Significant correlations were noted for dose vs dark pixel percentage and for dark pixel percentage vs phase II formalin behavior. The greater the toxin dose the greater the loss of NK-1R staining and the greater the attenuation of phase II formalin behavior. These results indicate that the toxin effects on pain behavior are proportional to the degree of loss of lamina I NK-1R expressing neurons.
Related Products: SSP-SAP (Cat. #IT-11)
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)
Inhibition of neuropathic pain by selective ablation of brainstem medullary cells expressing the µ-opioid receptor.
Porreca F, Burgess SE, Gardell LR, Vanderah TW, Malan TP Jr, Ossipov MH, Lappi DA, Lai J (2001) Inhibition of neuropathic pain by selective ablation of brainstem medullary cells expressing the µ-opioid receptor. J Neurosci 21(14):5281-5288. doi: 10.1523/JNEUROSCI.21-14-05281.2001
Summary: The presence of descending projections in the pain pathway raises the possibility that abnormal sustained activity may perpetuate chronic pain. Using 3-ng injections of dermorphin-SAP (Cat #IT-12) on either side of the RVM in rats the authors both prevented and reversed neuropathic pain caused by spinal nerve ligation.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12)
p75-expressing elements are necessary for anti-allodynic effects of spinal clonidine and neostigmine.
Paqueron X, Li X, Eisenach JC (2001) p75-expressing elements are necessary for anti-allodynic effects of spinal clonidine and neostigmine. Neuroscience 102(3):681-686. doi: 10.1016/s0306-4522(00)00528-5
Summary: It has been suggested that alpha2-adrenergic agonists produce analgesia by activating spinal cholinergic neurons. The authors reason that since spinal cholinergic neurons in the ventral horn express p75 following peripheral nerve trauma, cholinergic dorsal horn neurons might also. Instead, they find that dorsal horn neurons express little or no p75 under normal conditions or following spinal nerve ligation. Since dorsal horn neurons do not express p75 they are not eliminated by 192-Saporin (0.1-0.6 µg; Cat. #IT-01), but the data indicate that p75-expressing elements do play a role in pain transmission in the dorsal horn. The authors note that when afferents that express p75 are eliminated, mechanical hypersensitivity is unaffected, but the reduction of hypersensitivity by alpha2-adrenergic agonists or cholinergic agents is blocked.
Related Products: 192-IgG-SAP (Cat. #IT-01)
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)