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Central cholinergic depletion induced by 192 IgG-saporin alleviates the sedative effects of propofol in rats.
Pain L, Jeltsch H, Lehmann O, Lazarus C, Laalou FZ, Cassel JC (2000) Central cholinergic depletion induced by 192 IgG-saporin alleviates the sedative effects of propofol in rats. Brit J Anaesth 85(6):869-873. doi: 10.1093/bja/85.6.869
Summary: In order to examine the effect of cholinergic depletion on the sedative potency of propofol in rats the authors injected 1 µg of 192-Saporin (Cat. #IT-01) into each lateral ventricle. The findings indicate a ~50% reduction in sedative potency in lesioned rats.
Related Products: 192-IgG-SAP (Cat. #IT-01)
Prevention and treatment of a spontaneous pain-like behavior following excitotoxic spinal cord injury (SCI) by ablation of neurons expressing the substance P receptor.
Yezierski RP, Yu CG, Wiley RG (2000) Prevention and treatment of a spontaneous pain-like behavior following excitotoxic spinal cord injury (SCI) by ablation of neurons expressing the substance P receptor. Neuroscience 2000 Abstracts 733.9. Society for Neuroscience, New Orleans, LA.
Summary: Intraspinal injection of the AMPA/metabotropic agonist quisqualic acid (QUIS) leads to the onset of excessive grooming behavior with an average onset time of 11-15 days. This behavior has been proposed as a model of chronic central pain following SCI (Yezierski et al., 1998). An important histological correlate of this behavior is a pattern of neuronal loss that includes the neck of the dorsal horn with sparing of the superficial laminae. Previously, we speculated that laminae I projection neurons might be part of the substrate responsible for the onset and progression of injury induced excessive grooming behavior. To test this hypothesis we evaluated the effects of the [Sar9,Met(OH)11]substance P-saporin (SSP-SAP) neurotoxin delivered directly to the dorsal surface of the cord in ‘prevention’ and ‘treatment’ protocols. Two groups of animals were injected with 125mM QUIS. One group received a treatment of SSP-SAP (10μl; 15 or 30ng/μl) for ten minutes immediately after QUIS injection. The second group was treated with 30ng/μl within 5 days after the onset of excessive grooming behavior. The results showed that only 30% (3/10) of the animals receiving SSP-SAP in the prevention protocol developed excessive grooming behavior compared to a norm of 80-90%, and those that developed the behavior had a delayed onset (18-26 days) and small skin area targeted for grooming. Animals receiving SSP-SAP treatment after the onset of grooming had significantly less grooming than animals not receiving treatment. Staining for the NK-1R receptor showed that animals with minimal grooming behavior had a significant decrease in lamina I staining with normal staining around the central canal and IML. In conclusion the results have shown that ablation of lamina I substance P receptive neurons significantly delayed the onset and progression of a spontaneous pain-like behavior induced by excitotoxic SCI.
Related Products: SSP-SAP (Cat. #IT-11)
Dermorphin-saporin targets tonic descending facilitation in the rostral ventromedial medulla to block and reverse neuropathic pain.
Burgess SE, Vanderah TW, Mantyh PW, Malan Jr TP, Ossipov MH, Lappi D, Lai J, Porreca F (2000) Dermorphin-saporin targets tonic descending facilitation in the rostral ventromedial medulla to block and reverse neuropathic pain. Neuroscience 2000 Abstracts 243.6. Society for Neuroscience, New Orleans, LA.
Summary: The hypothesis that chronic pain from L5/L6 spinal nerve ligation (SNL) is due to tonic activation of descending pain facilitation mechanisms was explored by selective targeting mu (μ) opioid receptor expressing cells in the RVM (i.e., presumably, ON cells). Rats were treated with a single RVM injection of dermorphin (DERM)(μ agonist), saporin (SAP), or dermorphin-saporin conjugate (DERM-SAP) and responses to non-noxious (von Frey filaments) or noxious (Hargreave’s test) stimuli characterized. DERM-SAP retained high affinity for μ receptors and acutely produced antinociception (tail-flick test), indicating agonist actions of the conjugate. Decreased staining of μ receptor-expressing cells was seen in superficial dorsal horn and in dorsal root ganglia 28 days after intrathecal injection of DERM-SAP, but not DERM or SAP. RVM DERM-SAP, DERM or SAP did not significantly alter baseline thresholds to von Frey filaments or noxious heat applied to the paw over 28 days. At day 28, RVM pretreated rats were subjected to sham- or SNL surgery and responses to tactile and heat stimuli monitored 7 days later (i.e., 35 days after the RVM pretreatment). DERM and SAP pretreated SNL rats showed the expected development of tactile allodynia and thermal hyperalgesia, while DERM-SAP pretreated rats did not. The RVM pretreatments did not alter responses in sham-operated controls. Administration of RVM DERM-SAP, but not SAP or DERM, to SNL rats showed full reversal of established allodynia/hyperalgesia by day 14. RVM pretreatment with β-funaltrexamine (β-FNA; opioid μ antagonist) prevented the antiallodynic and antihyperalgesic effects of subsequent DERM-SAP injection. These data, together with findings of blockade of SNL pain with RVM lidocaine or lesions of the dorsolateral funiculus, support the possibility of tonic activation of descending facilitation as a basis for chronic neuropathic pain.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12)
Distribution of mu-opioid receptors and activated G-proteins in rat cingulate cortex and alterations following removal of noradrenergic afferents.
Vogt LJ, Sim-Selley LJ, Childers SR, Wiley RG, Vogt BA (2000) Distribution of mu-opioid receptors and activated G-proteins in rat cingulate cortex and alterations following removal of noradrenergic afferents. Neuroscience 2000 Abstracts 238.1. Society for Neuroscience, New Orleans, LA.
Summary: Anterior cingulate cortex (ACC) is involved in acute and chronic pain processing. Here we define opioid architecture throughout rat cingulate cortex, relate mu-opioid receptor and G-protein stimulated binding in particular layers, and localize binding to noradrenergic terminals with immunotoxin lesions (anti-DBH-saporin). [3H]DAMGO binding was highest in areas 32 and 24 with a peak in layer I. Midcingulate area 24′ and posterior area 29 had lower and homogeneous binding. DAMGO stimulated [35S]GTPγS binding in area 24′ was similar to that in areas 32 and 24, while area 29 had very low and homogeneous binding. Undercut lesions reduced [3H]DAMGO binding in all layers with greatest loss in layer I, while DAMGO-stimulated [35S]GTPγS binding losses occurred only in layers I-III. Since neurons in the midline thalamic nuclei and locus coeruleus synthesize mu-opioid receptors, noradrenergic afferents were removed with anti-DBH-saporin. This toxin reduced [3H]DAMGO binding only in layer I of areas 32 and 24, while DAMGO-stimulated [35S]GTPγS binding increased in layer II of areas 32 and 24, had no changes in area 24′, and decreased binding in layer I of area 29. Thus, in addition to their actions on ACC neurons, other sites of opiate drug actions are through mu-opioid heteroreceptors on glutamatergic thalamic and noradrenergic locus coeruleus afferents to ACC.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Chronic noradrenergic spinal denervation in rats does not produce long-term hyperalgesia.
Jasmin L, Arsenault P, Ohara PT, Marchand S (2000) Chronic noradrenergic spinal denervation in rats does not produce long-term hyperalgesia. Neuroscience 2000 Abstracts 243.7. Society for Neuroscience, New Orleans, LA.
Summary: Pharmacological studies have established that noradrenaline tonically inhibits spinal nociceptive transmission. We tested the hypothesis that chronically decreasing spinal noradrenaline would result in a disinhibition of nociceptive afferents resulting in behavioral hyperalgesia. We destroyed noradrenergic cells innervating the spinal cord using dopamine beta-hydroxylase antibodies linked to the neurotoxin saporin (anti-DBH-Sap). Male rats (n=6) were injected intrathecally with 4µg/10µl of anti-DBH-Sap, and their responses to nociceptive and non-nociceptive stimuli was monitored over a period of 65 days. Compared to controls (n=6), a significant (p< 0.05) decrease to hot plate (46oC) nociceptive responses could be observed during the first week post-treatment, but no differences were found at later times. At no point was there any altered response to innocuous stimuli. When tested for response to cold water stress, both treated and control animals showed analgesia, demonstrating that descending pain inhibition could still be activated. At 65 days, a formalin test showed no difference between treated (1.1 +/-0.5) and control (0.8 +/-0.5) groups. Post-mortem immunostaining of spinal cords for DBH, however, confirmed that noradrenergic denervation of the spinal cord had occurred in treated animals. These results suggest that a reorganization of the spinal cord following noradrenergic denervation is sufficient to reestablish normal nociceptive responses.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
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.
Related Products: SP-SAP (Cat. #IT-07)
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.
Related Products: SP-SAP (Cat. #IT-07)
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.
Related Products: SP-SAP (Cat. #IT-07)
Combined lesions of cholinergic and serotonergic neurons in the rat brain using 192 IgG-Saporin and 5,7-dihydroxytryptamine: neurochemical and behavioural characterization.
Lehmann O, Jeltsch H, Lehnardt O, Pain L, Lazarus C, Cassel JC (2000) Combined lesions of cholinergic and serotonergic neurons in the rat brain using 192 IgG-Saporin and 5,7-dihydroxytryptamine: neurochemical and behavioural characterization. Eur J Neurosci 12:67-79. doi: 10.1046/j.1460-9568.2000.00881.x
Summary: Lesioning of septohippocampal pathways has often been used as a model for Alzheimer’s disease because these lesions alter cognitive capabilities such as spatial memory. Recent work in the behavioral neurosciences has shown that other neurotransmitter systems such as GABAergic, noradrenergic, and serotonergic systems also play a role in learning and memory. Lehmann et al. combined the effects of the cholinergic immunotoxin 192-SAP (Cat. #IT-01) and the serotonergic toxin 5,7-dihydroxytryptamine to examine interactions between these two pathways. The effects of lesioning these two pathways in concert indicate that they both play roles in cognitive functions related to working memory. [192-SAP 2 µg/lateral ventricle]
Related Products: 192-IgG-SAP (Cat. #IT-01)
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).
Related Products: SP-SAP (Cat. #IT-07)