- Email: [email protected]
(634)
Abstracts
S15
(628) Kappa opioid mediation in a new murine model for neuropathic injury to trigeminal nerve
(630) Refer to Oral Paper Session 330
M Xu, MR Byers, L Gendron, C Chavkin; Departments of Pharmacology and Anesthesiology, University of Washington, Seattle Trigeminal nerve damage can lead to neuropathic pain including trigeminal neuralgia, a severely debilitating chronic pain syndrome. We have devised a mouse model of trigeminal neuralgia using a partial ligation of the infraorbital nerve (pIONL) that induces persistent pain behaviors and morphological changes in brainstem. This novel model will allow determination of the basic mechanisms underlying trigeminal neuropathy using genetically engineered mice. Previous studies showed that the endogenous opioid dynorphin is released following nerve injury-induced neuropathic pain, and we found that sustained dynorphin release stimulated kappa opioid receptors (KOR) to cause astroglial proliferation in mouse spinal cord after sciatic injury. Using the pIONL model, we performed behavioral analyses to test the kinetics of the allodynic pain response. We found that mice developed mechanical allodynia lasted for over 4 weeks, and KOR⫺/⫺ mice showed significantly more allodynia than WT mice; the expression of the glial cell marker GFAP was increased in solitary nucleus, paratrgimenal nucleus and the transition area between nucleus caudalis and nucleus interpolaris ipsilateral to the injury side; and this increased GFAP staining was not evident in KOR⫺/⫺ mice. Cell proliferation marker BrdU staining was increased in the caudal medulla of the brainstem in the ispilateral side of the injury. These studies using the pIONL model allow us to determine the extent to which KOR mediated glial responses contribute to the allodynia and changes in mouse behavior. Insights derived from this analysis of trigeminal nerve injury may suggest better treatments of trigeminal pain. Supported by: Allan and Phyllis Treuer Endowment for Pain Research
(631) Refer to Oral Paper Session 330
(629) Eugenol for the treatment of neuropathic pain evaluated in a sciatic nerve cuff implantation rat model
(634) Epidural Ngx 424, an ampa-kainate receptor antagonist, produces analgesia in rats after plantar incision
P Vachon, S Gue´nette, A Ross, F Beaudry; Faculty of Veterinary Medicine, St-Hyacinthe, QC, Canada The main purpose of this study was to determine the pharmacokinetics of eugenol in normal rats following a gavage administration and its analgesic properties in a rat model of neuropathic pain. Following eugenol administration (40mg/kg), blood samples (0.3 mL) were taken by jugular venipuncture at 1, 2, 4, 6, 8, and 12 h from male Spague-Dawley rats (n⫽6, BW 300-350g). Following centrifugation plasma was analysed by LC/MS/MS using a new method of derivitization with dansyl chloride. Pharmacokinetic results are : AUCinf 18,210 ng.min/mL, clearance 2 mL/ min/kg, VSS 441 mL/kg and T1/2 73.5 min. Eugenol also appeared to have some enterohepatic recirculation that suggests some build up of the plasma concentration following repeated administrations. PK results suggest that eugenol is bioavailable and that it could distribute to the central nervous system (high VSS and known lipophilicity). Since eugenol is a capsaicine-like molecule and that vanilloid receptors are known to play a role in neuropathic pain, a second study was performed. Male Spague-Dawley rats (n⫽12, BW 300-350g) were used. Pain perception was evaluated using thermal sensitivity (Hargreaves test) to determine the level of hyperalgesia. Reaction time was from the onset of the light beam to the lifting of the rat’s posterior paw. Following 5 days of behavioral testing rats were implanted with a PE-50 cuff around the sciatic nerve to induce neuropathic pain. Tests were performed for 5 days to determine the level of hyperalgesia in all animals. Following this period, one group (n⫽6) received a daily dose of eugenol (40mg/kg) and the other group served as a control. Statistical evaluations (repeated linear model) reveal a significant increase and progressive tolerance to thermal stimulation after 5 days of eugenol treatments (p⬍0,005) compared to controls. Eugenol could therefore be used for neuropathic pain as suggested from results with sciatic nerve cuff-implanted Sprague-Dawley rats.
H Jin, T Brennan; School of Medicine, Iowa City, IA Excitatory amino acid receptors are important for sensory transmission in the spinal cord. We studied the analgesic effects of epidural administration of NGX424, a competitive non-methyl-D-aspartate (nonNMDA) ionotropic excitatory amino acid (EAA) receptor antagonist, in normal rats and in rats after hindpaw incision. After institutional approval, rats were acclimated to testing for withdrawal to radiant heat applied to the hindpaw. Then using halothane anesthesia, PE10 catheters were inserted into the lumbar epidural space using a small lumbar incision. The next day, a baseline behavioral test (nonevoked guarding pain, heat withdrawal latency, mechanical withdrawal threshold) was performed. Rats were administered NGX424 72 nmoles or the vehicle solution 5% dextrose. Drug was injected and rats were tested for the next hour. Motor function was evaluated by placing reflex and ambulation. On postoperative day 1, NGX decreased the median guarding pain score from 8 to 0 (P⬍0.05). Vehicle had no effect; guarding was 10 before injection and 9 afterwards. In another group, NGX increased the median withdrawal threshold from 44 mN to 114 mN (P⬍0.05); vehicle had no effect (28 mN before and 28 mN after injection). Epidural NGX increased the withdrawal latency from 5 ⫾ 1 to 9 ⫾ 3 sec (P⬍0.05) whereas vehicle again had no effect (5 ⫾ 1 to 5 ⫾ 1 sec ). The median placing and ambulation after NGX were not different compared to vehicle. Drugs like NGX424 that block non-NMDA ionotropic EAA receptors may be an alternative to local anesthetics and morphine for epidural analgesia in humans after surgery.
(632) Refer to Oral Paper Session 330
B02 - Animal Pain Models: Other (633) Pain suppression following NMDA receptor activation in the rostral anterior cingulated cortex of rats CA Greer; Wayne State University, Detroit, MI Society for Neuroscience abstract
S15
(628) Kappa opioid mediation in a new murine model for neuropathic injury to trigeminal nerve
(630) Refer to Oral Paper Session 330
M Xu, MR Byers, L Gendron, C Chavkin; Departments of Pharmacology and Anesthesiology, University of Washington, Seattle Trigeminal nerve damage can lead to neuropathic pain including trigeminal neuralgia, a severely debilitating chronic pain syndrome. We have devised a mouse model of trigeminal neuralgia using a partial ligation of the infraorbital nerve (pIONL) that induces persistent pain behaviors and morphological changes in brainstem. This novel model will allow determination of the basic mechanisms underlying trigeminal neuropathy using genetically engineered mice. Previous studies showed that the endogenous opioid dynorphin is released following nerve injury-induced neuropathic pain, and we found that sustained dynorphin release stimulated kappa opioid receptors (KOR) to cause astroglial proliferation in mouse spinal cord after sciatic injury. Using the pIONL model, we performed behavioral analyses to test the kinetics of the allodynic pain response. We found that mice developed mechanical allodynia lasted for over 4 weeks, and KOR⫺/⫺ mice showed significantly more allodynia than WT mice; the expression of the glial cell marker GFAP was increased in solitary nucleus, paratrgimenal nucleus and the transition area between nucleus caudalis and nucleus interpolaris ipsilateral to the injury side; and this increased GFAP staining was not evident in KOR⫺/⫺ mice. Cell proliferation marker BrdU staining was increased in the caudal medulla of the brainstem in the ispilateral side of the injury. These studies using the pIONL model allow us to determine the extent to which KOR mediated glial responses contribute to the allodynia and changes in mouse behavior. Insights derived from this analysis of trigeminal nerve injury may suggest better treatments of trigeminal pain. Supported by: Allan and Phyllis Treuer Endowment for Pain Research
(631) Refer to Oral Paper Session 330
(629) Eugenol for the treatment of neuropathic pain evaluated in a sciatic nerve cuff implantation rat model
(634) Epidural Ngx 424, an ampa-kainate receptor antagonist, produces analgesia in rats after plantar incision
P Vachon, S Gue´nette, A Ross, F Beaudry; Faculty of Veterinary Medicine, St-Hyacinthe, QC, Canada The main purpose of this study was to determine the pharmacokinetics of eugenol in normal rats following a gavage administration and its analgesic properties in a rat model of neuropathic pain. Following eugenol administration (40mg/kg), blood samples (0.3 mL) were taken by jugular venipuncture at 1, 2, 4, 6, 8, and 12 h from male Spague-Dawley rats (n⫽6, BW 300-350g). Following centrifugation plasma was analysed by LC/MS/MS using a new method of derivitization with dansyl chloride. Pharmacokinetic results are : AUCinf 18,210 ng.min/mL, clearance 2 mL/ min/kg, VSS 441 mL/kg and T1/2 73.5 min. Eugenol also appeared to have some enterohepatic recirculation that suggests some build up of the plasma concentration following repeated administrations. PK results suggest that eugenol is bioavailable and that it could distribute to the central nervous system (high VSS and known lipophilicity). Since eugenol is a capsaicine-like molecule and that vanilloid receptors are known to play a role in neuropathic pain, a second study was performed. Male Spague-Dawley rats (n⫽12, BW 300-350g) were used. Pain perception was evaluated using thermal sensitivity (Hargreaves test) to determine the level of hyperalgesia. Reaction time was from the onset of the light beam to the lifting of the rat’s posterior paw. Following 5 days of behavioral testing rats were implanted with a PE-50 cuff around the sciatic nerve to induce neuropathic pain. Tests were performed for 5 days to determine the level of hyperalgesia in all animals. Following this period, one group (n⫽6) received a daily dose of eugenol (40mg/kg) and the other group served as a control. Statistical evaluations (repeated linear model) reveal a significant increase and progressive tolerance to thermal stimulation after 5 days of eugenol treatments (p⬍0,005) compared to controls. Eugenol could therefore be used for neuropathic pain as suggested from results with sciatic nerve cuff-implanted Sprague-Dawley rats.
H Jin, T Brennan; School of Medicine, Iowa City, IA Excitatory amino acid receptors are important for sensory transmission in the spinal cord. We studied the analgesic effects of epidural administration of NGX424, a competitive non-methyl-D-aspartate (nonNMDA) ionotropic excitatory amino acid (EAA) receptor antagonist, in normal rats and in rats after hindpaw incision. After institutional approval, rats were acclimated to testing for withdrawal to radiant heat applied to the hindpaw. Then using halothane anesthesia, PE10 catheters were inserted into the lumbar epidural space using a small lumbar incision. The next day, a baseline behavioral test (nonevoked guarding pain, heat withdrawal latency, mechanical withdrawal threshold) was performed. Rats were administered NGX424 72 nmoles or the vehicle solution 5% dextrose. Drug was injected and rats were tested for the next hour. Motor function was evaluated by placing reflex and ambulation. On postoperative day 1, NGX decreased the median guarding pain score from 8 to 0 (P⬍0.05). Vehicle had no effect; guarding was 10 before injection and 9 afterwards. In another group, NGX increased the median withdrawal threshold from 44 mN to 114 mN (P⬍0.05); vehicle had no effect (28 mN before and 28 mN after injection). Epidural NGX increased the withdrawal latency from 5 ⫾ 1 to 9 ⫾ 3 sec (P⬍0.05) whereas vehicle again had no effect (5 ⫾ 1 to 5 ⫾ 1 sec ). The median placing and ambulation after NGX were not different compared to vehicle. Drugs like NGX424 that block non-NMDA ionotropic EAA receptors may be an alternative to local anesthetics and morphine for epidural analgesia in humans after surgery.
(632) Refer to Oral Paper Session 330
B02 - Animal Pain Models: Other (633) Pain suppression following NMDA receptor activation in the rostral anterior cingulated cortex of rats CA Greer; Wayne State University, Detroit, MI Society for Neuroscience abstract