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Animal pain models
Abstracts (629) Neurochemical changes in the RVM associated with a peripheral inflammatory pain stimulus V. Smith, C. Beyer, M. Brandt; Wyeth Research, Princeton, NJ The purpose of the current study was to investigate neurochemical changes in the rostral ventromedial medulla (RVM) following a peripheral inflammatory pain stimulus in rats. In vivo microdialysis probes were surgically implanted into the RVM. Baseline neurochemical samples were collected every 20-min, after which baseline thermal sensitivity was assessed. After neurochemical and behavioral baselines were established, a dose of 0.1 mg of prostaglandin E2 (PGE2 ) was then injected (0.05 ml) into the left hind footpad and thermal hypersensitivity was assessed every 20-min starting 10-min after PGE2 injection; microdialysate was drawn every 20-min starting 20-min after PGE2 injection. PGE2 produced maximal thermal hypersensitivity 10-min after administration, which correlated with a 230% increase of extracellular serotonin levels in the RVM. Thermal hypersensitivity persisted even though serotonin levels decreased. In contrast, norepinephrine, dopamine, GABA and glutamate levels were not significantly changed from baseline over the course of the study. A dose of morphine (5.6 mg/kg; IP) that attenuated PGE2-induced thermal hypersensitivity also attenuated the increase of serotonin in the RVM. In contrast, morphine did not modify other neurochemicals. The results of the present study show that increases in serotonin correlate with the initiation of thermal hypersensitive but not the maintenance of peripheral inflammatory pain. Additionally, the current study demonstrates that the combination of behavioral endpoints with microdialysis could lead to important insights related to pain circuitry and novel target identification.
(630) The effect of diet on the development of chronic neuropathic sensory disorders in three models of partial sciatic nerve injury J. Pe´ rez, M. Ware, G. Bennett, Y. Shir; Pain Centre and Anesthesia Research Unit, McGill University Health Centre, Montreal, QC Diet is a significant predictor for levels of chronic neuropathic sensory disorders (CNSD) in rats undergoing a partial sciatic nerve ligation injury (the PSL model). We have shown that this dietary effect depends on both the protein and fat content of the diet (see our adjacent abstract). Although similar chronic behavioral signs of both spontaneous and evoked pain are seen with different models of surgically-induced neuropathic pain, it has been suggested that these models might differ in their pathophysiological basis. For example, the local inflammatory component of the chronic constriction injury (CCI model) could play a more central role in the development of CNSD(Maves TJ, et al, Pain 54;57-69:1993), compared with the spinal nerve ligation (SNL) and the PSL models. The aim was to compare the effect of diet on CNSD in different models of surgically-induced neuropathic pain. Two different diets were tested in three models of partial nerve injury (PSL, CCI, SNL). These diets differed in their protein and their fat source (soy protein/ corn oil vs. albumin protein/canola oil). These diets have been chosen since they were associated with significantly different levels of CNSD in the PSL model. Rats were fed the two experimental diets a week before surgery and 2 weeks thereafter, and tactile and heat pain thresholds were tested on days 3, 7 and 14 postoperative. All rats developed significant tactile allodynia and heat hyperalgesia following the different surgeries. Feeding rats with the soy/corn diet was significantly associated, however, with suppressed CNSD levels in PSL, but not CCI and SNL-injured rats. CCI and SNL-injured rats might share some similar pathophysiological characteristics, making them less susceptible to the effect of diet.
17 (631) Electrophysiological and morphological studies on the effect of antibodies to TGF-1 and TGF-2 at a site of sciatic nerve repair P. Robinson, K. Smith, A. Loescher, F. Boissonade, S. Atkins, M. Ferguson; University of Sheffield, Sheffield Scar formation at a site of nerve injury can cause a mechanical barrier to axonal regeneration and lead to the development multiple axon sprouts to form a neuroma. We have evaluated the hypothesis that the application of a scar-preventing agent to a nerve repair site would enhance regeneration and reduce neuroma formation. The left sciatic nerve was exposed under general anaesthesia (Fentanyl/Fluanisone 0.8ml/kg & Midazolam 4mg/kg, i.p. Janissen/Roche) in 18 adult Sprague-Dawley rats. In 12 animals the nerve was sectioned and immediately re-approximated using 4 epineurial sutures, and in 6 of these neutralising antibodies to TGF-1 & TGF-2 (100g of each in 100l PBS, R & D systems) were injected into and around the proximal and distal nerve stumps. The 6 other animals acted as controls. After 7 weeks the extent of regeneration was assessed by determining the ratio of the compound action potential (CAP) modulus evoked by electrical stimulation of the nerve 2mm distal or proximal to the repair site, and by counting the number of myelinated axons at the same sites. After administration of antibodies CAP ratios were significantly smaller than in controls (Mann-Whitney U test, p⬍0.01), but not after repair alone. In both nerve injury groups the myelinated fibre counts were significantly increased distal to the injury site (Mann-Whitney U test, p⬍0.05), but there was no difference between these two groups. We conclude that administration of antibodies did not enhance regeneration or reduce the development of multiple axonal sprouts at the repair site. Supported by the Wellcome Trust.
(632) Sensitivity of plantar vs dorsal stimulation in measuring analgesic effect of high and low efficacy analgesics R. Soignier, P. Nolan, D. Paul, H. Gould; Louisiana State University Health Sciences Center, New Orleans, LA We have recently proposed that mechanical nociception resulting from an intraplantar injection of complete Freund’s adjuvant (CFA) is best measured with an ElectroVonFrey anesthesiometer when the stimulus is delivered to the dorsal surface of the paw. In order to determine the sensitivity of dorsal stimulation in identifying an analgesic effect of specific drug treatments, we compared mechanical hypersensitivity differences in CFA-induced hyperalgesia in rats treated with a low efficacy analgesic (ibuprofen) and a high efficacy analgesic (morphine) using both plantar and dorsal stimulation. For this, mechanical stimulation was administered perpendicular to either the dorsal or the plantar surface of the hindpaws with an IITC ElectroVonFrey anesthesiometer in rats that had been treated with either morphine (10 mg/kg), ibuprofen (100mg/kg), or vehicle prior to receiving a subcutaneous injection of CFA into the hindpaw. Prior to CFA injection, dorsal stimulation, unlike plantar stimulation, produced a consistent aversive withdrawal response thus providing a more accurate measure of the nociceptive threshold. After CFA, an analgesic effect was observed both for ibuprofen and morphine, but only when the injected paws were stimulated from the dorsal surface. We conclude that stimulation of the dorsal surface provides a more sensitive measure of analgesic effect. Supported LA Board of Regents HEF 2000-05-07.
(630) The effect of diet on the development of chronic neuropathic sensory disorders in three models of partial sciatic nerve injury J. Pe´ rez, M. Ware, G. Bennett, Y. Shir; Pain Centre and Anesthesia Research Unit, McGill University Health Centre, Montreal, QC Diet is a significant predictor for levels of chronic neuropathic sensory disorders (CNSD) in rats undergoing a partial sciatic nerve ligation injury (the PSL model). We have shown that this dietary effect depends on both the protein and fat content of the diet (see our adjacent abstract). Although similar chronic behavioral signs of both spontaneous and evoked pain are seen with different models of surgically-induced neuropathic pain, it has been suggested that these models might differ in their pathophysiological basis. For example, the local inflammatory component of the chronic constriction injury (CCI model) could play a more central role in the development of CNSD(Maves TJ, et al, Pain 54;57-69:1993), compared with the spinal nerve ligation (SNL) and the PSL models. The aim was to compare the effect of diet on CNSD in different models of surgically-induced neuropathic pain. Two different diets were tested in three models of partial nerve injury (PSL, CCI, SNL). These diets differed in their protein and their fat source (soy protein/ corn oil vs. albumin protein/canola oil). These diets have been chosen since they were associated with significantly different levels of CNSD in the PSL model. Rats were fed the two experimental diets a week before surgery and 2 weeks thereafter, and tactile and heat pain thresholds were tested on days 3, 7 and 14 postoperative. All rats developed significant tactile allodynia and heat hyperalgesia following the different surgeries. Feeding rats with the soy/corn diet was significantly associated, however, with suppressed CNSD levels in PSL, but not CCI and SNL-injured rats. CCI and SNL-injured rats might share some similar pathophysiological characteristics, making them less susceptible to the effect of diet.
17 (631) Electrophysiological and morphological studies on the effect of antibodies to TGF-1 and TGF-2 at a site of sciatic nerve repair P. Robinson, K. Smith, A. Loescher, F. Boissonade, S. Atkins, M. Ferguson; University of Sheffield, Sheffield Scar formation at a site of nerve injury can cause a mechanical barrier to axonal regeneration and lead to the development multiple axon sprouts to form a neuroma. We have evaluated the hypothesis that the application of a scar-preventing agent to a nerve repair site would enhance regeneration and reduce neuroma formation. The left sciatic nerve was exposed under general anaesthesia (Fentanyl/Fluanisone 0.8ml/kg & Midazolam 4mg/kg, i.p. Janissen/Roche) in 18 adult Sprague-Dawley rats. In 12 animals the nerve was sectioned and immediately re-approximated using 4 epineurial sutures, and in 6 of these neutralising antibodies to TGF-1 & TGF-2 (100g of each in 100l PBS, R & D systems) were injected into and around the proximal and distal nerve stumps. The 6 other animals acted as controls. After 7 weeks the extent of regeneration was assessed by determining the ratio of the compound action potential (CAP) modulus evoked by electrical stimulation of the nerve 2mm distal or proximal to the repair site, and by counting the number of myelinated axons at the same sites. After administration of antibodies CAP ratios were significantly smaller than in controls (Mann-Whitney U test, p⬍0.01), but not after repair alone. In both nerve injury groups the myelinated fibre counts were significantly increased distal to the injury site (Mann-Whitney U test, p⬍0.05), but there was no difference between these two groups. We conclude that administration of antibodies did not enhance regeneration or reduce the development of multiple axonal sprouts at the repair site. Supported by the Wellcome Trust.
(632) Sensitivity of plantar vs dorsal stimulation in measuring analgesic effect of high and low efficacy analgesics R. Soignier, P. Nolan, D. Paul, H. Gould; Louisiana State University Health Sciences Center, New Orleans, LA We have recently proposed that mechanical nociception resulting from an intraplantar injection of complete Freund’s adjuvant (CFA) is best measured with an ElectroVonFrey anesthesiometer when the stimulus is delivered to the dorsal surface of the paw. In order to determine the sensitivity of dorsal stimulation in identifying an analgesic effect of specific drug treatments, we compared mechanical hypersensitivity differences in CFA-induced hyperalgesia in rats treated with a low efficacy analgesic (ibuprofen) and a high efficacy analgesic (morphine) using both plantar and dorsal stimulation. For this, mechanical stimulation was administered perpendicular to either the dorsal or the plantar surface of the hindpaws with an IITC ElectroVonFrey anesthesiometer in rats that had been treated with either morphine (10 mg/kg), ibuprofen (100mg/kg), or vehicle prior to receiving a subcutaneous injection of CFA into the hindpaw. Prior to CFA injection, dorsal stimulation, unlike plantar stimulation, produced a consistent aversive withdrawal response thus providing a more accurate measure of the nociceptive threshold. After CFA, an analgesic effect was observed both for ibuprofen and morphine, but only when the injected paws were stimulated from the dorsal surface. We conclude that stimulation of the dorsal surface provides a more sensitive measure of analgesic effect. Supported LA Board of Regents HEF 2000-05-07.