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Claire E Hulsebosch - One of the best experts on this subject based on the ideXlab platform.
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Strain and model differences in behavioral outcomes after spinal cord injury in rat.
Journal of Neurotrauma, 2001Co-Authors: Charles D. Mills, Bryan C. Hains, Kathia M. Johnson, Claire E HulseboschAbstract:Spinal cord injury (SCI) results in loss of function below the level of injury and the development of chronic central pain (CCP) syndromes. Since different strains may develop and express chronic pain behaviors differently, we evaluated behavioral outcomes (locomotor recovery and the development of mechanical and Thermal Allodynia) in three commonly used strains of rats (Long-Evans, Wistar, and Sprague-Dawley) using two models of SCI. The two models examined were contusion at T10 (NYU impactor, 12.5 mm height) and the T13 hemisection. Mechanical stimulation (von Frey filaments) revealed significantly lower baseline responses for Long-Evans rats and significantly higher baseline paw withdrawal latencies to Thermal stimulation for Wistar rats compared to the other strains. Following contusion SCI, Long-Evans rats had the highest percentage of animals that developed mechanical Allodynia (73%), while Sprague-Dawley rats had the highest percentages (75%) following hemisection SCI. Interestingly, the Sprague-Dawley rats had the highest percentage (87%) to develop Thermal Allodynia following contusion SCI, while 100% of both Long-Evans and Sprague Dawley rats developed Thermal Allodynia in the hemisection model. Locomotor recovery after SCI was similar for each model in that Long-Evans rats recovered slower and to a lesser extent than the other strains. In each model, Sprague-Dawley rats recovered faster and achieved greater function. Overall, the hemisection model produced a larger percentage of animals that developed CCP and had greater responses to mechanical stimulation. Thus, it appears that strain selection has a greater impact on locomotor recovery and model selection has a greater impact on the development of CCP following SCI. Furthermore, these results suggest that genetic factors may play a role in recovery following SCI.
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AIDA reduces glutamate release and attenuates mechanical Allodynia after spinal cord injury.
Neuroreport, 2000Co-Authors: Charles D. Mills, Kathia M. Johnson, David J Mcadoo, Claire E HulseboschAbstract:Spinal cord injury (SCI) leads to an increase in extracellular excitatory amino acid (EAA) concentrations, resulting in glutamate receptor-mediated excitotoxicity and central sensitization. To test contributions of group I metabotropic glutamate receptors (mGluRs) in SCI induced release of glutamate and in behavioral outcomes of central sensitization following injury, we administered 1-aminoindan-1,5-dicarboxylic acid (AIDA; 0.1 nmol intraspinally), a potent group I mGluR antagonist, to rats immediately after spinal cord contusion injury. EAAs were collected by microdialysis and quantified using HPLC. AIDA significantly decreased extracellular glutamate but not aspartate concentrations and significantly attenuated the development of mechanical but not Thermal Allodynia. These results suggest mGluRs play an important role in injury-induced EAA release and in central sensitization following SCI.
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transplants of adrenal medullary chromaffin cells reduce forelimb and hindlimb Allodynia in a rodent model of chronic central pain after spinal cord hemisection injury
Experimental Neurology, 2000Co-Authors: Bryan C. Hains, Kathy M Chastain, Alex W Everhart, David J Mcadoo, Claire E HulseboschAbstract:Abstract In the majority of patients, spinal cord injury (SCI) results in abnormal pain syndromes in which nonnoxious stimuli become noxious (Allodynia). To reduce Allodynia, it would be desirable to implant a permanent biological pump such as adrenal medullary chromaffin cells (AM), which secrete catecholamines and opioid peptides, both antinociceptive substances, near the spinal cord. We tested this approach using a recently developed a mammalian SCI model of chronic central pain, which results in development of mechanical and Thermal Allodynia. Thirty day-old male Sprague–Dawley rats were spinally hemisected at T13 and allowed 4 weeks for recovery of locomotor function and development of Allodynia. Nonimmunosuppressed injured animals received either control-striated muscle (n = 7) or AM (n = 10) transplants. Nociceptive behavior was tested for 4 weeks posttransplant as measured by paw withdrawals to von Frey filaments, radiant heat, and pin prick stimuli. Hemisected animals receiving AM demonstrated statistically significant reductions in both fore- and hindlimb mechanical and Thermal Allodynia, but not analgesia, when compared to hemisected animals receiving striated muscle transplants (P
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alleviation of mechanical and Thermal Allodynia by cgrp8 37 in a rodent model of chronic central pain
Pain, 2000Co-Authors: Adrianne D Bennett, Kathy M Chastain, Claire E HulseboschAbstract:CGRP8-37 is a truncated version of calcitonin gene-related peptide (CGRP) that binds to the CGRP receptor with similar affinity but does not activate the receptor and is a highly selective CGRP receptor antagonist. CGRP and activation of its receptor appear to play a role in peripheral inflammatory and neuropathic models of pain although there is considerable controversy. The aim of this study was to examine possible anti-nociceptive effects of CGRP8-37 on a model of chronic central neuropathic pain known to develop weeks after spinal hemisection. Adult male Sprague–Dawley rats were given a spinal hemisection (N=34) or a sham surgery (N=10) at the T13 spinal segment. An externally accessible PE-10 intrathecal catheter that terminated at T13 was used for drug delivery. Animals were allowed to recover for 4 weeks at which time the hemisected animals displayed mechanical and Thermal Allodynia bilaterally, in both forelimbs and hindlimbs. CGRP8-37 was delivered just prior to a testing session in 1, 5, 10, or 50 nM doses in artificial cerebral spinal fluid in 10 μl volumes. CGRP8-37 was effective in alleviating mechanical and Thermal Allodynia in a dose-dependent manner (P<0.05). The 50 nM dose was most efficacious for both forelimb and hindlimb responses (P<0.05). The period of efficacy was 10 min to onset for a duration of 20 min. Post-drug washout responses were not statistically significant compared to pre-drug responses. The sham control groups demonstrated no statistically significant difference at any dose of CGRP8-37 when compared to pre-surgical baseline values. In conclusion, CGRP8-37 is effective in abolishing mechanical and Thermal Allodynia produced by spinal hemisection. Consequently, the CGRP receptor may play a role in chronic central neuropathic pain and offers a novel therapeutic approach to managing chronic central pain.
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Alleviation of mechanical and Thermal Allodynia by CGRP8-37 in a rodent model of chronic central pain
Pain, 2000Co-Authors: Adrianne D Bennett, Kathy M Chastain, Claire E HulseboschAbstract:CGRP8-37 is a truncated version of calcitonin gene-related peptide (CGRP) that binds to the CGRP receptor with similar affinity but does not activate the receptor and is a highly selective CGRP receptor antagonist. CGRP and activation of its receptor appear to play a role in peripheral inflammatory and neuropathic models of pain although there is considerable controversy. The aim of this study was to examine possible anti-nociceptive effects of CGRP8-37 on a model of chronic central neuropathic pain known to develop weeks after spinal hemisection. Adult male Sprague–Dawley rats were given a spinal hemisection (N=34) or a sham surgery (N=10) at the T13 spinal segment. An externally accessible PE-10 intrathecal catheter that terminated at T13 was used for drug delivery. Animals were allowed to recover for 4 weeks at which time the hemisected animals displayed mechanical and Thermal Allodynia bilaterally, in both forelimbs and hindlimbs. CGRP8-37 was delivered just prior to a testing session in 1, 5, 10, or 50 nM doses in artificial cerebral spinal fluid in 10 μl volumes. CGRP8-37 was effective in alleviating mechanical and Thermal Allodynia in a dose-dependent manner (P
Alex W Everhart - One of the best experts on this subject based on the ideXlab platform.
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transplants of adrenal medullary chromaffin cells reduce forelimb and hindlimb Allodynia in a rodent model of chronic central pain after spinal cord hemisection injury
Experimental Neurology, 2000Co-Authors: Bryan C. Hains, Kathy M Chastain, Alex W Everhart, David J Mcadoo, Claire E HulseboschAbstract:Abstract In the majority of patients, spinal cord injury (SCI) results in abnormal pain syndromes in which nonnoxious stimuli become noxious (Allodynia). To reduce Allodynia, it would be desirable to implant a permanent biological pump such as adrenal medullary chromaffin cells (AM), which secrete catecholamines and opioid peptides, both antinociceptive substances, near the spinal cord. We tested this approach using a recently developed a mammalian SCI model of chronic central pain, which results in development of mechanical and Thermal Allodynia. Thirty day-old male Sprague–Dawley rats were spinally hemisected at T13 and allowed 4 weeks for recovery of locomotor function and development of Allodynia. Nonimmunosuppressed injured animals received either control-striated muscle (n = 7) or AM (n = 10) transplants. Nociceptive behavior was tested for 4 weeks posttransplant as measured by paw withdrawals to von Frey filaments, radiant heat, and pin prick stimuli. Hemisected animals receiving AM demonstrated statistically significant reductions in both fore- and hindlimb mechanical and Thermal Allodynia, but not analgesia, when compared to hemisected animals receiving striated muscle transplants (P
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intrathecal administration of an nmda or a non nmda receptor antagonist reduces mechanical but not Thermal Allodynia in a rodent model of chronic central pain after spinal cord injury
Brain Research, 2000Co-Authors: Adrianne D Bennett, Alex W Everhart, Claire E HulseboschAbstract:Spinal cord injuries (SCI) result in a devastating loss of function and chronic central pain syndromes frequently develop in the majority of these patients. The present study uses a rodent spinal hemisection model of SCI in which mechanical and Thermal Allodynia develops by 24 days after injury. Post-operative paw withdrawal responses to low threshold and high threshold mechanical stimuli compared to pre-operative responses (4.78, 9.96, and 49.9 mN) were increased and were statistically significant (p<0.05) for both forelimbs and hindlimbs indicating the development of mechanical Allodynia. By contrast, post-operatively, the temperature at which paw withdrawal accompanied by paw lick occurred was significantly decreased (p<0.05), indicating the development of Thermal Allodynia. The intrathecal application of either D-AP5, a competitive NMDA receptor antagonist, or NBQX-disodium salt, a competitive non-NMDA AMPA/kainate receptor antagonist, alleviated the mechanical Allodynia and lowered the threshold of response for the high threshold mechanical stimuli in a dose-dependent manner, and these decreases were statistically significant (p<0.05). By contrast, neither the D-AP5 nor the NBQX produced a statistically significant change in the Thermal Allodynia behavior in either forelimbs or hindlimbs in the hemisected group. No significant changes in locomotion scores, and thus no sedation, were demonstrated by the hemisected group for the doses tested. These data support the potential efficacy of competitive excitatory amino acid receptor antagonists in the treatment of chronic central pain, particularly where input from low threshold mechanical afferents trigger the onset of the painful sensation. Furthermore, these data suggest a role for both NMDA and non-NMDA receptors in the development of plastic changes in the spinal cord that provide the underlying mechanisms for central neuropathic pain.
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Intrathecal administration of an NMDA or a non-NMDA receptor antagonist reduces mechanical but not Thermal Allodynia in a rodent model of chronic central pain after spinal cord injury.
Brain Research, 2000Co-Authors: Adrianne D Bennett, Alex W Everhart, Claire E HulseboschAbstract:Spinal cord injuries (SCI) result in a devastating loss of function and chronic central pain syndromes frequently develop in the majority of these patients. The present study uses a rodent spinal hemisection model of SCI in which mechanical and Thermal Allodynia develops by 24 days after injury. Post-operative paw withdrawal responses to low threshold and high threshold mechanical stimuli compared to pre-operative responses (4.78, 9.96, and 49.9 mN) were increased and were statistically significant (p
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Mechanical and Thermal Allodynia in chronic central pain following spinal cord injury
Pain, 1996Co-Authors: Marc D. Christensen, Alex W Everhart, Jason T Pickelman, Claire E HulseboschAbstract:Spinal cord injury (SCI) results in variable motor recoveries and chronic central pain syndromes develop in the majority of SCI patients. To provide a basis for further studies, we report a new rodent model of chronic central pain following spinal cord trauma. Male Sprague-Dawley rats (N = 10) were hemisectioned at T13 and were tested both preoperatively and postoperatively and compared to sham-operated controls (N = 10) for locomotor function, and mechanical and Thermal thresholds of both paw withdrawal and supraspinal responses. Results support the development and persistence of Allodynia which persists for 160 days. Locomotor function was tested using the Basso, Beattie and Bresnahan (BBB) open field test and only the limb ipsilateral to the hemisection was affected, demonstrating acute flaccid paralysis with motor recovery which approached normal values by postoperative day (POD) 15. Prior to the hemisection, the rats showed little to no paw withdrawal response to von Frey stimulation of 4.41 mN or 9.41 mN in both forelimbs and hindlimbs. Postoperatively, responses in both ipsilateral and contralateral forelimbs and hindlimbs increased over time and the increase was statistically significant compared to intra-animal presurgical and sham control values (P < 0.05). There were no significant side-to-side differences in limb responses preoperatively or beyond POD 15. The forelimbs and hindlimbs responded to von Frey hair strengths of 122 mN preoperatively and postoperatively with similar withdrawal frequencies that were not statistically significant. Preoperatively, the paw withdrawal latency to heat stimuli was 22.9 ± 3.0 (mean ± SE) and 20.1 ± 3.1 sec for the hindlimbs and forelimbs, respectively. Postoperatively, the mean hindlimb and forelimb latency of paw withdrawals decreased to 11.9 ± 1.8 and 9.2 ± 2.5 sec, respectively. This decrease in Thermal thresholds is statistically significant when compared to intra-animal preoperative and sham control values (P < 0.05). These data indicate that somatosensory thresholds for non-noxious mechanical and radiant heat which elicit paw withdrawal (flexor reflex) are significantly lowered following SCI. To further support the development and persistence of chronic pain following hemisection, supraspinal responses such as paw lick, head turns, attacking the stimulus, and vocalizations were elicited in response to mechanical and Thermal stimuli and were statistically significant compared to presurgical intra-animal or sham control values (P < 0.05). Hemisected animals vocalized to von Frey hair bending forces of 49.8 with a mean of 6.0 ± 1.2 times out of 10 stimuli compared to intra-animal presurgical and sham control values of zero. Supraspinal responses of hemisected animals to Thermal stimuli occurred at lower temperatures that were statistically significant compared to sham control or preoperative values (P < 0.05). These chronic changes in thresholds to both mechanical and Thermal stimuli represent the development and persistence of mechanical and Thermal Allodynia after SCI.
James H. Woods - One of the best experts on this subject based on the ideXlab platform.
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local inhibitory effects of dynorphin a 1 17 on capsaicin induced Thermal Allodynia in rhesus monkeys
European Journal of Pharmacology, 2000Co-Authors: K.j. Willmont, Andrew Burritt, Victor J. Hruby, James H. WoodsAbstract:Although dynorphin A-(1–17) has been characterized in vitro as a high efficacy κ-opioid receptor agonist, functional studies of dynorphin A-(1–17) following central or systemic administration indicate the involvement of both opioid and non-opioid components. The aim of this study was to investigate whether local administration of dynorphin-related analogs can attenuate capsaicin (8-methyl-N-vanillyl-6-nonenamide)-induced nociception and what type of opioid receptor mediates the local action of dynorphin A-(1–17) in monkeys. Capsaicin (100 μg) was used to evoke a nociceptive response, Thermal Allodynia, which was manifested as a reduced tail-withdrawal latency in normally innocuous 46°C warm water. Co-administration of dynorphin A-(1–17) (0.3–10 μg) with capsaicin in the tail dose-dependently inhibited Thermal Allodynia; however, both non-opioid fragments dynorphin A-(2–17) (10–300 μg) and dynorphin A-(2–13) (10–300 μg) were ineffective. Local antiAllodynia of dynorphin A-(1–17) was antagonized by a small dose (100 μg) of an opioid receptor antagonist, quadazocine, applied s.c. in the tail. Pretreatment with a selective κ-opioid receptor antagonist, nor-binaltorphimine (nor-BNI), s.c. 320 μg in the tail also reversed local antiAllodynia of dynorphin A-(1–17). Both locally effective doses of antagonists, when applied s.c. in the back, did not antagonize local dynorphin A-(1–17), indicating that peripheral κ-opioid receptors selectively mediated the local action of dynorphin A-(1–17) in the tail. In addition, a much larger dose of dynorphin A-(1–17) (1000 μg), when administered s.c. in the back or i.m. in the thigh, did not cause sedative or diuretic effects. These results suggest that in vivo opioid actions of dynorphin-related peptides can be differentiated locally in this procedure. They also indicate that local application of peptidic ligands may be a useful medication for localized pain.
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Local inhibitory effects of dynorphin A-(1–17) on capsaicin-induced Thermal Allodynia in rhesus monkeys
European Journal of Pharmacology, 2000Co-Authors: K.j. Willmont, Andrew Burritt, Victor J. Hruby, James H. WoodsAbstract:Although dynorphin A-(1–17) has been characterized in vitro as a high efficacy κ-opioid receptor agonist, functional studies of dynorphin A-(1–17) following central or systemic administration indicate the involvement of both opioid and non-opioid components. The aim of this study was to investigate whether local administration of dynorphin-related analogs can attenuate capsaicin (8-methyl-N-vanillyl-6-nonenamide)-induced nociception and what type of opioid receptor mediates the local action of dynorphin A-(1–17) in monkeys. Capsaicin (100 μg) was used to evoke a nociceptive response, Thermal Allodynia, which was manifested as a reduced tail-withdrawal latency in normally innocuous 46°C warm water. Co-administration of dynorphin A-(1–17) (0.3–10 μg) with capsaicin in the tail dose-dependently inhibited Thermal Allodynia; however, both non-opioid fragments dynorphin A-(2–17) (10–300 μg) and dynorphin A-(2–13) (10–300 μg) were ineffective. Local antiAllodynia of dynorphin A-(1–17) was antagonized by a small dose (100 μg) of an opioid receptor antagonist, quadazocine, applied s.c. in the tail. Pretreatment with a selective κ-opioid receptor antagonist, nor-binaltorphimine (nor-BNI), s.c. 320 μg in the tail also reversed local antiAllodynia of dynorphin A-(1–17). Both locally effective doses of antagonists, when applied s.c. in the back, did not antagonize local dynorphin A-(1–17), indicating that peripheral κ-opioid receptors selectively mediated the local action of dynorphin A-(1–17) in the tail. In addition, a much larger dose of dynorphin A-(1–17) (1000 μg), when administered s.c. in the back or i.m. in the thigh, did not cause sedative or diuretic effects. These results suggest that in vivo opioid actions of dynorphin-related peptides can be differentiated locally in this procedure. They also indicate that local application of peptidic ligands may be a useful medication for localized pain.
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BW373U86, a δ-opioid receptor agonist, reverses bradykinin-induced Thermal Allodynia in rhesus monkeys
European Journal of Pharmacology, 1995Co-Authors: Eduardo R. Butelman, S. Stevens Negus, Michael B. Gatch, Kwen Jen Chang, James H. WoodsAbstract:Abstract The synthetic δ-opioid receptor agonist BW373U86 (0.18–0.56 mg/kg s.c.) was studied in rhesus monkeys with a warm-water, tail-withdrawal assay, designed to detect bradykinin (0.1 μg) and prostaglandin E 2 (5–15.8 μg)-induced Thermal Allodynia. BW373U86 dose-dependently reversed bradykinin Allodynia, but was ineffective against prostaglandin E 2 Allodynia. The BW373U86 dose-effect curve was shifted to the right by the δ-opioid receptor-selective antagonist naltrindole (1.0 mg/kg) but not by the μ-opioid receptor-selective antagonist quadazocine (0.1 mg/kg). The present findings add to the conditions in which δ-opioid receptor-mediated behavioral effects have been detected in primates, and suggest that δ-opioid agonists may be of therapeutic interest in the treatment of some types of hyperalgesic conditions.
Adrianne D Bennett - One of the best experts on this subject based on the ideXlab platform.
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alleviation of mechanical and Thermal Allodynia by cgrp8 37 in a rodent model of chronic central pain
Pain, 2000Co-Authors: Adrianne D Bennett, Kathy M Chastain, Claire E HulseboschAbstract:CGRP8-37 is a truncated version of calcitonin gene-related peptide (CGRP) that binds to the CGRP receptor with similar affinity but does not activate the receptor and is a highly selective CGRP receptor antagonist. CGRP and activation of its receptor appear to play a role in peripheral inflammatory and neuropathic models of pain although there is considerable controversy. The aim of this study was to examine possible anti-nociceptive effects of CGRP8-37 on a model of chronic central neuropathic pain known to develop weeks after spinal hemisection. Adult male Sprague–Dawley rats were given a spinal hemisection (N=34) or a sham surgery (N=10) at the T13 spinal segment. An externally accessible PE-10 intrathecal catheter that terminated at T13 was used for drug delivery. Animals were allowed to recover for 4 weeks at which time the hemisected animals displayed mechanical and Thermal Allodynia bilaterally, in both forelimbs and hindlimbs. CGRP8-37 was delivered just prior to a testing session in 1, 5, 10, or 50 nM doses in artificial cerebral spinal fluid in 10 μl volumes. CGRP8-37 was effective in alleviating mechanical and Thermal Allodynia in a dose-dependent manner (P<0.05). The 50 nM dose was most efficacious for both forelimb and hindlimb responses (P<0.05). The period of efficacy was 10 min to onset for a duration of 20 min. Post-drug washout responses were not statistically significant compared to pre-drug responses. The sham control groups demonstrated no statistically significant difference at any dose of CGRP8-37 when compared to pre-surgical baseline values. In conclusion, CGRP8-37 is effective in abolishing mechanical and Thermal Allodynia produced by spinal hemisection. Consequently, the CGRP receptor may play a role in chronic central neuropathic pain and offers a novel therapeutic approach to managing chronic central pain.
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Alleviation of mechanical and Thermal Allodynia by CGRP8-37 in a rodent model of chronic central pain
Pain, 2000Co-Authors: Adrianne D Bennett, Kathy M Chastain, Claire E HulseboschAbstract:CGRP8-37 is a truncated version of calcitonin gene-related peptide (CGRP) that binds to the CGRP receptor with similar affinity but does not activate the receptor and is a highly selective CGRP receptor antagonist. CGRP and activation of its receptor appear to play a role in peripheral inflammatory and neuropathic models of pain although there is considerable controversy. The aim of this study was to examine possible anti-nociceptive effects of CGRP8-37 on a model of chronic central neuropathic pain known to develop weeks after spinal hemisection. Adult male Sprague–Dawley rats were given a spinal hemisection (N=34) or a sham surgery (N=10) at the T13 spinal segment. An externally accessible PE-10 intrathecal catheter that terminated at T13 was used for drug delivery. Animals were allowed to recover for 4 weeks at which time the hemisected animals displayed mechanical and Thermal Allodynia bilaterally, in both forelimbs and hindlimbs. CGRP8-37 was delivered just prior to a testing session in 1, 5, 10, or 50 nM doses in artificial cerebral spinal fluid in 10 μl volumes. CGRP8-37 was effective in alleviating mechanical and Thermal Allodynia in a dose-dependent manner (P
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intrathecal administration of an nmda or a non nmda receptor antagonist reduces mechanical but not Thermal Allodynia in a rodent model of chronic central pain after spinal cord injury
Brain Research, 2000Co-Authors: Adrianne D Bennett, Alex W Everhart, Claire E HulseboschAbstract:Spinal cord injuries (SCI) result in a devastating loss of function and chronic central pain syndromes frequently develop in the majority of these patients. The present study uses a rodent spinal hemisection model of SCI in which mechanical and Thermal Allodynia develops by 24 days after injury. Post-operative paw withdrawal responses to low threshold and high threshold mechanical stimuli compared to pre-operative responses (4.78, 9.96, and 49.9 mN) were increased and were statistically significant (p<0.05) for both forelimbs and hindlimbs indicating the development of mechanical Allodynia. By contrast, post-operatively, the temperature at which paw withdrawal accompanied by paw lick occurred was significantly decreased (p<0.05), indicating the development of Thermal Allodynia. The intrathecal application of either D-AP5, a competitive NMDA receptor antagonist, or NBQX-disodium salt, a competitive non-NMDA AMPA/kainate receptor antagonist, alleviated the mechanical Allodynia and lowered the threshold of response for the high threshold mechanical stimuli in a dose-dependent manner, and these decreases were statistically significant (p<0.05). By contrast, neither the D-AP5 nor the NBQX produced a statistically significant change in the Thermal Allodynia behavior in either forelimbs or hindlimbs in the hemisected group. No significant changes in locomotion scores, and thus no sedation, were demonstrated by the hemisected group for the doses tested. These data support the potential efficacy of competitive excitatory amino acid receptor antagonists in the treatment of chronic central pain, particularly where input from low threshold mechanical afferents trigger the onset of the painful sensation. Furthermore, these data suggest a role for both NMDA and non-NMDA receptors in the development of plastic changes in the spinal cord that provide the underlying mechanisms for central neuropathic pain.
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Intrathecal administration of an NMDA or a non-NMDA receptor antagonist reduces mechanical but not Thermal Allodynia in a rodent model of chronic central pain after spinal cord injury.
Brain Research, 2000Co-Authors: Adrianne D Bennett, Alex W Everhart, Claire E HulseboschAbstract:Spinal cord injuries (SCI) result in a devastating loss of function and chronic central pain syndromes frequently develop in the majority of these patients. The present study uses a rodent spinal hemisection model of SCI in which mechanical and Thermal Allodynia develops by 24 days after injury. Post-operative paw withdrawal responses to low threshold and high threshold mechanical stimuli compared to pre-operative responses (4.78, 9.96, and 49.9 mN) were increased and were statistically significant (p
Mary Jeanne Kreek - One of the best experts on this subject based on the ideXlab platform.
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Antiallodynic Effects of Loperamide and Fentanyl against Topical Capsaicin-Induced Allodynia in Unanesthetized Primates
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Eduardo R. Butelman, Todd J. Harris, Mary Jeanne KreekAbstract:Capsaicin produces Thermal Allodynia in animals and humans by acting as an agonist at vanilloid receptor subtype 1 [VR1; also known as transient receptor potential vanilloid type 1 (TRPV1)]. VR1 receptors are widely distributed in the periphery (e.g., on primary afferent neurons). These studies examined the ability of loperamide (0.1–1 mg/kg s.c.; a μ-opioid agonist that is peripherally selective after systemic administration), in preventing and reversing Thermal Allodynia caused by topical capsaicin (0.004 M) in rhesus monkeys, within a tail withdrawal assay ( n = 4; 38°C and 42°C; normally non-noxious Thermal stimuli). The effects of loperamide were compared with those of the centrally penetrating μ-agonist, fentanyl (0.0032–0.032 mg/kg s.c.). We also characterized the allodynic effects of the endogenous VR1 agonist (“endovanilloid”), N -oleoyldopamine (OLDA; 0.0013–0.004 M). In this model, loperamide and fentanyl produced dose-dependent prevention of capsaicin-induced Allodynia, whereas only fentanyl produced robust reversal of ongoing Allodynia. Antagonism experiments with naltrexone (0.1 mg/kg s.c.) or its analog, methylnaltrexone (0.32 mg/kg s.c.), which does not readily cross the blood-brain barrier, suggest that the antiallodynic effects of loperamide and fentanyl were predominantly mediated by peripherally and centrally located μ-receptors, respectively. Loperamide and fentanyl (1 mg/kg and 0.032 mg/kg, respectively) also prevented OLDA (0.004 M)-induced Allodynia. Up to the largest dose studied, loperamide was devoid of Thermal antinociceptive effects at 48°C (a noxious Thermal stimulus, in the absence of capsaicin). By contrast, fentanyl (0.01–0.032 mg/kg) caused dose-dependent antinociception in this sensitive Thermal antinociceptive assay (a presumed centrally mediated effect). These studies show that loperamide, acting as a peripherally selective μ-agonist after systemic administration, can prevent capsaicin-induced Thermal Allodynia in primates in vivo, in the absence of Thermal antinociceptive effects.
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Topical Capsaicin-Induced Allodynia in Unanesthetized Primates: Pharmacological Modulation
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Eduardo R. Butelman, Todd J. Harris, Jonathan W. Ball, Mary Jeanne KreekAbstract:Topically administered capsaicin produces Thermal Allodynia, and this effect has been used to investigate pain transduction and its pharmacological modulation. This study investigated the parameters of topical capsaicin-induced Thermal Allodynia in unanesthetized rhesus monkeys and its pharmacological modulation by centrally acting compounds [a κ-opioid agonist: (5α,7α,8β)-(+)- N -methyl- N -(7-[1-pyrrolidinyl]-1-oxaspiro [4.5]dec-8-yl)-benzeneacetamide (U69,593); and noncompetitive N -methyl-d-aspartate (NMDA) antagonists: ketamine and MK-801 (dizocilpine)]. Rhesus monkeys ( n = 4) were studied within the warm water tail withdrawal assay (20-s maximum latency), using Thermal stimuli that are normally not noxious (38 and 42°C). Capsaicin was applied topically on the tail (0.0013 and 0.004 M capsaicin solution on a 1-cm 2 patch; 15-min contact). Topical capsaicin produced concentration-dependent Thermal Allodynia in both temperatures, robustly detected 15 to 90 min after topical capsaicin removal. A similar allodynic profile was observed with topical administration of the “endovanilloid” N -arachidonoyl-dopamine. The κ-agonist U69,593 (0.01-0.1 mg/kg, s.c.) dose dependently prevented capsaicin (0.004 M)-induced Allodynia in 38 and 42°C, and the largest U69,593 dose also reversed ongoing Allodynia within this model. Two NMDA antagonists, ketamine and MK-801 (0.32-1.8 and 0.032-0.056 mg/kg, respectively), also prevented capsaicin-induced Allodynia in 38°C, but only variably in 42°C, at doses that did not cause robust Thermal antinociceptive effects. At the largest doses studied, ketamine but not MK-801 also briefly reversed ongoing capsaicin-induced Allodynia. The present model of topical capsaicin administration may be used to study antiallodynic effects of opioid and nonopioid compounds, as well as their ability to prevent and reverse Allodynia, in unanesthetized nonhuman primates in the absence of tissue disruption.
