Document Detail

Ondansetron reverses antihypersensitivity from clonidine in rats after peripheral nerve injury: role of γ-aminobutyric acid in α2-adrenoceptor and 5-HT3 serotonin receptor analgesia.
MedLine Citation:
PMID:  22722575     Owner:  NLM     Status:  MEDLINE    
INTRODUCTION: Monoaminergic pathways, impinging an α2-adrenoceptors and 5-HT3 serotonin receptors, modulate nociceptive transmission, but their mechanisms and interactions after neuropathic injury are unknown. Here we examine these interactions in rodents after nerve injury.
METHODS: Male Sprague-Dawley rats following L5-L6 spinal nerve ligation (SNL) were used for either behavioral testing, in vivo microdialysis for γ-aminobutyric acid (GABA) and acetylcholine release, or synaptosome preparation for GABA release.
RESULTS: Intrathecal administration of the α2-adrenoceptor agonist (clonidine) and 5-HT3 receptor agonist (chlorophenylbiguanide) reduced hypersensitivity in SNL rats via GABA receptor-mediated mechanisms. Clonidine increased GABA and acetylcholine release in vivo in the spinal cord of SNL rats but not in normal rats. Clonidine-induced spinal GABA release in SNL rats was blocked by α2-adrenergic and nicotinic cholinergic antagonists. The 5-HT3 receptor antagonist ondansetron decreased and chlorophenylbiguanide increased spinal GABA release in both normal and SNL rats. In synaptosomes from the spinal dorsal horn of SNL rats, presynaptic GABA release was increased by nicotinic agonists and decreased by muscarinic and α2-adrenergic agonists. Spinally administered ondansetron significantly reduced clonidine-induced antihypersensitivity and spinal GABA release in SNL rats.
CONCLUSION: These results suggest that spinal GABA contributes to antihypersensitivity from intrathecal α2-adrenergic and 5-HT3 receptor agonists in the neuropathic pain state, that cholinergic neuroplasticity after nerve injury is critical for α2-adrenoceptor-mediated GABA release, and that blockade of spinal 5-HT3 receptors reduces α2-adrenoceptor-mediated antihypersensitivity via reducing total GABA release.
Ken-ichiro Hayashida; Masafumi Kimura; Masaru Yoshizumi; Shotaro Hobo; Hideaki Obata; James C Eisenach
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Anesthesiology     Volume:  117     ISSN:  1528-1175     ISO Abbreviation:  Anesthesiology     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-07-26     Completed Date:  2012-10-15     Revised Date:  2013-08-13    
Medline Journal Info:
Nlm Unique ID:  1300217     Medline TA:  Anesthesiology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  389-98     Citation Subset:  AIM; IM    
Wake Forest University School of Medicine, Winston Salem, NC, USA.
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MeSH Terms
Adrenergic alpha-2 Receptor Agonists / pharmacology
Analgesia / methods
Clonidine / pharmacology*
Disease Models, Animal
Ondansetron / pharmacology*
Pain / drug therapy
Pain Management / methods
Peripheral Nerve Injuries*
Rats, Sprague-Dawley
Receptors, Adrenergic, alpha-2 / drug effects*
Receptors, Serotonin, 5-HT3 / drug effects*
Serotonin Antagonists / pharmacology
gamma-Aminobutyric Acid / pharmacology*
Grant Support
Reg. No./Substance:
0/Adrenergic alpha-2 Receptor Agonists; 0/Receptors, Adrenergic, alpha-2; 0/Receptors, Serotonin, 5-HT3; 0/Serotonin Antagonists; 4205-90-7/Clonidine; 56-12-2/gamma-Aminobutyric Acid; 99614-02-5/Ondansetron

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