title: Role of spinal muscarinic and nicotinic receptors in clonidine-induced nitric oxide release in a rat model of neuropathic pain.
abstract: Intrathecal administration of alpha(2) adrenergic agonists, such as clonidine, is capable of alleviating neuropathic pain. Recent studies suggest that spinal nitric oxide (NO) mediates the analgesic effect of intrathecal clonidine. Furthermore, compared to nicotinic receptors, spinal muscarinic receptors play a greater role in the analgesic effect of intrathecal clonidine. In the present study, we tested a hypothesis that clonidine-evoked NO release is dependent primarily on muscarinic receptors in the spinal cord after nerve injury. A rat model of neuropathic pain was induced by ligation of the left L(5)/L(6) spinal nerves. Using an in vitro spinal cord perfusion preparation, the effect of muscarinic and nicotinic receptor antagonists on clonidine-evoked nitrite (a stable product of NO) release was determined. Both muscarinic and nicotinic antagonists dose-dependently attenuated clonidine-elicited nitrite release. In spinal cords from the neuropathic rats, the inhibitory effect of muscarinic receptor antagonists (atropine and scopolamine) on clonidine-elicited nitrite release was more potent than that of nicotinic receptor antagonists (mecamylamine and hexamethonium). However, in spinal cords obtained from sham animals, the inhibitory effect of muscarinic and nicotinic antagonists did not differ significantly. These results indicate that muscarinic, as well as nicotinic, receptors mediate clonidine-induced NO release in the spinal cord. These data also suggest that after nerve injury, the cascade of activation of alpha(2) adrenergic receptors-muscarinic receptors-NO in the spinal cord likely plays a predominant role in the analgesic effect of intrathecal clonidine on neuropathic pain.
authors.affiliation: Department of Anesthesiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1009, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Xu
authors.forename: S R
authors.initials: SR
authors.lastname: Chen
authors.forename: J
authors.initials: J
authors.lastname: Eisenach
authors.forename: H L
authors.initials: HL
authors.lastname: Pan
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D003000:Clonidine / Q000494:pharmacology*; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects* / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D013127:Spinal Nerves / Q000293:injuries
chemical_list: D000316:Adrenergic alpha-Agonists; D018727:Muscarinic Antagonists; D018733:Nicotinic Antagonists; D009573:Nitrites; D018341:Receptors, Adrenergic, alpha-2; D011976:Receptors, Muscarinic; D009569:Nitric Oxide; D003000:Clonidine