Spinal muscarinic and nicotinic subtypes activated by clonidine in postincisional pain.
BACKGROUND
A recent model of acute incisional pain has been characterized that strongly parallels the postoperative period in patients experiencing evoked pain. In that setting, abundant literature has revealed antihypersensitive effects produced by intrathecally administered alpha2-adrenergic receptor agonists, such as clonidine, in both animals and humans. Recent reports have suggested an obligatory role of spinal acetylcholine receptors in the analgesic action of intrathecal clonidine. The authors sought to determine the involvement of spinal muscarinic and nicotinic receptor subpopulations in the antihypersensitivity effect of intrathecal clonidine in a rodent model for human postoperative pain.


METHODS
After intrathecal catheterization, rats underwent superficial plantar incision. Clonidine or a combination of clonidine and muscarinic receptor subtype antagonists (M1, M2, M3, and M4) or nicotinic receptor subtype antagonists (alpha4beta2 and alpha7) were intrathecally administered, and withdrawal thresholds to mechanical stimuli were examined.


RESULTS
Spinal clonidine maximally reduced hypersensitivity adjacent to the wound 30 min after its injection. When animals were intrathecally pretreated with the M1 muscarinic antagonist toxin MT-7, the M3 muscarinic antagonist 4-diphenylacetoxy-N-methylpiperidine, and the M4 muscarinic antagonist toxin MT-3, clonidine lost its antihypersensitive action. When animals were intrathecally pretreated with the alpha4beta2 nicotinic receptor antagonist dihydro-beta-erythroidine, but not with the alpha7 nicotinic receptor antagonist methyllycaconitine, the antihypersensitivity action of clonidine was abolished.


CONCLUSIONS
These data indicate for the first time that the clonidine-induced increase in punctuate mechanical threshold is mediated via the activation of all but M2 muscarinic receptor subtypes, and via the activation of alpha4beta2 but not alpha7 nicotinic receptor subtypes in a rodent model for human postoperative pain.
Duflo
Frédéric
F
Department of Anesthesiology and Intensive Care, Hôpital de l'Hôtel-Dieu, Lyon, France. frederic.duflo@chu-lyon.fr
Boselli
Emmanuel
E
Ryvlin
Philippe
P
Chassard
Dominique
D
D000157:Aconitine / Q000031:analogs & derivatives / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology*; D003959:Diamines / Q000494:pharmacology; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D007278:Injections, Spinal; D008297:Male; D018721:Muscarinic Agonists; D018722:Nicotinic Agonists; D010146:Pain / Q000503:physiopathology*; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000187:drug effects; D043585:Receptor, Muscarinic M2 / Q000187:drug effects; D011976:Receptors, Muscarinic / Q000187:drug effects*; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013131:Spine / Q000187:drug effects*
D000316:Adrenergic alpha-Agonists; D003959:Diamines; D018721:Muscarinic Agonists; D018722:Nicotinic Agonists; D010880:Piperidines; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; C054634:methyllycaconitine; D004079:Dihydro-beta-Erythroidine; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium; D003000:Clonidine; C054938:methoctramine; D000157:Aconitine