SPINAL CHOLINERGIC ALPHA-2-ADRENERGIC INTERACTIONS IN ANALGESIA AND HEMODYNAMIC CONTROL - ROLE OF MUSCARINIC RECEPTOR SUBTYPES AND NITRIC-OXIDE

Intrathecal injection of neostigmine enhances antinociception from clo nidine while it counteracts clonidine-induced hypotension. This study further examined the pharmacology of neostigmine-clonidine interaction s in the spinal cord and focused on the roles of muscarinic receptor s ubtypes and local nitric oxide synthesis. Spinal neostigmine counterac ted clonidine-induced decreases in blood pressure and heart rate in co nscious sheep and this effect was blocked by spinal injection of the M (2) muscarinic antagonist, AFDX-116, but not by the M(1) muscarinic an tagonist, pirenzepine. Carbamylcholine injected spinally alone increas ed brood pressure and heart rate and these effects and neostigmine's h emodynamic interaction with clonidine were blocked by spinal injection of the nitric oxide synthase inhibitor, N-methyl-L-arginine. The auth ors also investigated antinociceptive interactions by using a mechanic al pressure stimulus on the forelimb of conscious sheep. Spinal clonid ine produced dose-dependent antinociception, which was enhanced by neo stigmine and antagonized by N-methyl-L-arginine. NADPH diaphorase stai ning of sheep spinal cord revealed dense localization to the superfici al dorsal horn and the intermediolateral cell column. These results su ggest that counteraction of spinal clonidine-induced hypotension by ne ostigmine is due to stimulation of spinal M, muscarinic receptors and synthesis of nitric oxide. Nitric oxide synthesis is also necessary fo r clonidine-induced antinociception in sheep.