A CHOLINERGIC INTERACTION IN ALPHA(2) ADRENOCEPTOR-MEDIATED ANTINOCICEPTION IN SHEEP

Intraspinal administration of alpha2 adrenergic agonists produces anal gesia, but clinical application of these agents is limited by dose-dep endent sedation and hypotension. Recently, neostigmine has been demons trated to counteract hypotension in sheep and enhance antinociception to tail flick in rats from spinally administered alpha2 adrenergic ago nists. We investigated this spinal interaction further in chronically prepared, conscious sheep, testing antinociception with a mechanical p ressure stimulus on the forelimb. Clonidine produced dose-dependent an tinociception which was antagonized by idazoxan and enhanced by neosti gmine, although it was unaltered by methylatropine. Clonidine increase d acetylcholine in cerebrospinal fluid, an effect potentiated by physo stigmine and blocked by idazoxan. The highly lipid-soluble alpha2 adre nergic agonists dexmedetomidine and clonidine produced antinociception , whereas the poorly lipid-soluble ST-91 (2,[2,6-diethylphenylamino]-2 -imidazoline) produced antinociception only at much larger doses and d id not affect cerebrospinal fluid levels of acetylcholine. In human vo lunteers, epidurally administered clonidine increased cerebrospinal fl uid acetylcholine levels at the time of peak analgesia. These results support the existence of an interaction between alpha2 adrenergic and cholinergic mechanisms of analgesia at the spinal level and underscore the importance of lipid solubility in the actions of spinally adminis tered drugs in sheep.