NEOSTIGMINE COUNTERACTS SPINAL CLONIDINE-INDUCED HYPOTENSION IN SHEEP

Background: Intraspinal clonidine injection produces analgesia free of respiratory depression, but also decreases blood pressure and causes sedation. Spinal neostigmine injection alone increases blood pressure in animals and enhances clonidine-induced analgesia. Methods: To test whether neostigmine would alter clonidine-induced hypotension, nine chronically prepared sheep received intrathecal injections of saline or neostigmine (150, 300, 1,000 mug) followed in 15 min by 200 mug clonidine. Results: Clonidine plus saline decreased mean arterial pressure by 12 +/- 3% associated with small, statistically nonsignificant decreases in heart rate, cardiac output, and systemic vascular resistance. Prior injection of neostigmine diminished hypotension 60 min after clonidine injection in a dose-dependent manner. To further define the time course and pharmacology of this interaction, seven other sheep received intrathecal saline, neostigmine (1,000 mug), or neostigmine plus methylatropine (1,000 mug) 75 min prior to 200 mug clonidine. With this longer interval between injections, neostigmine abolished clonidine-induced hypotension, and this protective effect was inhibited by methylatropine. To test whether rostral spread of neostigmine in cerebrospinal fluid would alter its hemodynamic effects, we injected intrathecal neostigmine into the upper cervical site. Intrathecal neostigmine increased mean arterial pressure and heart rate at this site to a degree similar to that in the thoracic area, with no effect on behavioral or arterial blood gas tensions. Conclusions. These data are consistent with neostigmine's counteraction of clonidine-induced hypotension by a spinal muscarinic mechanism and support investigation of spinal alpha2-adrenergic-cholinergic combinations for pain therapy.