Rats chronically implanted with intrathecal catheters displayed a dose-dependent increase in the hot-plate, tail-flick response latencies, and decreased the magnitude of the writhing response following the injection of certain cholinomimetics into the subarachnoid space through the indwelling catheter. The structure-activity relationship for these agents is oxotremorine greater than carbachol greater than acetylcholine + physostigmine much much greater than acetylcholine = nicotine-HCl = 0. Atropine, but not naloxone, strychnine, picrotoxin, curare or methysergide and phentolamine, reversed the antinociceptive effect. This suggests the involvement of muscarinic cholinergic mechanisms. Experiments with intrathecal injection of carbachol into the spinal subarachnoid space of cats fitted with intrathecal catheters also revealed a potent antinociceptive effect which was completely antagonized by atropine. The effect was somatotopically limited with the skin surfaces innervated by cord segments nearest the catheter tip showing the most significant effect with the shortest latency of onset. This observation, together with the absence of changes in general reflex motor function or postural control further indicated a selective spinal effectiveness of muscarinic agonists after low dose intrathecal administration.