A central cholinergic mechanism has been implicated in the production of analgesia by narcotic agents ( 1, 2). Parasympathomimetic agents depress operant behavior in several species without depressing escape behavior (3, 4) and have been reported to potentiate analgesia induced by morphine and related drugs ( 1, 5-7). Moreover, recent studies have indicated that some cholinergic compounds may exert direct analgesic effects (2,(8)(9)(10)(11). The present study was undertaken using the anticholinesterase agents neostigmine and physostigmine, and the direct cholinomimetic pilocarpine to determine the extent of analgesia provided by these agents alone and to determine whether or not the muscarinic blocking agents atropine and scopolamine would antagonize this effect.Methods. The radiant heat "tail-flick" was used to determine analgesia and to quantitate tolerance to physostigmine sulfate and pilocarpine hydrochloride. The apparatus used was constructed as a metal box containing a ventilation fan and a small asbestos lined circular opening at the top. Just below this opening a nickel wire coil serving as the heat source was extended and controlled by a remote power switch operated in conjunction with a stopwatch. The mean, control reaction time of 382 male Holtzman rats (150-158 g nonfasted) used in this study was 5.62 t 0.04 (SEM) sec. Reaction times were assessed immediately before injection of drugs and 30 min after injection of drugs. The EAD50 was defined as the dosage (mg/kg) of drug that increased reaction time by 50% in one-half of the animals tested; each animal served as his own control. Each animal in the tolerance study received two EAD90 doses (50% increase in the reaction time in 90% of the animals tested) of physostigmine on the first day. There was a 5 hr interval between the two doses. On Days 2, 3 and 4 each animal received, in two daily injections, twice the amount of drug administered on Day 1. Pilocarpine animals were treated similarly. Drugs were freshly prepared in saline (0.9% NaC1) and administered in a 2 ml/kg injection volume (sc) . Atropine sulfate and scopolamine hydrochloride were tested for antagonism of analgesia induced by pilocarpine and physostigmine. The EADB50 was defined as the dose of scopolamine or atropine that inhibited analgesia in 50% of the animals given an EADgg dose of pilocarpine or physostigmine. The EADs0, EADgO, EADgs and EADBso values for all drugs used in this study are expressed as the weight of the salt form of each drug. The effective dose and 95% confidence limits for each drug tested were determined by the statistical methods of Litchfield and Wilcoxon (12).Results. Physostigmine and pilocarpine produced analgesia when administeredin acute studies. The EAD5O for physostigmine was 0.13 mg/kg and 5.7 mg/kg for pilocarpine (Table I). Neostigmine bromide failed to produce any measurable analgesic effect with doses between 0.12 and 0.24 mg/kg. This dose range did produce serious side effects and closely approached the LD50 for the drug. Animals pretreated with mult...

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