The role of cholinergic systems in the expression of morphine withdrawal

Both oxotremorine and physostigmine both in doses ranging from 25 to 100 micrograms/kg produced dose-dependent attenuation of withdrawal jumping and potentiation of 'wet dog' shakes, burrowing, hypothermia and body weight loss precipitated by naloxone (1 mg/kg, i.p.) in morphine-dependent mice. On the other hand, atropine sulphate (2-20 mg/kg) dose-dependently attenuated all naloxone precipitated withdrawal symptoms except withdrawal hypothermia which was further potentiated. However, the peripherally acting derivative atropine methyl nitrate (2-10 mg/kg) also attenuated all naloxone-induced withdrawal symptoms except jumping, which was not significantly modified. Hyoscine (0.2-20 mg/kg) exhibited a biphasic effect on withdrawal jumping. Withdrawal jumping was potentiated by low and attenuated by high doses of hyoscine. Withdrawal body weight loss was dose-dependently attenuated but 'wet dog' shakes, burrowing and hypothermia were markedly potentiated by hyoscine. Our results suggest that a combination of central muscarinic activation and peripheral muscarinic blockade can partially ameliorate precipitated morphine withdrawal. Differences observed between atropine and hyoscine with regard to their modifying effects on withdrawal symptoms may be explained on the basis that the drugs may be acting on the different subpopulations of the muscarinic receptor or through non-cholinergic systems.