The role of the cholinergic system in the development of increased naloxone potency in mice

Pretreatment of mice with the anticholinesterase (anti ChE) drugs tacrine or physostigmine augmented the antinociceptive potency of morphine given 3 h later, but had no effect on the antagonist potency of naloxone. Pretreatment with either of these anti ChE drugs together with morphine not only augmented the potency of a subsequent dose of morphine, but also enhanced the antagonist potency of naloxone to a greater extent than after pretreating with morphine only. Neostigmine did not affect the potency of either morphine or naloxone, suggesting that this phenomenon involved central cholinergic mechanisms. Atropine prevented the increase in naloxone potency caused by morphine pretreatment, and greatly reduced the effect of morphine plus the anti ChE drugs. The effects of these various pretreatments on the development of “acute dependence” to morphine was also studied. None of the three anti ChE drugs caused any change in this phenomenon, as tested by naloxone-precipitated jumping, although this was significantly increased by pretreatment with either atropine sulphate or atropine methyl nitrate. It is concluded that the increase in naloxone potency following morphine pretreatment involves both a cholinergic mechanism plus narcotic analgesic action. This phenomenon does not seem to be related to the development of either acute tolerance or acute dependence.