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In vitro receptor binding studies with paraoxon treated rat brain membranes, and stability studies using HPLC analysis, showed a negligible opiate receptor affinity for the morphinomimetic agent nicomorphine and its hydrolysis product 3-nicotinoylmorphine. Two other hydrolysis products, 6-nicotinoylmorphine and morphine, had a high affinity in the nanomolar range and are probably the active metabolites of nicomorphine.

Rats chronically implanted with intrathecal catheters displayed a dose-dependent increase in the hot-place and tail-flick response latencies following the injection of morphine or nicomorphine into the subarachnoid space through the indwelling catheter. Naloxone inhibited the antinociceptic effect of both opiate drugs, but the inhibition of nicomorphine-induced antinociception was incomplete. To evaluate the importance of cholinergic mechanisms in opiate effectiveness, the interactions with atropine or physostigmine were evaluated. Atropine reduced the effects of morphine and abolished the effects of nicomorphine at the doses used. Physostigmine markedly potentiated morphine effectiveness, but had a negligible effect on nicomorphine effectiveness. It is proposed that these differences relate to a specific cholinergic mechanism involved in antinociception after intrathecal nicomorphine. The data indicate that at a spinal level cholinergic mechanisms are relevant to opiate effectiveness.