Metanicotine [N-methyl-4-(3-pyridinyl)-3-
butene-1-
amine], a novel neuronal
nicotinic agonist, was found to bind with high affinity (K(i) = 24 nM) to rat brain [(3)H]
nicotine binding sites and it generalized to
nicotine in a dose-dependent manner in the
drug discrimination procedure.
Metanicotine produced significant antinociceptive effects in mice and rats subjected to either acute thermal (tail-flick), mechanical (paw-pressure), chemical (para-
phenylquinone), persistent (
Formalin), and chronic (
arthritis)
pain stimuli.
Metanicotine was about 5-fold less potent than
nicotine in the tail-flick test after s.c administration, but slightly more potent after central administration. Its duration of action was longer than that of
nicotine.
Nicotinic antagonists,
mecamylamine and
dihydro-beta-erythroidine, blocked
metanicotine-induced antinociception in the different
pain models. However, the antinociceptive effect was not affected by pretreatment with either
naloxone or by
atropine, confirming that
metanicotine exerts its antinociceptive effect via nicotinic rather than either
opioid or
muscarinic mechanisms. In contrast to
nicotine, antinociceptive effects of
metanicotine were observed at doses that had virtually no effect on spontaneous activity and body temperature in mice. These data indicate that
metanicotine is a centrally acting neuronal
nicotinic agonist with preferential antinociceptive effects in animals. Thus,
metanicotine and related
nicotinic agonists may have great potential for development as a new class of
analgesics.