Improgan, a congener of the H(2) antagonist
cimetidine, produces non-
opioid antinociception which is blocked by the CB(1) antagonist
rimonabant, implying a
cannabinoid mechanism of action. Since
cannabinoids produce
hypothermia as well as antinociception in rodents, the present study investigated the pharmacological activity of
improgan on core body temperature and nociceptive (tail flick) responses.
Improgan (60, 100 and 140 microg, intraventricular [ivt]) elicited significant decreases in core temperature 3-30 min following injection with a maximal hypothermic effect of -1.3 degrees C. Pretreatment with
rimonabant (50 microg, ivt) produced a statistically significant but incomplete (29-42%) antagonism of
improgan hypothermia. In control experiments, the CB(1) agonist
CP-55,940 (37.9 microg, ivt) induced significant decreases in core temperature (-1.8 degrees C) 3-30 min following injection. However, unlike the case with
improgan, pretreatment with
rimonabant completely blocked
CP-55,940 hypothermia. Furthermore,
CP-55,940 and
improgan elicited maximal antinociception over the same time course and dose ranges, and both effects were attenuated by
rimonabant. These results show that, like
cannabinoid agonists in the rat,
improgan produces antinociception and
hypothermia which is blocked by a CB(1) antagonist. Unlike
cannabinoid agonists, however,
improgan does not produce locomotor inhibition at antinociceptive doses. Additional experiments were performed to determine the effect of CC12, a recently discovered
improgan antagonist which lacks affinity at CB(1) receptors. Pretreatment with CC12 (183 microg, ivt) produced complete inhibition of both the antinociception and the
hypothermia produced by
improgan, suggesting the possible role of an unknown
improgan receptor in both of these effects.