Improgan-induced hypothermia: A role for cannabinoid receptors in improgan-induced changes in nociceptive threshold and body temperature

Abstract

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 140μg, intraventricular [ivt]) elicited significant decreases in core temperature 3-30 min following injection with a maximal hypothermic effect of −1.3°C. Pretreatment with rimonabant (50μg, ivt) produced a statistically significant, but incomplete (29% -42%) antagonism of improgan hypothermia. In control experiments, the CB 1 agonist CP-55, 940 (37.9μg, ivt) induced significant decreases in core temperature (−1.8°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 (183μg, 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.

Physiological Basis for Inhibition of Morphine and Improgan Antinociception by CC12, a P450 Epoxygenase Inhibitor

“…1, which also shows the effect of CC12 pretreatment on improgan antinociception), consistent with previous work in awake, behaving animals (Hough et al 2007). Ongoing discharges of OFF-and ON-cells were unaffected by CC12.…”

“…As shown previously in awake, behaving animals (Hough et al 2007), CC12 pretreatment significantly attenuated the antinociceptive actions of improgan (Fig. 1).…”

“…An important pathway for arachidonic acid metabolism, P450 epoxygenase was subsequently shown to be required for the antinociceptive effects of a novel nonopioid analgesic, improgan (Hough et al 2009a). These findings provided a pharmacological explanation for the earlier report that the P450 epoxygenase inhibitor CC12 {[4(5)-[(4-iodobenzyl)thiomethyl]-1H-imidazole]} was able to block both morphine and improgan antinociception (Hough et al 2007;Stadel et al 2008). Although these results suggested that P450 enzymes represent a point of convergence of both opioid and nonopioid analgesic mechanisms in the brain stem, no neurophysiological studies of P450 inhibitors on identified brain stem pain-modulating neurons have yet been performed.…”

“…CC12 hydrochloride (Hough et al 2007) was dissolved in saline, with pH adjusted to 4.5-5. Improgan base (Hough et al 2000) was dissolved in dilute HCl, neutralized to pH 5.5 to 6, and diluted with saline.…”

“…Because CC12 attenuates the analgesic actions of opioids, as well as improgan, in awake, behaving animals (Hough et al 2007), we next determined whether CC12 interfered with the responses of OFF-and ON-cells to morphine. As in awake animals, CC12 attenuated the antinociceptive effect of morphine (Fig.…”