Central antinociception induced by µ‐opioid receptor agonist morphine, but not δ‐ or κ‐, is mediated by cannabinoid CB₁receptor

Abstract

Background and purpose: It has been demonstrated that cannabinoids evoke the release of endogenous opioids to produce antinociception; however, no information exists regarding the participation of cannabinoids in the antinociceptive mechanisms of opioids. The aim of the present study was to determine whether endocannabinoids are involved in central antinociception induced by activation of µ‐, δ‐ and κ‐opioid receptors. Experimental approach: Nociceptive threshold to thermal stimulation was measured according to the tail‐flick test in Swiss mice. Morphine (5 µg), SNC80 (4 µg), bremazocine (4 µg), AM251 (2 and 4 µg), AM630 (2 and 4 µg) and MAFP (0.1 and 0.4 µg) were administered by the intracerebroventricular route. Key results: The CB 1 ‐selective cannabinoid receptor antagonist AM251 completely reversed the central antinociception induced by morphine in a dose‐dependent manner. In contrast, the CB 2 ‐selective cannabinoid receptor antagonist AM630 did not antagonize this effect. Additionally, the administration of the anandamide amidase inhibitor, MAFP, significantly enhanced the antinociception induced by morphine. In contrast, the antinociceptive effects of δ‐ and κ‐opioid receptor agonists were not affected by the cannabinoid antagonists. The antagonists alone caused no hyperalgesic or antinociceptive effects. Conclusions and implications: The results provide evidence for the involvement of cannabinoid CB 1 receptors in the central antinociception induced by activation of µ‐opioid receptors by the agonist morphine. The release of endocannabinoids appears not to be involved in central antinociception induced by activation of κ‐ and δ‐opioid receptors.