Central antinociception induced by mu-opioid receptor agonist morphine, but not delta- or kappa-, is mediated by cannabinoid CB1 receptor

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 mu-, delta- and kappa-opioid receptors.

Experimental approach: Nociceptive threshold to thermal stimulation was measured according to the tail-flick test in Swiss mice. Morphine (5 microg), SNC80 (4 microg), bremazocine (4 microg), AM251 (2 and 4 microg), AM630 (2 and 4 microg) and MAFP (0.1 and 0.4 microg) 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 delta- and kappa-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 mu-opioid receptors by the agonist morphine. The release of endocannabinoids appears not to be involved in central antinociception induced by activation of kappa- and delta-opioid receptors.

Figures

Figure 1

Antagonism induced by i.c.v. administration of AM251 on the central antinociception produced by morphine. AM251 (2 and 4 µg) was administered 1 min prior to morphine (Mor, 5 µg). This antagonist did not significantly modify the nociceptive threshold in control mice. Each point represents the mean ± SEM for five mice per group. *Indicates a significant difference compared to Veh1 + Veh2-injected group (analysis of variance + Bonferroni test, P < 0.05). Veh1, vehicle1 (20% DMSO in saline); Veh2, vehicle2 (saline).

Figure 2

Effect of i.c.v. administration of AM630 on the central antinociception produced by morphine. AM630 (2 and 4 µg) was administered 1 min prior to morphine (Mor, 5 µg). Each point represents the mean ± SEM for five mice per group. *Indicates a significant difference compared to Veh1 + Veh2-injected group (analysis of variance + Bonferroni test, P < 0.05). Veh1, vehicle1 (20% DMSO in saline); Veh2, vehicle2 (saline).

Figure 3

Effect of i.c.v. administration of AM251 and AM630 on the central antinociception produced by SNC80 (A) or bremazocine (B). AM251 (4 µg) or AM630 (4 µg) was administered 1 min prior to SNC80 (4 µg) or bremazocine (BRE; 4 µg). Each point represents the mean ± SEM for five mice per group. *Indicates a significant difference compared to Veh1 + Veh2-injected group (analysis of variance + Bonferroni test, P < 0.05). Veh1, vehicle1 (20% DMSO in saline); Veh2, vehicle2 [20% DMSO in saline (A) or saline (B)].

Figure 4

Potentiation of morphine-induced antinociception by MAFP. The MAFP (0.1 and 0.2 µg) was administered 1 min prior to morphine (2.5 µg). This drug alone (0.2 µg) did not induce any effect. Each point represents the mean ± SEM for five mice per group. *Indicates a significant difference compared to Veh1 + Veh2-injected group (analysis of variance + Bonferroni test, P < 0.05). Veh1, vehicle1 (10% DMSO in saline); Veh2, vehicle 2 (saline).