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Background and purpose: Although participation of opioids in antinociception induced by cannabinoids has been documented, there is little information regarding the participation of cannabinoids in the antinociceptive mechanisms of opioids. The aim of the present study was to determine whether endocannabinoids could be involved in peripheral antinociception induced by activation of m-, d-and k-opioid receptors. Experimental approach: Nociceptive thresholds to mechanical stimulation of rat paws treated with intraplantar prostaglandin E 2 (PGE 2 , 2 mg) to induce hyperalgesia were measured 3 h after injection using an algesimetric apparatus. Opioid agonists-yl(4-methoxyphenyl) methanone (AM630) (12.5-100 mg); and an inhibitor of methyl arachidonyl fluorophosphonate (MAFP) (1-4 mg) were also injected in the paw. Key results: The CB 1 -selective cannabinoid receptor antagonist AM251 completely reversed the peripheral antinociception induced by morphine in a dose-dependent manner. In contrast, the CB 2 -selective cannabinoid receptor antagonist AM630 elicited partial antagonism of this effect. In addition, the administration of the fatty acid amide hydrolase inhibitor, MAFP, enhanced the antinociception induced by morphine. The cannabinoid receptor antagonists AM251 and AM630 did not modify the antinociceptive effect of SNC80 or bremazocine. The antagonists alone did not cause any hyperalgesic or antinociceptive effect. Conclusions and implications: Our results provide evidence for the involvement of endocannabinoids, in the peripheral antinociception induced by the m-opioid receptor agonist morphine. The release of cannabinoids appears not to be involved in the peripheral antinociceptive effect induced by k-and d-opioid receptor agonists.

Key results: The CB1-selective cannabinoid receptor antagonist AM251 completely reversed the central antinociception induced by morphine in a dose-dependent manner. In contrast, the CB2-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 d-and k-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 CB1 receptors in the central antinociception induced by activation of m-opioid receptors by the agonist morphine. The release of endocannabinoids appears not to be involved in central antinociception induced by activation of k-and d-opioid receptors.

BackgroundSome peptides purified from the venom of the spider Phoneutria nigriventer have been identified as potential sources of drugs for pain treatment. In this study, we characterized the antinociceptive effect of the peptide PnPP-19 on the central nervous system and investigated the possible involvement of opioid and cannabinoid systems in its action mechanism.MethodsNociceptive threshold to thermal stimulation was measured according to the tail-flick test in Swiss mice. All drugs were administered by the intracerebroventricular route.ResultsPnPP-19 induced central antinociception in mice in the doses of 0.5 and 1 μg. The non-selective opioid receptor antagonist naloxone (2.5 and 5 μg), μ-opioid receptor antagonist clocinnamox (2 and 4 μg), δ-opioid receptor antagonist naltrindole (6 and 12 μg) and CB1 receptor antagonist AM251 (2 and 4 μg) partially inhibited the antinociceptive effect of PnPP-19 (1 μg). Additionally, the anandamide amidase inhibitor MAFP (0.2 μg), the anandamide uptake inhibitor VDM11 (4 μg) and the aminopeptidase inhibitor bestatin (20 μg) significantly enhanced the antinociception induced by a low dose of PnPP-19 (0.5 μg). In contrast, the κ-opioid receptor antagonist nor-binaltorphimine (10 μg and 20 μg) and the CB2 receptor antagonist AM630 (2 and 4 μg) do not appear to be involved in this effect.ConclusionsPnPP-19-induced central antinociception involves the activation of CB1 cannabinoid, μ- and δ-opioid receptors. Mobilization of endogenous opioids and cannabinoids might be required for the activation of those receptors, since inhibitors of endogenous substances potentiate the effect of PnPP-19. Our results contribute to elucidating the action of the peptide PnPP-19 in the antinociceptive pathway.

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