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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.

Background and Purpose The synthetic peptide PnPP‐19 has been studied as a new drug candidate to treat erectile dysfunction. However, PnTx2–6, the spider toxin from which the peptide was designed, induces hyperalgesia. Therefore, we intended to investigate the role of PnPP‐19 in the nociceptive pathway. Experimental Approach Nociceptive thresholds were measured by paw pressure test. PnPP‐19 was administered intraplantarly alone or with selective cannabinoid or opioid receptor antagonists. The hydrolysis of PnPP‐19 by neutral endopeptidase (NEP) (EC 3.4.24.11), an enzyme that cleaves enkephalin, was monitored by HPLC and the cleavage sites were deduced by LC–MS. Inhibition by PnPP‐19 and Leu‐enkephalin of NEP enzyme activity was determined spectrofluorimetrically. Key Results PnPP‐19 (5, 10 and 20 μg per paw) induced peripheral antinociception in rats. Specific antagonists of μ opioid receptors (clocinnamox), δ opioid receptors (naltrindole) and CB1 receptors (AM251) partly inhibited the antinociceptive effect of PnPP‐19. Inhibition of fatty acid amide hydrolase by MAFP or of anandamide uptake by VDM11 enhanced PnPP‐19‐induced antinociception. NEP cleaved PnPP‐19 only after a long incubation, and Ki values of 35.6 ± 1.4 and 14.6  ± 0.44 μmol·L−1 were determined for PnPP‐19 and Leu‐enkephalin respectively as inhibitors of NEP activity. Conclusions and Implications Antinociception induced by PnPP‐19 appears to involve the inhibition of NEP and activation of CB1, μ and δ opioid receptors. Our data provide a greater understanding of the antinociceptive effects of PnPP‐19. This peptide could be useful as a new antinociceptive drug candidate.

Our results suggest that ketamine stimulates the L-arginine/NO/cyclic GMP pathway via neuronal NO synthase to induce peripheral antinociceptive effects.