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 μ‐, δ‐ and κ‐opioid receptors.Experimental approach: Nociceptive thresholds to mechanical stimulation of rat paws treated with intraplantar prostaglandin E₂(PGE₂, 2 μg) to induce hyperalgesia were measured 3 h after injection using an algesimetric apparatus. Opioid agonists morphine (200 μg), (+)‐4‐[(alphaR)‐alpha‐((2S,5R)‐4‐Allyl‐2,5‐dimethyl‐1‐piperazinyl)‐3‐ methoxybenzyl]‐N,N‐diethylbenzamide (SNC80) (80 μg), bremazocine (50 μg); cannabinoid receptor antagonistsN‐(piperidin‐1‐yl)‐5‐(4‐ iodophenyl)‐1‐(2,4‐dichlorophenyl)‐4‐methyl‐1H‐pyrazole‐3‐carboxamide (AM251) (20–80 μg), 6‐iodo‐2‐methyl‐1‐[2‐(4‐morpholinyl) ethyl]‐1H‐indol‐3‐yl(4‐methoxyphenyl) methanone (AM630) (12.5–100 μg); and an inhibitor of methyl arachidonyl fluorophosphonate (MAFP) (1–4 μg) were also injected in the paw.Key results: The CB₁‐selective cannabinoid receptor antagonist AM251 completely reversed the peripheral antinociception induced by morphine in a dose‐dependent manner. In contrast, the CB₂‐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 μ‐opioid receptor agonist morphine. The release of cannabinoids appears not to be involved in the peripheral antinociceptive effect induced by κ‐ and δ‐opioid receptor agonists.British Journal of Pharmacology(2008)154, 1143–1149; doi:10.1038/bjp.2008.175; published online 12 May 2008

Onists anandamide and N-palmitoyl-ethanolamine (PEA), respectively, are able to induce peripheral antinociception via an adrenergic mechanism. METHODS: All drugs were administered locally into the right hindpaw of male Wistar rats. The rat paw pressure test was used, with hyperalgesia induced by intraplantar injection of prostaglandin E2 (2 μg). RESULTS: Anandamide, 12.5 ng/paw, 25 ng/paw, and 50 ng/paw elicited a local peripheral antinociceptive effect that was antagonized by CB1 cannabinoid receptor antagonist AM251, 20 µg/paw, 40 µg/paw, and 80 µg/paw, but not by CB2 cannabinoid receptor antagonist AM630, 100 µg/paw. PEA, 5 µg/paw, 10 µg/paw, and 20 µg/paw, elicited a local peripheral antinociceptive effect that was antagonized by AM630, 25 µg/paw, 50 µg/paw, and 100 µg/paw, but not by AM251, 80 µg/paw. Antinociception induced by anandamide or PEA was antagonized by the nonselective α2 adrenoceptor antagonist yohimbine, 05 µg/paw, 10 µg/paw, and 20 µg/paw, and by the selective α2C adrenoceptor antagonist rauwolscine, 10 µg/paw, 15 µg/paw, and 20 µg/paw, but not by the selective antagonists for α2A, α2B, and α2D adrenoceptor subtypes, 20 μg/paw. The antinociceptive effect of the cannabinoids was also antagonized by the nonselective α1 adrenoceptor antagonist prazosin, 0.5 µg/paw, 1 µg/paw, and 2 µg/paw, and by the nonselective β adrenoceptor antagonist propranolol, 150 ng/paw, 300 ng/paw, and 600 ng/paw. Guanethidine, which depletes peripheral sympathomimetic amines (30 mg/kg/animal, once a day for 3 days), restored approximately 70% the anandamide-induced and PEA-induced peripheral antinociception. Furthermore, acute injection of the norepinephrine reuptake inhibitor reboxetine, 30 µg/paw, intensified the antinociceptive effects of low-dose anandamide, 12.5 ng/paw, and PEA, 5 µg/paw. CONCLUSIONS: This study provides evidence that anandamide and PEA induce peripheral antinociception activating CB1 and CB2 cannabinoid receptors, respectively, stimulating an endogenous norepinephrine release that activates peripheral adrenoceptors inducing antinociception. (Anesth Analg 2013;116:–72)...

Idal analgesics, cholinergic agonist, and α2C adrenoceptor agonist. In this study, we investigated whether ketamine, a dissociative anesthetic N-methyl-d-aspartate receptor antagonist, was also capable of activating the l-arginine/NO/cGMP pathway and eliciting peripheral antinociception. METHODS: The rat paw pressure test was used, with hyperalgesia induced by intraplantar injection of prostaglandin E2. All drugs were locally administered into the right hindpaw of male Wistar rats. RESULTS: Ketamine (10, 20, 40, 80 μg/paw) elicited a local antinociceptive effect that was antagonized by the nonselective NOS inhibitor l-NOARG (12, 18, and 24 μg/paw) and by the selective neuronal NOS inhibitor l-NPA (12, 18, and 24 μg/paw). In another experiment, we used the inhibitors l-NIO and l-NIL (24 μg/paw) to selectively inhibit endothelial and inducible NOS, respectively. These 2 drugs were ineffective at blocking the effects of the peripheral ketamine injection. In addition, the level of nitrite in the homogenized paw indicated that exogenous ketamine is able to induce NO release. The soluble guanylyl cyclase inhibitor ODQ (25, 50, and 100 μg/paw) blocked the action of ketamine, and the cGMP-phosphodiesterase inhibitor zaprinast (50 μg/paw) enhanced the antinociceptive effects of low-dose ketamine (10 μg/paw). CONCLUSIONS: Our results suggest that ketamine stimulates the l-arginine/NO/cyclic GMP pathway via neuronal NO synthase to induce peripheral antinociceptive effects....