The μ‐opioid receptor agonist morphine, but not agonists at δ‐ or κ‐opioid receptors, induces peripheral antinociception mediated by cannabinoid receptors

• Published in: British journal of pharmacology Vol. 154; no. 5; pp. 1143 - 1149
• Main Authors: Da Fonseca Pacheco, D, Klein, A, De Castro Perez, A, Da Fonseca Pacheco, C M, De Francischi, J N, Duarte, I D G
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-07-2008; Nature Publishing Group
• Subjects: Amidohydrolases - antagonists & inhibitors; Amidohydrolases - metabolism; Analgesics, Opioid - pharmacology; Animals; Arachidonic Acids - pharmacology; Benzamides - pharmacology; Benzomorphans - pharmacology; bremazocine; Cannabinoid Receptor Modulators - metabolism; CB1 receptor; CB2 receptor; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Hyperalgesia - chemically induced; Hyperalgesia - metabolism; Hyperalgesia - prevention & control; Indoles - pharmacology; Male; Morphine; Morphine - pharmacology; Organophosphonates - pharmacology; Pain - chemically induced; Pain - metabolism; Pain - prevention & control; Pain Measurement; peripheral antinociception; Piperazines - pharmacology; Piperidines - pharmacology; Pyrazoles - pharmacology; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1 - drug effects; Receptor, Cannabinoid, CB1 - metabolism; Receptor, Cannabinoid, CB2 - drug effects; Receptor, Cannabinoid, CB2 - metabolism; Receptors, Opioid, delta - agonists; Receptors, Opioid, kappa - agonists; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - metabolism; Research Papers; SNC80
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/bjp.2008.175

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 antagonists N‐(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