This study provides evidence that the peripheral antinociceptive effect of the cannabinoid receptor agonist anandamide may result from l-arginine/NO/cGMP pathway activation and that the opioid system is also involved.

No abstract

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.

Background and Purpose: Central anti-nociceptive actions of baclofen involve activation of K þ channels.Here we assessed what types of K þ channel might participate in the peripheral anti-nociception induced by baclofen. Experimental approach: Nociceptive thresholds to mechanical stimulation in rat paws treated with intraplantar prostaglandin E 2 .(PGE 2 ) to induce hyperalgesia were measured 3h after PGE 2 injection. Other agents were also given by intraplantar injection Key results: Baclofen elicited a dose-dependent (15 -240 mg per paw) anti-nociceptive effect. An intermediate dose of baclofen (60 mg) did not produce antinociception in the contralateral paw, showing its peripheral site of action. The GABA B receptor antagonist saclofen (12.5 -100 mg per paw) antagonized, in a dose-dependent manner, peripheral antinociception induced by baclofen (60 mg), suggesting a specific effect. This antinociceptive action of baclofen was unaffected by bicuculline, GABA A receptor antagonist (80 mg per paw), or by (1,2,5,6 tetrahydropyridin-4-yl) methylphosphinic acid, GABA C receptor antagonist (20 mg per paw). The peripheral antinociception induced by baclofen (60 mg) was reversed, in a dose-dependent manner, by the voltage-dependent K þ channel blockers tetraethylammonium (7.5 -30 mg per paw) and 4-aminopyridine (2.5 -10 mg per paw). The blockers of other K þ channels, glibenclamide (160 mg), tolbutamide (320 mg), charybdotoxin (2 mg), dequalinium (50 mg) and caesium (500 mg) had no effect. Conclusions and Implications: This study provides evidence that the peripheral antinociceptive effect of the GABA B receptor agonist baclofen results from the activation of tetraethylammonium-sensitive K þ channels. Other K þ channels appear not to be involved.

No abstract