1 It is well-established that inhibitors of cyclo-oxygenase (COX) and hence of prostaglandin (PG) biosynthesis reverse in¯ammatory hyperalgesia and oedema in both human and animal models of in¯ammatory pain. 2 Paw oedema and hyperalgesia in rats were induced by injecting carrageenan (250 mg paw 71 ) into a hindpaw. Both in¯ammatory responses were followed for 24 h after the injection, measuring hyperalgesia by decreased pain threshold in the paws and oedema by plethysmography. 3 Three selective inhibitors of cyclo-oxygenase-2 (COX-2), celecoxib, rofecoxib and SC 236, given systemically in a range of doses, before the in¯ammatory stimulus, abolished carrageenan-induced hyperalgesia with little reduction of oedema. These inhibitors also induced hypoalgesia, increasing nociceptive thresholds in the in¯amed paw above normal, non-in¯amed levels. This hypoalgesia was lost at the higher doses of the selective inhibitors, although hyperalgesia was still prevented. 4 In paws injected with saline only, celecoxib, given at the dose inducing the maximum hypoalgesia after carrageenan, did not alter the nociceptive thresholds. 5 Two non-selective inhibitors of COX-2, indomethacin and piroxicam, abolished hyperalgesia and reduced oedema but did not induce hypoalgesia. 6 Celecoxib given locally into the paw also abolished in¯ammatory hyperalgesia and induced hypoalgesia without reducing oedema. 7 We conclude that hypoalgesia is expressed only over a critical range of COX-2 inhibition and that concomitant inhibition of COX-1 prevents expression of hypoalgesia, although hyperalgesia is still prevented. 8 Our results suggest a novel anti-nociceptive pathway mediating hypoalgesia, involving COX-2 selectively and having a clear peripheral component. This peripheral component can be further explored for therapeutic purposes.

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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 analgesics, paracetamol and dipyrone are weak inhibitors of the cyclooxygenase isoforms 1 or 2 (COX-1, COX-2) but more potent on COX-3. Both are also weak anti-inflammatory agents, relative to their analgesic and antipyretic activities. In a model of inflammatory pain mediated by prostaglandins, both compounds were analgesic. We have analysed this shared effect further in order to elucidate the underlying mechanisms. Experimental approach: Inflammation was induced in one hind paw of rats by intraplantar injection of 250 mg l-carrageenan (CG) and the contralateral paw injected with saline. Nociceptive thresholds to mechanical stimulation were measured immediately before and for 6 h after, injection of CG. The analgesics were s.c. or locally (intraplantar) injected either 30 min before or 2 h after CG. In some groups, naltrexone was injected (s.c. or intraplantar), 1 h before CG. Key results: Pretreatment with paracetamol or dipyrone (60-360 mg kg À1 ) reversed hyperalgesia induced by CG and increased nociceptive threshold in the inflamed paw above the basal level (hypoalgesia). Paracetamol, but not dipyrone, also raised nociceptive thresholds in the non-inflamed paw. Subcutaneous, but not local, administration of naltrexone, a specific opioid antagonist, reversed the hypoalgesia induced by paracetamol, but similar naltrexone treatment had no effect on dipyrone-induced analgesia. Conclusions and implications: Although both paracetamol and dipyrone are inhibitors of COX isoforms and thus of prostaglandin biosynthesis and were analgesic in our model, their analgesic actions were functionally and mechanistically different. Satisfactory mechanisms of action for these analgesics still remain to be established.