Antiinflammatory action of endocannabinoid palmitoylethanolamide and the synthetic cannabinoid nabilone in a model of acute inflammation in the rat

Abstract

1. The antiinflammatory activity of synthetic cannabinoid nabilone in the rat model of carrageenan-induced acute hindpaw inflammation was compared with that of the endocannabinoid palmitoylethanolamide and the nonsteroidal antiinflammatory drug indomethacin. 2. Preliminary experiments in rats used a tetrad of behavioural tests, specific for tetrahydrocannabinol-type activity in the CNS. These showed that the oral dose of nabilone 2.5 mg kg(-1) had no cannabinoid psychoactivity. 3. Intraplantar injection of carrageenan (1% w v(-1)) elicited a time-dependent increase in paw volume and thermal hyperalgesia. 4. Nabilone (0.75, 1.5, 2.5 mg kg(-1), p.o.), given 1 h before carrageenan, reduced the development of oedema and the associated hyperalgesia in a dose-related manner. Nabilone 2.5 mg kg(-1), palmitoylethanolamide 10 mg kg(-1) and indomethacin 5 mg kg(-1), given p.o. 1 h before carrageenan, also reduced the inflammatory parameters in a time-dependent manner. 5. The selective CB(2) cannabinoid receptor antagonist [N-[(1S)-endo-1,3,3-trimethyl bicyclo [2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3 carboxamide] (SR 144528), 3 mg kg(-1) p.o. 1 h before nabilone and palmitoylethanolamide, prevented the anti-oedema and antihyperalgesic effects of the two cannabinoid agonists 3 h after carrageenan. 6. Our findings show the antiinflammatory effect of nabilone and confirm that of palmitoylethanolamide indicating that these actions are mediated by an uncharacterized CB(2)-like cannabinoid receptor.

Figure 1

Time course of behavioural effects induced by oral nabilone in the rat. Each point represents the mean±s.e.mean of 3 – 4 animals. ^***P<0.001, ^**P<0.01 vs vehicle; •••P<0.001, ••P<0.01, •P<0.05 vs nabilone 2.5 mg kg⁻¹.

Figure 2

Effect of palmitoylethanolamide (PEA) 10 mg kg⁻¹, nabilone (NAB) 2.5 mg kg⁻¹ and indomethacin (ID) 5 mg kg⁻¹ given orally to the rat 1 h before carrageenan, on oedema (a) and ipsilateral hindpaw withdrawal latency (b) 1, 2, 3 and 10 h after injection of carrageenan. Each point represents the mean±s.e.mean of 6 – 9 animals. ^***P<0.001, ^*P<0.05 vs vehicle.

Figure 3

Dose-response relationships for anti-oedema (a) and antihyperalgesic effect (b) of nabilone orally administered in the rat 1 h before carrageenan. The response was measured at 3 h after injection of carrageenan. Each symbol represents the mean±s.e.mean of four animals.

Figure 4

Effect of SR 144528 (SR) 3 mg kg⁻¹, p.o. in the rat 1 h before palmitoylethanolamide (PEA) 10 mg kg⁻¹ p.o., nabilone (NAB) 2.5 mg kg⁻¹ p.o., indomethacin (ID) 5 mg kg⁻¹ p.o. or vehicle, on oedema 3 h after injection of carrageenan. Each point represents the mean±s.e.mean of 10 – 15 animals. ^***P<0.001, ^**P<0.01 vs vehicle; +P<0.05 vs PEA; ♦♦P<0.01 vs NAB.

Figure 5

Effect of SR 144528 (SR) 3 mg kg⁻¹, p.o. in the rat 1 h before palmitoylethanolamide (PEA) 10 mg kg⁻¹ p.o., nabilone (NAB) 2.5 mg kg⁻¹ p.o., indomethacin (ID) 5 mg kg⁻¹ p.o. or vehicle, on ipsilateral hindpaw withdrawal latency 3 h after injection of carrageenan. Baseline hindpaw withdrawal latencies measured before carrageenan were not different from each other. Thus in the figure the base indicates the baseline ipsilateral hindpaw withdrawal latencies of vehicle-treated rats. Each point represents the mean±s.e.mean of 10 – 15 animals. ^***P<0.001 vs vehicle; •••P<0.001, ••P<0.01 vs base; +++P<0.001 vs PEA; ♦♦P<0.01 vs NAB.