Cannabidiol, the major non-psychoactive component of marijuana, has various pharmacological actions of clinical interest. It is reportedly effective as an anti-inflammatory and anti-arthritic in murine collagen-induced arthritis. The present study examined the anti-inflammatory and anti-hyperalgesic effects of cannabidiol, administered orally (5-40 mg/kg) once a day for 3 days after the onset of acute inflammation induced by intraplantar injection of 0.1 ml carrageenan (1% w/v in saline) in the rat. At the end of the treatment prostaglandin E2 (PGE2) was assayed in the plasma, and cyclooxygenase (COX) activity, production of nitric oxide (NO; nitrite/nitrate content), and of other oxygen-derived free radicals (malondialdehyde) in inflamed paw tissues. All these markers were significantly increased following carrageenan. Thermal hyperalgesia, induced by carrageenan and assessed by the plantar test, lasted 7 h. Cannabidiol had a time- and dose-dependent anti-hyperalgesic effect after a single injection. Edema following carrageenan peaked at 3 h and lasted 72 h; a single dose of cannabidiol reduced edema in a dose-dependent fashion and subsequent daily doses caused further time- and dose-related reductions. There were decreases in PGE2 plasma levels, tissue COX activity, production of oxygen-derived free radicals, and NO after three doses of cannabidiol. The effect on NO seemed to depend on a lower expression of the endothelial isoform of NO synthase. In conclusion, oral cannabidiol has a beneficial action on two symptoms of established inflammation: edema and hyperalgesia.

1 The antiin¯ammatory activity of synthetic cannabinoid nabilone in the rat model of carrageenaninduced acute hindpaw in¯ammation was compared with that of the endocannabinoid palmitoylethanolamide and the nonsteroidal antiin¯ammatory drug indomethacin. 2 Preliminary experiments in rats used a tetrad of behavioural tests, speci®c for tetrahydrocannabinol-type activity in the CNS. These showed that the oral dose of nabilone 2.5 mg kg 71 had no cannabinoid psychoactivity. 3 Intraplantar injection of carrageenan (1% w v 71 ) elicited a time-dependent increase in paw volume and thermal hyperalgesia. 4 Nabilone (0.75, 1.5, 2.5 mg kg 71 , 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 71 , palmitoylethanolamide 10 mg kg 71 and indomethacin 5 mg kg 71 , given p.o. 1 h before carrageenan, also reduced the in¯ammatory 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 71 p.o. 1 h before nabilone and palmitoylethanolamide, prevented the anti-oedema and antihyperalgesic e ects of the two cannabinoid agonists 3 h after carrageenan. 6 Our ®ndings show the antiin¯ammatory e ect of nabilone and con®rm that of palmitoylethanolamide indicating that these actions are mediated by an uncharacterized CB 2 -like cannabinoid receptor.

1 The anti-in¯ammatory activity of the endogenous fatty acid amide palmitoylethanolamide and its relationship to cyclo-oxygenase (COX) activity, nitric oxide (NO) and oxygen free radical production were investigated in the rat model of carrageenan-induced acute paw in¯ammation and compared with the nonsteroidal anti-in¯ammatory drug (NSAID) indomethacin. 2 Palmitoylethanolamide (1, 3, 5, 10 mg kg 71 ; p.o.) and indomethacin (5 mg kg 71 ; p.o.) were administered daily after the onset of in¯ammation for three days and the paw oedema was measured daily; 24 h after the last dose (fourth day) the rats were killed and the COX activity and the content of nitrite/nitrate (NO 2 7 /NO 3 7 ), malondialdehyde (MDA), endothelial and inducible nitric oxide synthase (eNOS and iNOS) were evaluated in the paw tissues. , eNOS and MDA were increased in the in¯amed paw, but iNOS was not present. Palmitoylethanolamide (10 mg kg 71 ) and indomethacin markedly reduced these increases. 4 Our ®ndings show, for the ®rst time, that palmitoylethanolamide has a curative e ect in a model of acute in¯ammation. The inhibition of COX activity and of NO and free radical production at the site of in¯ammation might account for this activity.

The antinociceptive properties of cannabinoids in persistent pain are not fully elucidated. We investigated the effect of repeated treatment with the synthetic cannabinoid receptor agonist WIN 55,212-2 on the neuropathic pain induced in rats by chronic constriction of the sciatic nerve. WIN 55,212-2 administered daily throughout the development of neuropathy reversed the hyperalgesia, at a dose (0.1 mg kg À1 , s.c.) that had no effect on the nociceptive responses of either paw contralateral to the sciatic ligation or of animals subjected to sham surgery. At 14 days after injury, the levels of mediators known to be involved in neuropathic pain, such as prostaglandin E2, NO and the neuronal NOS, were increased. Repeated treatment with WIN 55,212-2 abolished these increases. In the light of the current clinical need for neuropathic pain treatments, these findings indicate that cannabinoid agonists, at doses devoid of psychoactive effects, could constitute important compounds for the development of new analgesics.

Different stressful conditions such as hypoxia, nutrient deprivation, pH changes, or reduced vascularization, potentially able to act as growth-limiting factors for tumor cells, activate the unfolded protein response (UPR). UPR is therefore involved in tumor growth and adaptation to severe environments and is generally cytoprotective in cancer. The present review describes the molecular mechanisms underlying UPR and able to promote survival and proliferation in cancer. The critical role of UPR activation in tumor growth promotion is discussed in detail for a few paradigmatic tumors such as prostate cancer and melanoma.