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In the present work we investigated on rat splenocytes long-term interactions between opioid and cannabinoid drugs in terms of a common regulation of cAMP intracellular pathway. Both morphine and the synthetic cannabinoid compound CP-55,940 inhibited in a concentration-dependent manner the intracellular cAMP level in splenocytes stimulated by forskolin. The in vitro combination of submaximal concentrations of the two drugs did not yield any additive effect on the inhibition induced by the two drugs. In splenocytes taken from rats chronically treated with CP-55,940 (0.2 mg/kg i.p., twice a day for 4.5 days) or morphine (5 mg/kg s.c., twice a day for 6.5 days) and in vitro exposed to either CP-55,940 or morphine, it was found a desensitisation and cross-desensitisation to the inhibitory effects on cAMP production induced by the two drugs. Binding experiments on the cannabinoid receptors level in spleen coronal sections after in vivo chronic administration of morphine, revealed that there was no changes in the binding of [H3]-CP-55,940. Thus, these results strengthen the hypothesis of cAMP as part of the common intracellular pathway shared by opiates and cannabinoids at immune cell level.

Cannabinoids have been shown to affect immune responses, acting on different populations of immune cells. In the present paper we analyze the ability of in vivo and in vitro treatment with the potent synthetic cannabinoid CP55,940 to interfere with an important function of rat peritoneal macrophages, i.e. spontaneous migration and formyl-metionyl-leucine-phenylalanine (fMLP)-induced chemotaxis, that were assessed by the use of a Boyden-modified microchemotaxis chamber. When added in vitro, CP55,940 induced a significant and dose-dependent inhibition of both spontaneous migration and fMLP-induced chemotaxis. Both the Cannabinoid Receptor 1 (CB1) and the Cannabinoid Receptor 2 (CB2) antagonists were able to block the CP55,940-induced inhibition of spontaneous migration, although the CB2 antagonist was more potent and only the CB2 antagonist was able to reverse the effect of CP55,940 on fMLP-induced chemotaxis. Similarly, in the in vivo experiments, 1 h after the acute subcutaneous administration of 0.4 mg/kg of CP55,940, both spontaneous motility and chemotaxis were reduced. The pretreatment with the CB2 antagonist, but not with the CB1 antagonist, was able to prevent this effect. Our data confirm that cannabinoids can affect some macrophage functions, mainly throughout CB2 receptors, and suggest that the development of specific CB2 ligands may lead to an interesting new class of anti-inflammatory drugs.

We studied the effect of acute (1 h) or chronic exposure (7 and 14 days) to delta9-tetrahydrocannabinol (delta9-THC) on immune parameters in male Swiss mice. One hour after a dose of 10 mg/kg s.c., the splenocyte proliferative response to ConA and NK activity were not inhibited, but there was a significant decrease in the production of IL-2. After 7 days of treatment, when mice were tolerant to delta9-THC-induced analgesia, these functional parameters were strongly inhibited and there was a persistent reduction in IL-2 and IFNgamma. With 14 days exposure to the drug, splenocyte proliferation was significantly reduced only with 5 microg/ml ConA, and NK activity was still significantly depressed (about 37%). IL-2 had returned to the control value, whereas IFNgamma was still 40% down. Flow cytometry analysis of spleen cell composition indicated no changes after the acute and 7 day treatments, but at 14 days there was a 20% decrease in the number of T lymphocytes, mirrored by a 26% increase of B lymphocytes. In conclusion, in vivo exposure to psychoactive doses of delta9-THC has profound effects on immune function. This implies some important questions in relation to the liberalization of marijuana and its therapeutic uses.