Cannabinoid CB2 receptor attenuates morphine-induced inflammatory responses in activated microglial cells

BACKGROUND AND PURPOSE Among several pharmacological properties, analgesia is the most common feature shared by either opioid or cannabinoid systems. Cannabinoids and opioids are distinct drug classes that have been historically used separately or in combination to treat different pain states. In the present study, we characterized the signal transduction pathways mediated by cannabinoid CB2 and mu-opioid receptors in quiescent and LPS-stimulated murine microglial cells. EXPERIMENTAL APPROACH We examined the effects of mu-opioid and CB2 receptor stimulation on phosphorylation of MAPKs and Akt and on IL-1 beta, TNF-alpha, IL-6 and NO production in primary mouse microglial cells. KEY RESULTS Morphine enhanced release of the proinflammatory cytokines, IL-1 beta, TNF-alpha, IL-6, and of NO via mu-opioid receptor in activated microglial cells. In contrast, CB2 receptor stimulation attenuated morphine-induced microglial proinflammatory mediator increases, interfering with morphine action by acting on the Akt-ERK1/2 signalling pathway. CONCLUSIONS AND IMPLICATIONS Because glial activation opposes opioid analgesia and enhances opioid tolerance and dependence, we suggest that CB2 receptors, by inhibiting microglial activity, may be potential targets to increase clinical efficacy of opioids.