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 CB(2 ) and µ-opioid receptors in quiescent and lipopolysaccharide (LPS)-stimulated murine microglial cells. Experimental approach: We examined the effects of µ-opioid and CB(2) receptor stimulation on phosphorylation of mitogen-activated protein kinases (MAPKs) and Akt and on interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6 and nitric oxide (NO) production in primary mouse microglial cells. Key results: We demonstated that morphine enhances the release of the IL-1β, TNF-α??IL-6 proinflammatory cytokines and NO via µ-opioid receptor in activated microglial cells. In contrast, CB(2) receptor stimulation attenuates morphine-induced microglial proinflammatory mediator increases interfering with morphine-action by acting on Akt-ERK1/2 signalling. Conclusions and implications: Because glial activation opposes opioid analgesia and enhances opioid tolerance and dependence, we suggest that CB(2) receptors, by inhibiting microglial activity, may be potential targets to increase clinical efficacy of opioids
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