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Selective ligands of A(1), A(2A), A(2B) and A(3) adenosine receptors are likely to find applications in the treatment of pain, ischemic conditions, glaucoma, asthma, arthritis, cancer and other disorders in which inflammation is a feature. The aim of this review is to provide an overview of the present knowledge regarding the role of these adenosine receptors in health and disease.

Increased production of proinflammatory cytokines has a prominent role in tolerance to opioids. The objectives of this study were to examine whether μ‐opioid receptor affects proinflammatory signalling through the activation of NF‐kB in microglia. The novelty of the described research is that a low dose of morphine, exerting its effects via the μ‐opioid receptor, increases the DNA‐binding activity of NF‐kB via PKCε, while a high dose of morphine triggers a nonopiate receptor response mediated by TLR4 and, interestingly, PKCε signalling. The identification of morphine as a crucial upstream regulator of PKCε‐NF‐κB signalling in microglia argues for a central role of these pathways in neuroinflammation development and progression. Therefore, the morphine‐PKCε‐NF‐κB pathway may provide novel targets to induce neuroprotective mechanisms, thereby reducing tolerance to opioids.

BACKGROUND AND PURPOSEAmong 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 m-opioid receptors in quiescent and LPS-stimulated murine microglial cells. EXPERIMENTAL APPROACHWe examined the effects of m-opioid and CB2 receptor stimulation on phosphorylation of MAPKs and Akt and on IL-1b, TNF-a, IL-6 and NO production in primary mouse microglial cells. KEY RESULTSMorphine enhanced release of the proinflammatory cytokines, IL-1b, TNF-a, IL-6, and of NO via m-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 IMPLICATIONSBecause 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. AM 251, AM 630, Abbreviations

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