Among several pharmacological properties, analgesia is the most common feature shared by either opioid or cannabinoid systems. In the nervous system, neurotransmission and neuroinflammation are mediated by the endocannabinoid signalling system. Two subtypes of the mammalian cannabinoid receptors, CB1 and CB2, have been identified. Opioids produce their pharmacological effects by acting mainly through three types of receptors, namely μ, δ and κ. Anti-nociceptive tolerance to opioids severely limits their clinical efficacy for the treatment of chronic pain syndromes. It has been demonstrated that glia has a central role in the development of morphine tolerance. Microglia, a specialized population of macrophages found in the CNS, are quiescent in normal brain. However, after CNS injury these cells can be activated by cytokines produced by infiltrating immune effector cells. Interestingly, receptors for opioids and cannabinoids are coupled to similar intracellular signalling mechanisms leading to a decrease in cAMP production through the activation of Gi proteins. Therefore, following the discovery that opioids and cannabinoids produce not only similar biochemical effects but also similar pharmacological effects, the interaction between these two classes of drugs has been extensively studied. In the present study, at first we characterized the signal transduction pathways affected by CB2 receptors in quiescent and activated murine microglia. Our results demonstrated that CB2 receptors stimulation, through MAPK pathway modulation, may promote anti-inflammatory responses in activated microglia. Next, we investigated whether and how CB2 receptor stimulation affected opioid actions on activated microglia. The results indicate that morphine increases PKCε expression and activation and stimulates Akt pathway upstream of ERK1/2 and iNOS in activated microglia. Furthermore, we found that morphine enhanced the release of IL-1β, TNF-α, IL-6 and of NO via μ- opioid receptor-PKCε signalling pathway in activated microglial cells, mediating a proinflammatory phenotype in mouse microglial cells. Interestingly, CB2 receptor stimulation attenuated morphine-induced microglial proinflammatory mediator increases, interfering with morphine action by acting on the Akt-ERK1/2 signalling pathway. 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.

CANNABINOID CB2 AND μ-OPIOID RECEPTORS SIGNALLING IN MICROGLIAL CELLS: POTENTIAL TARGETS TO INCREASE CLINICAL EFFICACY OF OPIOIDS

FAZZI, Debora
2015

Abstract

Among several pharmacological properties, analgesia is the most common feature shared by either opioid or cannabinoid systems. In the nervous system, neurotransmission and neuroinflammation are mediated by the endocannabinoid signalling system. Two subtypes of the mammalian cannabinoid receptors, CB1 and CB2, have been identified. Opioids produce their pharmacological effects by acting mainly through three types of receptors, namely μ, δ and κ. Anti-nociceptive tolerance to opioids severely limits their clinical efficacy for the treatment of chronic pain syndromes. It has been demonstrated that glia has a central role in the development of morphine tolerance. Microglia, a specialized population of macrophages found in the CNS, are quiescent in normal brain. However, after CNS injury these cells can be activated by cytokines produced by infiltrating immune effector cells. Interestingly, receptors for opioids and cannabinoids are coupled to similar intracellular signalling mechanisms leading to a decrease in cAMP production through the activation of Gi proteins. Therefore, following the discovery that opioids and cannabinoids produce not only similar biochemical effects but also similar pharmacological effects, the interaction between these two classes of drugs has been extensively studied. In the present study, at first we characterized the signal transduction pathways affected by CB2 receptors in quiescent and activated murine microglia. Our results demonstrated that CB2 receptors stimulation, through MAPK pathway modulation, may promote anti-inflammatory responses in activated microglia. Next, we investigated whether and how CB2 receptor stimulation affected opioid actions on activated microglia. The results indicate that morphine increases PKCε expression and activation and stimulates Akt pathway upstream of ERK1/2 and iNOS in activated microglia. Furthermore, we found that morphine enhanced the release of IL-1β, TNF-α, IL-6 and of NO via μ- opioid receptor-PKCε signalling pathway in activated microglial cells, mediating a proinflammatory phenotype in mouse microglial cells. Interestingly, CB2 receptor stimulation attenuated morphine-induced microglial proinflammatory mediator increases, interfering with morphine action by acting on the Akt-ERK1/2 signalling pathway. 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.
MERIGHI, Stefania
CUNEO, Antonio
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2388989
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