The role of the CB2 receptor and human CB2 receptor variants in neuropathic pain

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Our previous research has indicated that CB2 receptors regulate inflammatory responses in the central nervous system after peripheral nerve injury by modulating the activity of microglia cells. Microglia activity is enhanced under neuropathic pain conditions in mice with a genetic deletion of the CB2 receptor encoding Cnr2 gene and enhanced in transgenic animals overexpressing this receptor. This project will investigate the molecular mechanisms that contribute to the enhanced microglia response. We will also address the possible involvement of other cells in the enhanced neuropathic pain phenotype of CB2-/- mice. For this purpose, we will establish mouse strains with a CB2 deletion in microglia, astrocytes and neurons using conditional CB2 knockout (CB2-/-) mice that were generated during the first funding period. The effects of the disruption of CB2 receptor signaling in these cells will be studied by analyzing the behavioral responses in animal models of inflammatory and neuropathic pain. We will also investigate molecular changes associated with these chronic pain conditions, which were also characterized during the first funding period. A further goal of this study is the functional analysis of human CB2 receptor variants in neuropathic pain. For this purpose we are in the process of establishing “humanized” mice, in which the mouse receptors is replaced with the human CB2 receptor variants.