Protective role of neuronal and lymphoid cannabinoid CB2 receptors in neuropathic pain

Cannabinoid CB₂ receptor (CB₂) agonists are potential analgesics void of psychotropic effects. Peripheral immune cells, neurons and glia express CB₂; however, the involvement of CB₂ from these cells in neuropathic pain remains unresolved. We explored spontaneous neuropathic pain through on-demand self-administration of the selective CB₂ agonist JWH133 in wild-type and knockout mice lacking CB₂ in neurons, monocytes or constitutively. Operant self-administration reflected drug-taking to alleviate spontaneous pain, nociceptive and affective manifestations. While constitutive deletion of CB₂ disrupted JWH133-taking behavior, this behavior was not modified in monocyte-specific CB₂ knockouts and was increased in mice defective in neuronal CB₂ knockouts suggestive of increased spontaneous pain. Interestingly, CB₂-positive lymphocytes infiltrated the injured nerve and possible CB₂transfer from immune cells to neurons was found. Lymphocyte CB₂depletion also exacerbated JWH133 self-administration and inhibited antinociception. This work identifies a simultaneous activity of neuronal and lymphoid CB₂that protects against spontaneous and evoked neuropathic pain.