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

Cannabinoid CB 2 receptor (CB 2 ) agonists are potential analgesics void of psychotropic effects. Peripheral immune cells, neurons and glia express CB 2 ; however, the involvement of CB 2 from these cells in neuropathic pain remains unresolved. We explored spontaneous neuropathic pain through on-demand self-administration of the selective CB 2 agonist JWH133 in wild-type and knockout mice lacking CB 2 in neurons, monocytes or constitutively. Operant self-administration reflected drug-taking to alleviate spontaneous pain, nociceptive and affective manifestations. While constitutive deletion of CB 2 disrupted JWH133-taking behavior, this behavior was not modified in monocyte-specific CB 2 knockouts and was increased in mice defective in neuronal CB 2 knockouts suggestive of increased spontaneous pain. Interestingly, CB 2 -positive lymphocytes infiltrated the injured nerve and possible CB 2 transfer from immune cells to neurons was found. Lymphocyte CB 2 depletion also exacerbated JWH133 self-administration and inhibited antinociception. This work identifies a simultaneous activity of neuronal and lymphoid CB 2 that protects against spontaneous and evoked neuropathic pain.