Protective role of neuronal and lymphoid cannabinoid CB(2) 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.