Protective role of neuronal and lymphoid cannabinoid CB(2) receptors in neuropathic pain

Cabañero, David; Ramírez-López, Angela; Drews, Eva; Schmöle, Anne; Otte, David M; Wawrzczak-Bargiela, Agnieszka; Huerga Encabo, Hector; Kummer, Sami; Ferrer-Montiel, Antonio; Przewlocki, Ryszard; Zimmer, Andreas; Maldonado, Rafael

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.