Cabañero Ferri, DavidRamírez-López, AngelaDrews, EvaSchmöle, AnneOtte, David M.Wawrzczak-Bargiela, AgnieszkaHuerga Encabo, Hector, 1989-Kummer, Sami, 1985-Ferrer-Montiel, AntonioPrzewlocki, RyszardZimmer, AndreasMaldonado, Rafael, 1961-2021-06-182021-06-182020Cabañero D, Ramírez-López A, Drews E, Schmöle A, Otte DM, Wawrzczak-Bargiela A, Huerga Encabo H, Kummer S, Ferrer-Montiel A, Przewlocki R, Zimmer A, Maldonado R. Protective role of neuronal and lymphoid cannabinoid CB2 receptors in neuropathic pain. Elife. 2020 Jul 20; 9: e55582. DOI: 10.7554/eLife.555822050-084Xhttp://hdl.handle.net/10230/47932Cannabinoid 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.application/pdfengCopyright © 2020, Cabañero et al. This article is distributed under the terms of the Creative Commons Attribution License, http://creativecommons.org/licenses/by/4.0/ which permits unrestricted use and redistribution provided that the original author and source are credited.info:eu-repo/semantics/articlehttp://dx.doi.org/10.7554/eLife.55582Cannabinoid cb2 receptorHuman biologyMedicinemouseNeuroimmune interactionsNeuronal and lymphocyte cannabinoid receptorsNeuropathic painNeuroscienceOperant drug self-administrationSpontaneous paininfo:eu-repo/semantics/openAccess