Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain; Institute of Research, Development and Innovation in Healthcare Biotechnology of Elche (IDiBE), Universidad Miguel Hernández de Elche, Alicante, Spain
Angela Ramírez-López
Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
Eva Drews
Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany
Anne Schmöle
Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany
David M Otte
Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany
Agnieszka Wawrzczak-Bargiela
Department of Pharmacology, Laboratory of Pharmacology and Brain Biostructure, Maj Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
Hector Huerga Encabo
Immunology Unit, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain; Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom
Sami Kummer
Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
Antonio Ferrer-Montiel
Institute of Research, Development and Innovation in Healthcare Biotechnology of Elche (IDiBE), Universidad Miguel Hernández de Elche, Alicante, Spain
Ryszard Przewlocki
Department of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
Andreas Zimmer
Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany
Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain; IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
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.
