Role of the endocannabinoid system in a mouse model of Fragile X undergoing neuropathic pain

Autor: R. de la Torre, C. La Porta, D. Cabañero, Antoni Pastor, A. Ozaita, Á. Ramírez‐López, Rafael Maldonado
Rok vydání: 2021
Předmět:
Zdroj: European Journal of Pain. 25:1316-1328
ISSN: 1532-2149
1090-3801
DOI: 10.1002/ejp.1753
Popis: Background: Neuropathic pain is a complex condition characterized by sensory, cognitive and affective symptoms that magnify the perception of pain. The underlying pathogenic mechanisms are largely unknown and there is an urgent need for the development of novel medications. The endocannabinoid system modulates pain perception and drugs targeting the cannabinoid receptor type 2 (CB2) devoid of psychoactive side effects could emerge as novel analgesics. An interesting model to evaluate the mechanisms underlying resistance to pain is the fragile X mental retardation protein knockout mouse (Fmr1KO), a model of fragile X syndrome that exhibits nociceptive deficits and fails to develop neuropathic pain. Methods: A partial sciatic nerve ligation was performed to wild-type (WT) and Fmr1KO mice having (HzCB2 and Fmr1KO-HzCB2, respectively) or not (WT and Fmr1KO mice) a partial deletion of CB2 to investigate the participation of the endocannabinoid system on the pain-resistant phenotype of Fmr1KO mice. Results: Nerve injury induced canonical hypersensitivity in WT and HzCB2 mice, whereas this increased pain sensitivity was absent in Fmr1KO mice. Interestingly, Fmr1KO mice partially lacking CB2 lost this protection against neuropathic pain. Similarly, pain-induced depressive-like behaviour was observed in WT, HzCB2 and Fmr1KO-HzCB2 mice, but not in Fmr1KO littermates. Nerve injury evoked different alterations in WT and Fmr1KO mice at spinal and supra-spinal levels that correlated with these nociceptive and emotional alterations. Conclusions: This work shows that CB2 is necessary for the protection against neuropathic pain observed in Fmr1KO mice, raising the interest in targeting this receptor for the treatment of neuropathic pain. Significance: Neuropathic pain is a complex chronic pain condition and current treatments are limited by the lack of efficacy and the incidence of important side effects. Our findings show that the pain-resistant phenotype of Fmr1KO mice against nociceptive and emotional manifestations triggered by persistent nerve damage requires the participation of the cannabinoid receptor CB2, raising the interest in targeting this receptor for neuropathic pain treatment. Additional multidisciplinary studies more closely related to human pain experience should be conducted to explore the potential use of cannabinoids as adequate analgesic tools. This work was supported by research grants from the Spanish Ministry of Science and Innovation (#SAF2017-84060-R-AEI/FEDER-UE), the European Commission-DG Research (PainFact, #H2020-SC1-2019-2-RTD-848099), the Instituto de Salud Carlos III-RETICS (RTA, #RD16/0017/0020), the Spanish Ministerio de Sanidad, Servicios Sociales e Igualdad-Plan Nacional Sobre Drogas (#PNSD-2017I068) to RM; and the Catalan Government-AGAUR (#SGR2017-669 and ICREA Academia Award 2015 to RM and SGR2017-138 to RdlT). AR-L is the recipient of a FI predoctoral fellowship (Generalitat de Catalunya-AGAUR).
Databáze: OpenAIRE
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