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Blockade of the sigma-1 receptor relieves cognitive and emotional impairments associated to chronic osteoarthritis pain

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dc.contributor.author Carcolé, Mireia
dc.contributor.author Zamanillo, Daniel
dc.contributor.author Merlos, Manuel
dc.contributor.author Fernández-Pastor, Begoña
dc.contributor.author Cabañero Ferri, David
dc.contributor.author Maldonado, Rafael, 1961-
dc.date.accessioned 2019-09-06T14:15:47Z
dc.date.available 2019-09-06T14:15:47Z
dc.date.issued 2019
dc.identifier.citation Carcolé M, Zamanillo D, Merlos M, Fernández-Pastor B, Cabañero D, Maldonado R. Blockade of the sigma-1 receptor relieves cognitive and emotional impairments associated to chronic osteoarthritis pain. Front Pharmacol. 2019; 10:468. DOI 10.3389/fphar.2019.00468
dc.identifier.issn 1663-9812
dc.identifier.uri http://hdl.handle.net/10230/42253
dc.description.abstract Osteoarthritis is the most common musculoskeletal disease worldwide, often characterized by degradation of the articular cartilage, chronic joint pain and disability. Cognitive dysfunction, anxiety and depression are common comorbidities that impact the quality of life of these patients. In this study, we evaluated the involvement of sigma-1 receptor (σ1R) on the nociceptive, cognitive and emotional alterations associated with chronic osteoarthritis pain. Monosodium iodoacetate (MIA) was injected into the knee of Swiss-albino CD1 mice to induce osteoarthritis pain, which then received a repeated treatment with the σ1R antagonist E-52862 or its vehicle. Nociceptive responses and motor performance were assessed with the von Frey and the Catwalk gait tests. Cognitive alterations were evaluated using the novel object recognition task, anxiety-like behavior with the elevated plus maze and the zero-maze tests, whereas depressive-like responses were determined using the forced swimming test. We also studied the local effect of the σ1R antagonist on cartilage degradation, and its central effects on microglial reactivity in the medial prefrontal cortex. MIA induced mechanical allodynia and gait abnormalities that were prevented by the chronic treatment with the σ1R antagonist. E-52862 also reduced the memory impairment and the depressive-like behavior associated to osteoarthritis pain. Interestingly, the effect of E-52862 on depressive-like behavior was not accompanied by a modification of anxiety-like behavior. The pain-relieving effects of the σ1R antagonist were not due to a local effect on the articular cartilage, since E-52862 treatment did not modify the histological alterations of the knee joints. However, E-52862 induced central effects revealed by a reduction of the cortical microgliosis observed in mice with osteoarthritis pain. These findings show that σ1R antagonism inhibits mechanical hypersensitivity, cognitive deficits and depressive-like states associated with osteoarthritis pain in mice. These effects are associated with central modulation of glial activity but are unrelated to changes in cartilage degradation. Therefore, targeting the σ1R with E-52862 represents a promising pharmacological approach with effects on multiple aspects of chronic osteoarthritis pain that may go beyond the strict inhibition of nociception.
dc.description.sponsorship We acknowledge the financial support of the European Commission (FP7, NeuroPain #2013-602891), the Catalan Government (AGAUR, #SGR2017-669), the Spanish Instituto de Salud Carlos III (RTA, #RD16/0017/0020), and AGAUR (ICREA Academia Award 2015). MC is the recipient of an Industrial Doctorate contract from the Catalan Government and Laboratorios Esteve (AGAUR, #2014-DI-040). Partial support from FEDER funds is also acknowledged.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Frontiers
dc.relation.ispartof Front Pharmacol. 2019; 10:468
dc.rights © 2019 Carcolé, Zamanillo, Merlos, Fernández-Pastor, Cabañero and Maldonado. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (https://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
dc.rights.uri https://creativecommons.org/licenses/by/4.0/
dc.title Blockade of the sigma-1 receptor relieves cognitive and emotional impairments associated to chronic osteoarthritis pain
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.3389/fphar.2019.00468
dc.subject.keyword Osteoarthritis
dc.subject.keyword Pain
dc.subject.keyword Sigma-1 receptor
dc.subject.keyword Cognition
dc.subject.keyword Depression
dc.subject.keyword Microglia
dc.subject.keyword Medial prefrontal cortex
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/602891
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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