Dual Role of the Spinal Endocannabinoid System in Response to Noxious Stimuli: Antinociceptive Pathways and Neuropathic Pain Mechanisms

Neuropathic pain is a clinically challenging syndrome that is largely refractory to conventional therapies. It arises from lesions or diseases affecting somatosensory pathways, which trigger extensive neuroplastic and neuroimmune remodeling. Unlike nociceptive pain, which establishes a protective re...

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Autores: Saldaña, Raquel, Carrascosa, A., Torregrosa, Abraham B., Navarrete, Francisco, García-Gutiérrez, María Salud, Manzanares, Jorge
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/412114
Acceso en línea:http://hdl.handle.net/10261/412114
https://api.elsevier.com/content/abstract/scopus_id/105021582007
Access Level:acceso abierto
Palabra clave:Antinociception
Cannabinoid receptors
Central sensitization
Endocannabinoid system
Neuroinflammation
Neuropathic pain
Spinal cord
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spelling Dual Role of the Spinal Endocannabinoid System in Response to Noxious Stimuli: Antinociceptive Pathways and Neuropathic Pain MechanismsSaldaña, RaquelCarrascosa, A.Torregrosa, Abraham B.Navarrete, FranciscoGarcía-Gutiérrez, María SaludManzanares, JorgeAntinociceptionCannabinoid receptorsCentral sensitizationEndocannabinoid systemNeuroinflammationNeuropathic painSpinal cordNeuropathic pain is a clinically challenging syndrome that is largely refractory to conventional therapies. It arises from lesions or diseases affecting somatosensory pathways, which trigger extensive neuroplastic and neuroimmune remodeling. Unlike nociceptive pain, which establishes a protective response to tissue injury, neuropathic pain arises from maladaptive signaling within the nervous system. In this context, the spinal endocannabinoid system (ECS) has emerged as a pivotal modulator of nociceptive processing. However, its precise role in neuropathic pain remains debated due to its dual effects. Numerous studies report antinociceptive and neuroprotective effects; however, emerging data indicate that under specific pathological conditions, ECS activation may paradoxically facilitate pain transmission. This review examines spinal ECS context dependence, uncovering its bidirectional antinociceptive and pronociceptive effects in neuropathic pain. By integrating current evidence on cellular, molecular, and pathophysiological mechanisms, we delineate the factors that determine whether ECS modulation inhibits or promotes pain. A comprehensive understanding of these mechanisms is essential for optimizing cannabinoid-based strategies to maximize therapeutic benefits while minimizing adverse outcomes. Finally, we highlight the spinal cord's centrality as the principal site for the initiation and maintenance of neuropathic pain and advocate for rigorous translational research to clarify the therapeutic potential of spinal ECS-targeted interventions.This work was supported by Mutua Madrileña Foundation (UGP-22-010) and “Instituto de Investigación Biomedica y Sanitaria de Alicante” (ISABIAL) to J.M. The Instituto de Neurociencias is a “Centro de Excelencia Severo Ochoa” (CEX2021-001165-S) funded by “Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación” (MCIN/AEI/10.13039/501100011033).With funding from the Spanish government through the "Severo Ochoa Centre of Excelence" accreditation (CEX2021-001165-S)Peer reviewedMultidisciplinary Digital Publishing InstituteFundación Mutua MadrileñaInstituto de Investigación Sanitaria y Biomédica de AlicanteMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Saldaña, Raquel [0009-0006-1460-0391]Carrascosa, A. [0009-0004-4881-6997]Torregrosa, Abraham B. [0009-0004-3438-9162]Navarrete, Francisco [0000-0003-1251-6357]García-Gutiérrez, María Salud [0000-0001-6106-6247]Manzanares, Jorge [0000-0002-4681-1533]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202620262025info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_dcae04bcPublisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/412114https://api.elsevier.com/content/abstract/scopus_id/105021582007reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/CEX2021-001165-SInternational journal of molecular scienceshttps://doi.org/10.3390/ijms262110692Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/4121142026-05-22T06:33:51Z
dc.title.none.fl_str_mv Dual Role of the Spinal Endocannabinoid System in Response to Noxious Stimuli: Antinociceptive Pathways and Neuropathic Pain Mechanisms
title Dual Role of the Spinal Endocannabinoid System in Response to Noxious Stimuli: Antinociceptive Pathways and Neuropathic Pain Mechanisms
spellingShingle Dual Role of the Spinal Endocannabinoid System in Response to Noxious Stimuli: Antinociceptive Pathways and Neuropathic Pain Mechanisms
Saldaña, Raquel
Antinociception
Cannabinoid receptors
Central sensitization
Endocannabinoid system
Neuroinflammation
Neuropathic pain
Spinal cord
title_short Dual Role of the Spinal Endocannabinoid System in Response to Noxious Stimuli: Antinociceptive Pathways and Neuropathic Pain Mechanisms
title_full Dual Role of the Spinal Endocannabinoid System in Response to Noxious Stimuli: Antinociceptive Pathways and Neuropathic Pain Mechanisms
title_fullStr Dual Role of the Spinal Endocannabinoid System in Response to Noxious Stimuli: Antinociceptive Pathways and Neuropathic Pain Mechanisms
title_full_unstemmed Dual Role of the Spinal Endocannabinoid System in Response to Noxious Stimuli: Antinociceptive Pathways and Neuropathic Pain Mechanisms
title_sort Dual Role of the Spinal Endocannabinoid System in Response to Noxious Stimuli: Antinociceptive Pathways and Neuropathic Pain Mechanisms
dc.creator.none.fl_str_mv Saldaña, Raquel
Carrascosa, A.
Torregrosa, Abraham B.
Navarrete, Francisco
García-Gutiérrez, María Salud
Manzanares, Jorge
author Saldaña, Raquel
author_facet Saldaña, Raquel
Carrascosa, A.
Torregrosa, Abraham B.
Navarrete, Francisco
García-Gutiérrez, María Salud
Manzanares, Jorge
author_role author
author2 Carrascosa, A.
Torregrosa, Abraham B.
Navarrete, Francisco
García-Gutiérrez, María Salud
Manzanares, Jorge
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Fundación Mutua Madrileña
Instituto de Investigación Sanitaria y Biomédica de Alicante
Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
Saldaña, Raquel [0009-0006-1460-0391]
Carrascosa, A. [0009-0004-4881-6997]
Torregrosa, Abraham B. [0009-0004-3438-9162]
Navarrete, Francisco [0000-0003-1251-6357]
García-Gutiérrez, María Salud [0000-0001-6106-6247]
Manzanares, Jorge [0000-0002-4681-1533]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Antinociception
Cannabinoid receptors
Central sensitization
Endocannabinoid system
Neuroinflammation
Neuropathic pain
Spinal cord
topic Antinociception
Cannabinoid receptors
Central sensitization
Endocannabinoid system
Neuroinflammation
Neuropathic pain
Spinal cord
description Neuropathic pain is a clinically challenging syndrome that is largely refractory to conventional therapies. It arises from lesions or diseases affecting somatosensory pathways, which trigger extensive neuroplastic and neuroimmune remodeling. Unlike nociceptive pain, which establishes a protective response to tissue injury, neuropathic pain arises from maladaptive signaling within the nervous system. In this context, the spinal endocannabinoid system (ECS) has emerged as a pivotal modulator of nociceptive processing. However, its precise role in neuropathic pain remains debated due to its dual effects. Numerous studies report antinociceptive and neuroprotective effects; however, emerging data indicate that under specific pathological conditions, ECS activation may paradoxically facilitate pain transmission. This review examines spinal ECS context dependence, uncovering its bidirectional antinociceptive and pronociceptive effects in neuropathic pain. By integrating current evidence on cellular, molecular, and pathophysiological mechanisms, we delineate the factors that determine whether ECS modulation inhibits or promotes pain. A comprehensive understanding of these mechanisms is essential for optimizing cannabinoid-based strategies to maximize therapeutic benefits while minimizing adverse outcomes. Finally, we highlight the spinal cord's centrality as the principal site for the initiation and maintenance of neuropathic pain and advocate for rigorous translational research to clarify the therapeutic potential of spinal ECS-targeted interventions.
publishDate 2025
dc.date.none.fl_str_mv 2025
2026
2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_dcae04bc
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/412114
https://api.elsevier.com/content/abstract/scopus_id/105021582007
url http://hdl.handle.net/10261/412114
https://api.elsevier.com/content/abstract/scopus_id/105021582007
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/CEX2021-001165-S
International journal of molecular sciences
https://doi.org/10.3390/ijms262110692
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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