β–Lactam TRPM8 Antagonist RGM8-51 Displays Antinociceptive Activity in Different Animal Models
Transient receptor potential melastatin subtype 8 (TRPM8) is a cation channel extensively expressed in sensory neurons and implicated in different painful states. However, the effectiveness of TRPM8 modulators for pain relief is still a matter of discussion, since structurally diverse mod- ulators l...
| Autores: | , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/269728 |
| Acceso en línea: | http://hdl.handle.net/10261/269728 |
| Access Level: | acceso abierto |
| Palabra clave: | TRPM8 channels antagonist β–lactam oxaliplatin-induced peripheral neuropathy CCI chronic neuropathic nociception NTG-induced hyperesthesia |
| id |
ES_63002500ff1015a82d4f412e4e4c6fda |
|---|---|
| oai_identifier_str |
oai:digital.csic.es:10261/269728 |
| network_acronym_str |
ES |
| network_name_str |
España |
| repository_id_str |
|
| spelling |
β–Lactam TRPM8 Antagonist RGM8-51 Displays Antinociceptive Activity in Different Animal ModelsMartín-Escura, CristinaMedina-Peris, AliciaSpear, Luke A.Torre Martínez, Roberto de laOlivos-Oré, Luis A.Barahona, María VictoriaGonzález-Rodríguez, SaraFernández-Ballester, GregorioFernández-Carvajal, AsiaArtalejo, Antonio R.Ferrer-Montiel, AntonioGonzález-Muñiz, RosarioTRPM8 channelsantagonistβ–lactamoxaliplatin-induced peripheral neuropathyCCI chronic neuropathicnociceptionNTG-induced hyperesthesiaTransient receptor potential melastatin subtype 8 (TRPM8) is a cation channel extensively expressed in sensory neurons and implicated in different painful states. However, the effectiveness of TRPM8 modulators for pain relief is still a matter of discussion, since structurally diverse mod- ulators lead to different results, depending on the animal pain model. In this work, we described the antinociceptive activity of a β–lactam derivative, RGM8-51, showing good TRPM8 antagonist activity, and selectivity against related thermoTRP channels and other pain-mediating receptors. In primary cultures of rat dorsal root ganglion (DRG) neurons, RGM8-51 potently reduced menthol- evoked neuronal firing without affecting the major ion conductances responsible for action potential generation. This compound has in vivo antinociceptive activity in response to cold, in a mouse model of oxaliplatin-induced peripheral neuropathy. In addition, it reduces cold, mechanical and heat hypersensitivity in a rat model of neuropathic pain arising after chronic constriction of the sciatic nerve. Furthermore, RGM8-51 exhibits mechanical hypersensitivity-relieving activity, in a mouse model of NTG-induced hyperesthesia. Taken together, these preclinical results substantiate that this TRPM8 antagonist is a promising pharmacological tool to study TRPM8-related disease.This research was funded by the Spanish Ministerio de Ciencia y Universidades (MICYU- FEDER, RTI2018-097189-C2-1 to A.F.-M. and A.F.-C., and RTI2018-097189-C2-2 to R.G.-M.), Comu- nidad de Madrid (IND2017/BMD7673 to R.G.-M.) and the Spanish National Research Council (CSIC, 201980E030 to R.G.-M.), and Universidad Complutense de Madrid (PR75/18-21593, FEI20/35 and PID2019-109155RB-I00 to A.R.A.).Peer reviewedMultidisciplinary Digital Publishing InstituteMinisterio de Ciencia, Innovación y Universidades (España)Comunidad de MadridConsejo Superior de Investigaciones Científicas (España)Universidad Complutense de MadridConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202220222022info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/269728reponame: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 2017-2020/PID2019-109155RB-I00https://doi.org/10.3390/ijms23052692Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2697282026-05-22T06:33:51Z |
| dc.title.none.fl_str_mv |
β–Lactam TRPM8 Antagonist RGM8-51 Displays Antinociceptive Activity in Different Animal Models |
| title |
β–Lactam TRPM8 Antagonist RGM8-51 Displays Antinociceptive Activity in Different Animal Models |
| spellingShingle |
β–Lactam TRPM8 Antagonist RGM8-51 Displays Antinociceptive Activity in Different Animal Models Martín-Escura, Cristina TRPM8 channels antagonist β–lactam oxaliplatin-induced peripheral neuropathy CCI chronic neuropathic nociception NTG-induced hyperesthesia |
| title_short |
β–Lactam TRPM8 Antagonist RGM8-51 Displays Antinociceptive Activity in Different Animal Models |
| title_full |
β–Lactam TRPM8 Antagonist RGM8-51 Displays Antinociceptive Activity in Different Animal Models |
| title_fullStr |
β–Lactam TRPM8 Antagonist RGM8-51 Displays Antinociceptive Activity in Different Animal Models |
| title_full_unstemmed |
β–Lactam TRPM8 Antagonist RGM8-51 Displays Antinociceptive Activity in Different Animal Models |
| title_sort |
β–Lactam TRPM8 Antagonist RGM8-51 Displays Antinociceptive Activity in Different Animal Models |
| dc.creator.none.fl_str_mv |
Martín-Escura, Cristina Medina-Peris, Alicia Spear, Luke A. Torre Martínez, Roberto de la Olivos-Oré, Luis A. Barahona, María Victoria González-Rodríguez, Sara Fernández-Ballester, Gregorio Fernández-Carvajal, Asia Artalejo, Antonio R. Ferrer-Montiel, Antonio González-Muñiz, Rosario |
| author |
Martín-Escura, Cristina |
| author_facet |
Martín-Escura, Cristina Medina-Peris, Alicia Spear, Luke A. Torre Martínez, Roberto de la Olivos-Oré, Luis A. Barahona, María Victoria González-Rodríguez, Sara Fernández-Ballester, Gregorio Fernández-Carvajal, Asia Artalejo, Antonio R. Ferrer-Montiel, Antonio González-Muñiz, Rosario |
| author_role |
author |
| author2 |
Medina-Peris, Alicia Spear, Luke A. Torre Martínez, Roberto de la Olivos-Oré, Luis A. Barahona, María Victoria González-Rodríguez, Sara Fernández-Ballester, Gregorio Fernández-Carvajal, Asia Artalejo, Antonio R. Ferrer-Montiel, Antonio González-Muñiz, Rosario |
| author2_role |
author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Ministerio de Ciencia, Innovación y Universidades (España) Comunidad de Madrid Consejo Superior de Investigaciones Científicas (España) Universidad Complutense de Madrid Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72] |
| dc.subject.none.fl_str_mv |
TRPM8 channels antagonist β–lactam oxaliplatin-induced peripheral neuropathy CCI chronic neuropathic nociception NTG-induced hyperesthesia |
| topic |
TRPM8 channels antagonist β–lactam oxaliplatin-induced peripheral neuropathy CCI chronic neuropathic nociception NTG-induced hyperesthesia |
| description |
Transient receptor potential melastatin subtype 8 (TRPM8) is a cation channel extensively expressed in sensory neurons and implicated in different painful states. However, the effectiveness of TRPM8 modulators for pain relief is still a matter of discussion, since structurally diverse mod- ulators lead to different results, depending on the animal pain model. In this work, we described the antinociceptive activity of a β–lactam derivative, RGM8-51, showing good TRPM8 antagonist activity, and selectivity against related thermoTRP channels and other pain-mediating receptors. In primary cultures of rat dorsal root ganglion (DRG) neurons, RGM8-51 potently reduced menthol- evoked neuronal firing without affecting the major ion conductances responsible for action potential generation. This compound has in vivo antinociceptive activity in response to cold, in a mouse model of oxaliplatin-induced peripheral neuropathy. In addition, it reduces cold, mechanical and heat hypersensitivity in a rat model of neuropathic pain arising after chronic constriction of the sciatic nerve. Furthermore, RGM8-51 exhibits mechanical hypersensitivity-relieving activity, in a mouse model of NTG-induced hyperesthesia. Taken together, these preclinical results substantiate that this TRPM8 antagonist is a promising pharmacological tool to study TRPM8-related disease. |
| publishDate |
2022 |
| dc.date.none.fl_str_mv |
2022 2022 2022 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 Publisher's version info:eu-repo/semantics/publishedVersion |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10261/269728 |
| url |
http://hdl.handle.net/10261/269728 |
| 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 2017-2020/PID2019-109155RB-I00 https://doi.org/10.3390/ijms23052692 Sí |
| dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess |
| eu_rights_str_mv |
openAccess |
| 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 |
|
| _version_ |
1869409539898474496 |
| score |
15,81155 |