The antinociceptive effects of JWH-015 in chronic inflammatory pain are produced by nitric oxide-cGMP-PKG-KATP pathway activation mediated by opioids

Background: Cannabinoid 2 receptor (CB2R) agonists attenuate inflammatory pain but the precise mechanism implicated in these effects is not completely elucidated. We investigated if the peripheral nitric oxide-cGMP-protein kinase G (PKG)-ATP-sensitive K+ (KATP) channels signaling pathway triggered b...

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Autores: Negrete R., Hervera A., Leánez S., Martín-Campos J.M., Pol O.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2011
País:España
Institución:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
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Acceso en línea:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=11692
http://ddd.uab.cat/record/109304
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Palabra clave:1 (2,4 dichlorophenyl) 5 (4 iodophenyl) 4 methyl n (1 piperidyl) 1h pyrazole 3 carboxamide
17 methylnaloxone
1h 1,2,4 oxadiazolo[4,3 a]quinoxalin 1 one
2 methyl 3 (1 naphthoyl) 1 propylindole
6 iodo 3 (4 methoxybenzoyl) 2 methyl 1 (2 morpholinoethyl)indole
8 (4 chlorophenylthio) cyclic GMP
adenosine triphosphate sensitive potassium channel
cannabinoid 2 receptor
cyclic GMP dependent protein kinase
glibenclamide
messenger RNA
neuronal nitric oxide synthase
nitric oxide
nitric oxide synthase
8 (4 chlorophenylthio)guanosine 3',5' cyclic monophosphorothioate
8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate
analgesic agent
cannabinoid receptor
cyclic GMP
drug derivative
indole derivative
iodopravadoline
JHW 015
N-methylnaloxone
naloxone
narcotic analgesic agent
Nos1 protein, mouse
nucleotide
piperidine derivative
pyrazole derivative
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oai_identifier_str oai:iibsantpau.fundanetsuite.com:p11692
network_acronym_str ES
network_name_str España
repository_id_str
spelling The antinociceptive effects of JWH-015 in chronic inflammatory pain are produced by nitric oxide-cGMP-PKG-KATP pathway activation mediated by opioidsNegrete R.Hervera A.Leánez S.Martín-Campos J.M.Pol O.1 (2,4 dichlorophenyl) 5 (4 iodophenyl) 4 methyl n (1 piperidyl) 1h pyrazole 3 carboxamide17 methylnaloxone1h 1,2,4 oxadiazolo[4,3 a]quinoxalin 1 one2 methyl 3 (1 naphthoyl) 1 propylindole6 iodo 3 (4 methoxybenzoyl) 2 methyl 1 (2 morpholinoethyl)indole8 (4 chlorophenylthio) cyclic GMPadenosine triphosphate sensitive potassium channelcannabinoid 2 receptorcyclic GMP dependent protein kinaseglibenclamidemessenger RNAneuronal nitric oxide synthasenitric oxidenitric oxide synthase8 (4 chlorophenylthio)guanosine 3',5' cyclic monophosphorothioate8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioateadenosine triphosphate sensitive potassium channelanalgesic agentcannabinoid receptorcyclic GMPdrug derivativeglibenclamideindole derivativeiodopravadolineJHW 015N-methylnaloxonenaloxonenarcotic analgesic agentneuronal nitric oxide synthasenitric oxideNos1 protein, mousenucleotidepiperidine derivativepyrazole derivativeBackground: Cannabinoid 2 receptor (CB2R) agonists attenuate inflammatory pain but the precise mechanism implicated in these effects is not completely elucidated. We investigated if the peripheral nitric oxide-cGMP-protein kinase G (PKG)-ATP-sensitive K+ (KATP) channels signaling pathway triggered by the neuronal nitric oxide synthase (NOS1) and modulated by opioids, participates in the local antinociceptive effects produced by a CB2R agonist (JWH-015) during chronic inflammatory pain. Methodology/Principal Findings: In wild type (WT) and NOS1 knockout (NOS1-KO) mice, at 10 days after the subplantar administration of complete Freund's adjuvant (CFA), we evaluated the antiallodynic (von Frey filaments) and antihyperalgesic (plantar test) effects produced by the subplantar administration of JWH-015 and the reversion of their effects by the local co-administration with CB2R (AM630), peripheral opioid receptor (naloxone methiodide, NX-ME) or CB1R (AM251) antagonists. Expression of CB2R and NOS1 as well as the antinociceptive effects produced by a high dose of JWH-015 combined with different doses of selective L-guanylate cyclase (ODQ) or PKG (Rp-8-pCPT-cGMPs) inhibitors or a KATP channel blocker (glibenclamide), were also assessed. Results show that the local administration of JWH-015 dose-dependently inhibited the mechanical and thermal hypersensitivity induced by CFA which effects were completely reversed by the local co-administration of AM630 or NX-ME, but not AM251. Inflammatory pain increased the paw expression of CB2R and the dorsal root ganglia transcription of NOS1. Moreover, the antinociceptive effects of JWH-015 were absent in NOS1-KO mice and diminished by their co-administration with ODQ, Rp-8-pCPT-cGMPs or glibenclamide. Conclusions/Significance: These data indicate that the peripheral antinociceptive effects of JWH-015 during chronic inflammatory pain are mainly produced by the local activation of the nitric oxide-cGMP-PKG-KATP signaling pathway, triggered by NOS1 and mediated by endogenous opioids. These findings suggest that the activation of this pathway might be an interesting therapeutic target for the treatment of chronic inflammatory pain with cannabinoids. © 2011 Negrete et al.PUBLIC LIBRARY SCIENCE2011info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=11692http://ddd.uab.cat/record/109304PLoS OneISSN: 19326203reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p116922026-06-14T12:41:47Z
dc.title.none.fl_str_mv The antinociceptive effects of JWH-015 in chronic inflammatory pain are produced by nitric oxide-cGMP-PKG-KATP pathway activation mediated by opioids
title The antinociceptive effects of JWH-015 in chronic inflammatory pain are produced by nitric oxide-cGMP-PKG-KATP pathway activation mediated by opioids
spellingShingle The antinociceptive effects of JWH-015 in chronic inflammatory pain are produced by nitric oxide-cGMP-PKG-KATP pathway activation mediated by opioids
Negrete R.
1 (2,4 dichlorophenyl) 5 (4 iodophenyl) 4 methyl n (1 piperidyl) 1h pyrazole 3 carboxamide
17 methylnaloxone
1h 1,2,4 oxadiazolo[4,3 a]quinoxalin 1 one
2 methyl 3 (1 naphthoyl) 1 propylindole
6 iodo 3 (4 methoxybenzoyl) 2 methyl 1 (2 morpholinoethyl)indole
8 (4 chlorophenylthio) cyclic GMP
adenosine triphosphate sensitive potassium channel
cannabinoid 2 receptor
cyclic GMP dependent protein kinase
glibenclamide
messenger RNA
neuronal nitric oxide synthase
nitric oxide
nitric oxide synthase
8 (4 chlorophenylthio)guanosine 3',5' cyclic monophosphorothioate
8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate
adenosine triphosphate sensitive potassium channel
analgesic agent
cannabinoid receptor
cyclic GMP
drug derivative
glibenclamide
indole derivative
iodopravadoline
JHW 015
N-methylnaloxone
naloxone
narcotic analgesic agent
neuronal nitric oxide synthase
nitric oxide
Nos1 protein, mouse
nucleotide
piperidine derivative
pyrazole derivative
title_short The antinociceptive effects of JWH-015 in chronic inflammatory pain are produced by nitric oxide-cGMP-PKG-KATP pathway activation mediated by opioids
title_full The antinociceptive effects of JWH-015 in chronic inflammatory pain are produced by nitric oxide-cGMP-PKG-KATP pathway activation mediated by opioids
title_fullStr The antinociceptive effects of JWH-015 in chronic inflammatory pain are produced by nitric oxide-cGMP-PKG-KATP pathway activation mediated by opioids
title_full_unstemmed The antinociceptive effects of JWH-015 in chronic inflammatory pain are produced by nitric oxide-cGMP-PKG-KATP pathway activation mediated by opioids
title_sort The antinociceptive effects of JWH-015 in chronic inflammatory pain are produced by nitric oxide-cGMP-PKG-KATP pathway activation mediated by opioids
dc.creator.none.fl_str_mv Negrete R.
Hervera A.
Leánez S.
Martín-Campos J.M.
Pol O.
author Negrete R.
author_facet Negrete R.
Hervera A.
Leánez S.
Martín-Campos J.M.
Pol O.
author_role author
author2 Hervera A.
Leánez S.
Martín-Campos J.M.
Pol O.
author2_role author
author
author
author
dc.subject.none.fl_str_mv 1 (2,4 dichlorophenyl) 5 (4 iodophenyl) 4 methyl n (1 piperidyl) 1h pyrazole 3 carboxamide
17 methylnaloxone
1h 1,2,4 oxadiazolo[4,3 a]quinoxalin 1 one
2 methyl 3 (1 naphthoyl) 1 propylindole
6 iodo 3 (4 methoxybenzoyl) 2 methyl 1 (2 morpholinoethyl)indole
8 (4 chlorophenylthio) cyclic GMP
adenosine triphosphate sensitive potassium channel
cannabinoid 2 receptor
cyclic GMP dependent protein kinase
glibenclamide
messenger RNA
neuronal nitric oxide synthase
nitric oxide
nitric oxide synthase
8 (4 chlorophenylthio)guanosine 3',5' cyclic monophosphorothioate
8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate
adenosine triphosphate sensitive potassium channel
analgesic agent
cannabinoid receptor
cyclic GMP
drug derivative
glibenclamide
indole derivative
iodopravadoline
JHW 015
N-methylnaloxone
naloxone
narcotic analgesic agent
neuronal nitric oxide synthase
nitric oxide
Nos1 protein, mouse
nucleotide
piperidine derivative
pyrazole derivative
topic 1 (2,4 dichlorophenyl) 5 (4 iodophenyl) 4 methyl n (1 piperidyl) 1h pyrazole 3 carboxamide
17 methylnaloxone
1h 1,2,4 oxadiazolo[4,3 a]quinoxalin 1 one
2 methyl 3 (1 naphthoyl) 1 propylindole
6 iodo 3 (4 methoxybenzoyl) 2 methyl 1 (2 morpholinoethyl)indole
8 (4 chlorophenylthio) cyclic GMP
adenosine triphosphate sensitive potassium channel
cannabinoid 2 receptor
cyclic GMP dependent protein kinase
glibenclamide
messenger RNA
neuronal nitric oxide synthase
nitric oxide
nitric oxide synthase
8 (4 chlorophenylthio)guanosine 3',5' cyclic monophosphorothioate
8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate
adenosine triphosphate sensitive potassium channel
analgesic agent
cannabinoid receptor
cyclic GMP
drug derivative
glibenclamide
indole derivative
iodopravadoline
JHW 015
N-methylnaloxone
naloxone
narcotic analgesic agent
neuronal nitric oxide synthase
nitric oxide
Nos1 protein, mouse
nucleotide
piperidine derivative
pyrazole derivative
description Background: Cannabinoid 2 receptor (CB2R) agonists attenuate inflammatory pain but the precise mechanism implicated in these effects is not completely elucidated. We investigated if the peripheral nitric oxide-cGMP-protein kinase G (PKG)-ATP-sensitive K+ (KATP) channels signaling pathway triggered by the neuronal nitric oxide synthase (NOS1) and modulated by opioids, participates in the local antinociceptive effects produced by a CB2R agonist (JWH-015) during chronic inflammatory pain. Methodology/Principal Findings: In wild type (WT) and NOS1 knockout (NOS1-KO) mice, at 10 days after the subplantar administration of complete Freund's adjuvant (CFA), we evaluated the antiallodynic (von Frey filaments) and antihyperalgesic (plantar test) effects produced by the subplantar administration of JWH-015 and the reversion of their effects by the local co-administration with CB2R (AM630), peripheral opioid receptor (naloxone methiodide, NX-ME) or CB1R (AM251) antagonists. Expression of CB2R and NOS1 as well as the antinociceptive effects produced by a high dose of JWH-015 combined with different doses of selective L-guanylate cyclase (ODQ) or PKG (Rp-8-pCPT-cGMPs) inhibitors or a KATP channel blocker (glibenclamide), were also assessed. Results show that the local administration of JWH-015 dose-dependently inhibited the mechanical and thermal hypersensitivity induced by CFA which effects were completely reversed by the local co-administration of AM630 or NX-ME, but not AM251. Inflammatory pain increased the paw expression of CB2R and the dorsal root ganglia transcription of NOS1. Moreover, the antinociceptive effects of JWH-015 were absent in NOS1-KO mice and diminished by their co-administration with ODQ, Rp-8-pCPT-cGMPs or glibenclamide. Conclusions/Significance: These data indicate that the peripheral antinociceptive effects of JWH-015 during chronic inflammatory pain are mainly produced by the local activation of the nitric oxide-cGMP-PKG-KATP signaling pathway, triggered by NOS1 and mediated by endogenous opioids. These findings suggest that the activation of this pathway might be an interesting therapeutic target for the treatment of chronic inflammatory pain with cannabinoids. © 2011 Negrete et al.
publishDate 2011
dc.date.none.fl_str_mv 2011
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=11692
http://ddd.uab.cat/record/109304
url https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=11692
http://ddd.uab.cat/record/109304
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv PUBLIC LIBRARY SCIENCE
publisher.none.fl_str_mv PUBLIC LIBRARY SCIENCE
dc.source.none.fl_str_mv PLoS One
ISSN: 19326203
reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
instname_str Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
reponame_str r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
collection r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
repository.name.fl_str_mv
repository.mail.fl_str_mv
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