The Antinociceptive Effects of JWH-015 in Chronic Inflammatory Pain Are Produced by Nitric Oxide-cGMP-PKG-KATP Pathway Activation Mediated by Opioids

Negrete, Roger; Hervera, Arnau; Leánez, Sergi; Martín-Campos, Jesús M.; Pol, Olga

doi:10.1371/journal.pone.0026688

Cited by 33Pain Mechanisms and TreatmentsCannabis and Cannabinoid ResearchIon Channels and Receptors

The Antinociceptive Effects of JWH-015 in Chronic Inflammatory Pain Are Produced by Nitric Oxide-cGMP-PKG-KATP Pathway Activation Mediated by Opioids

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Negrete, Roger, Hervera, Arnau, Leánez, Sergi, Martín-Campos, Jesús M., Pol, Olga·2011·PLoS ONE

DOI 10.1371/journal.pone.0026688PMC PMC3198780

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Abstract

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.

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Intraplantar administration of the CB2 receptor agonist JWH015 reduces allodynia and hyperalgesia induced by CFA injection.
“Furthermore, intraplantar administration of the CB 2 receptor agonist JWH015 reduces allodynia and hyperalgesia induced by CFA injection (Negrete et al, 2011).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Negrete et al, 2011
The antinociceptive effects of JWH015 are mediated by CB2 receptors and μ opioid receptors (MORs).
“Unexpectedly, the antinociceptive effects of this drug are mediated by CB 2 receptors and μ opioid receptors (MORs).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Negrete et al, 2011

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Reis, G. M. L., Pacheco, D. F., Perez, A. C., Klein, A., Ramos, M. A., & Duarte, I. D. G. (2009) · Life Sciences · doi:10.1016/j.lfs.2009.06.012 · Cited by 41 · see citing works

Authors: Negrete, R., Hervera, A., Leánez, S., Martín-Campos, J. M., & Pol, O.
Affiliations: Universitat Autònoma de Barcelona (ES)
Hospital de Sant Pau (ES)
Corresponding author: Pol, Olga
ORCID: Negrete, Roger
Hervera, Arnau
Martín-Campos, Jesús M.
Pol, Olga
Venue: PLoS ONE
Publisher: Public Library of Science (PLoS)
Published: 2011-10-21
Volume: 6
Issue: 10
Pages: e26688
ISSN: 1932-6203 (ISSN-L)
DOI: 10.1371/journal.pone.0026688
PMC: PMC3198780
OpenAlex: W2054584829
Cited by: 33
References: 32
Citations by year: 2026: 1 · 2025: 4 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 3 · 2019: 2 · 2018: 1 · 2017: 1 · 2016: 1 · 2014: 3 · 2013: 5 · 2012: 2
FWCI: 2.18
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
Locations: PLoS ONE (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by)
LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics: Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
Keywords: JWH-015, chronic inflammatory pain, nitric oxide, cGMP signaling, protein kinase G, ATP-sensitive potassium channels, neuronal nitric oxide synthase, opioid modulation, antihyperalgesia, antiallodynia, complete Freund's adjuvant, dorsal root ganglia, CB1 receptor, glibenclamide, naloxone methiodide, AM630, AM251, neuropathic pain
MeSH terms: Quaternary Ammonium Compounds, Analgesics, Analgesics, Opioid, Animals, Glyburide, Cyclic GMP, Indoles, Naloxone, Nitric Oxide, Pain, Piperidines, Pyrazoles, Thionucleotides, Signal Transduction, Mice, Knockout, Receptors, Cannabinoid, Mice, Nitric Oxide Synthase Type I, KATP Channels, Cannabinoid Receptor Agonists, Cannabinoid Receptor Antagonists

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The Antinociceptive Effects of JWH-015 in Chronic Inflammatory Pain Are Produced by Nitric Oxide-cGMP-PKG-KATP Pathway Activation Mediated by Opioids

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