Abstract | BACKGROUND: 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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Authors | Roger Negrete, Arnau Hervera, Sergi Leánez, Jesús M Martín-Campos, Olga Pol |
Journal | PloS one
(PLoS One)
Vol. 6
Issue 10
Pg. e26688
( 2011)
ISSN: 1932-6203 [Electronic] United States |
PMID | 22031841
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate
- Analgesics
- Analgesics, Opioid
- Cannabinoid Receptor Agonists
- Cannabinoid Receptor Antagonists
- Indoles
- KATP Channels
- Piperidines
- Pyrazoles
- Quaternary Ammonium Compounds
- Receptors, Cannabinoid
- Thionucleotides
- Nitric Oxide
- Naloxone
- AM 251
- N-methylnaloxone
- Nitric Oxide Synthase Type I
- Nos1 protein, mouse
- Cyclic GMP
- Glyburide
- iodopravadoline
- JHW 015
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Topics |
- Analgesics
(therapeutic use)
- Analgesics, Opioid
(metabolism)
- Animals
- Cannabinoid Receptor Agonists
- Cannabinoid Receptor Antagonists
- Cyclic GMP
(analogs & derivatives, metabolism)
- Glyburide
(pharmacology)
- Indoles
(pharmacology, therapeutic use)
- KATP Channels
(metabolism)
- Mice
- Mice, Knockout
- Naloxone
(analogs & derivatives, pharmacology)
- Nitric Oxide
(metabolism)
- Nitric Oxide Synthase Type I
(genetics, metabolism)
- Pain
(drug therapy, immunology)
- Piperidines
(pharmacology)
- Pyrazoles
(pharmacology)
- Quaternary Ammonium Compounds
(pharmacology)
- Receptors, Cannabinoid
(metabolism)
- Signal Transduction
(drug effects)
- Thionucleotides
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