The antinociceptive effects of JWH-015 in chronic inflammatory pain are produced by nitric oxide-cGMP-PKG-KATP pathway activation mediated by opioids
| Autor: | Negrete, Roger, Hervera Abad, Arnau, Leánez, Sergi, Martín-Campos, Jesús M., Pol, Olga, Universitat Autònoma de Barcelona |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Indoles
medicine.medical_treatment lcsh:Medicine Gene Expression Nitric Oxide Synthase Type I Pharmacology chemistry.chemical_compound Behavioral Neuroscience Mice KATP Channels Piperidines Opioid receptor Anesthesiology Molecular Cell Biology Glyburide lcsh:Science Receptors Cannabinoid Cyclic GMP Endogenous opioid Neurons Mice Knockout Analgesics Multidisciplinary Naloxone Neurotransmitters Dolor crònic Analgesics Opioid Behavioral Pharmacology Hyperalgesia Medicine medicine.symptom Cellular Types medicine.drug Research Article Signal Transduction AM251 Agonist medicine.medical_specialty Drugs and Devices medicine.drug_class Cognitive Neuroscience Pain Nitric Oxide Signaling Pathways Nitric oxide Molecular Genetics Neuropharmacology Internal medicine medicine Pain Management Animals Biology Cannabinoid Receptor Antagonists Cannabinoid Receptor Agonists Chronic inflammatory pain lcsh:R Computational Biology Thionucleotides Quaternary Ammonium Compounds Endocrinology chemistry Cannabinoid receptor antagonist Pyrazoles lcsh:Q Cannabinoid Molecular Neuroscience Neuroscience |
| Zdroj: | PLoS ONE Dipòsit Digital de Documents de la UAB Universitat Autònoma de Barcelona PLoS ONE, Vol 6, Iss 10, p e26688 (2011) |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|