Abstract
BackgroundCannabinoid 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 FindingsIn 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/SignificanceThese 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.
Highlights
The activation of both cannabinoid receptors 1 (CB1R) and 2 (CB2R) reduce nociception in numerous animal pain models [1,2,3]
Antihyperalgesic (Fig. 2B) effects produced by a high dose of JWH015 in the ipsilateral paw of complete Freund’s adjuvant (CFA)-injected wild type (WT) mice were completely reversed by their subplantar co-administration with a selective Cannabinoid 2 receptor (CB2R) (AM630) or a peripheral opioid receptor (NX-ME) antagonist (p,0.001; paired Student’s t test compared to their corresponding contralateral paw)
We showed for first time that the local administration of JWH-015 dose-dependently inhibited the mechanical allodynia and thermal hyperalgesia induced by CFA through the activation of the peripheral nitric oxide-cGMP-PKGKATP channel signaling pathway, triggered by NOS1 and mediated by opioids
Summary
The activation of both cannabinoid receptors 1 (CB1R) and 2 (CB2R) reduce nociception in numerous animal pain models [1,2,3]. Several studies have shown that nitric oxide, synthesized by neuronal nitric oxide synthase (NOS1), mediates numerous inflammatory pain symptoms [9,10] and the local antinociceptive effects of opioids during inflammation is mainly produced by the activation of the peripheral nitric oxide-cGMP-protein kinase G (PKG)-ATP-sensitive K+ (KATP) channels signaling pathway [11,12,13]. The participation of the local endogenous opioid peptides as well as the nitric oxide-cGMPPKG-KATP signaling pathway in the peripheral antinociceptive effects produced by JWH-015 during chronic inflammatory pain is not known. We investigated if the peripheral nitric oxide-cGMP-protein kinase G (PKG)-ATPsensitive 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
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