Nom: ROGER Cognoms: NEGRETE BUELA Universitat on estudies: Universitat Autònoma de Barcelona (UAB)
Títol de la recerca: The antinociceptive effects of JWH-015 in chronic inflammatory pain are produced by the nitric oxide-cGMP-PKG-KATP pathway activation mediated by opioids Autor/s: Roger Negrete, Arnau Hervera, Sergi Leánez, Jesús M. Martín-Campos and Olga Pol Departament: Grup de Neurofarmacologia Molecular, Institut de Recerca de l’Hospital de la Sta Creu i Sant Pau & Institut de Neurociències, Universitat Autònoma de Barcelona Universitat: Universitat Autònoma de Barcelona (UAB) País: Espanya Abstract (màxim 500 paraules): 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: For this purpose, 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
and antihyperalgesic effects produced by the subplantar administration of JWH-015 and the reversion of
their effects by the local co-administration with a CB2R (AM630), a peripheral opioid receptor
(naloxone methiodide, NX-ME) or a CB1R (AM251) antagonist. 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.
The expression of CB2R and NOS1 in the dorsal root ganglia of WT and NOS1-KO mice, with and
without chronic peripheral inflammation, was also evaluated by using the real time PCR and western
blot assays. The mechanical allodynia and thermal hyperalgesia induced by CFA were measured by
using the von Frey filaments and plantar tests, respectively.
Results: Our 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. The antinociceptive effects of JWH-015
were absent in NOS1-KO mice and significantly diminished by their co-administration with different
doses of ODQ, Rp-8-pCPT-cGMPs or glibenclamide. Our data also demonstrate that chronic
inflammatory pain increased the dorsal root ganglia expression of NOS1, but not of CB2R.
Conclusions: These data indicate for first time the participation of the peripheral nitric oxide-cGMP-
PKG-KATP signaling pathway, activated by endogenous opioids, in the antinociceptive effects
produced by a CB2R agonist during chronic inflammatory pain. Our results also indicate that the
increased nitric oxide synthesized by NOS1 participates in the local antinociceptive effects produced by
a CB2R agonist during chronic inflammatory pain. These findings suggest that the activation of the
peripheral nitric oxide cGMP-PKG-KATP signaling pathway might be an interesting therapeutic target
for the treatment of chronic inflammatory pain with cannabinoids.
Authorship: The author has contributed in the design, performing of the experiments, the analyses of Publication: Part of these results has been presented as a communication to the 16th World Congress on
Basic and Clinical Pharmacology, held in Copenhagen, Denmark, July 2010 and published in the Basic & Clinical Pharmacology & Toxicology, 107 (Suppl. 1), 162-692:487, 2010
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PKG (Rp-8-pCPT-cGMPs) inhibitors or a KATP channel blocker (glibenclamide) were also assessed.
The expression of CB2R and NOS1 in the dorsal root ganglia of WT and NOS1-KO mice, with and
without chronic peripheral inflammation, was also evaluated by using the real time PCR and western
blot assays. The mechanical allodynia and thermal hyperalgesia induced by CFA were measured by
using the von Frey filaments and plantar tests, respectively.
Results: Our results show that the local administration of JWH-015 dose-dependently inhibited the