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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.

Negrete R, Hervera A, Leánez S, Martín-Campos JM, Pol O - PLoS ONE (2011)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Grup de Neurofarmacologia Molecular, Institut de Recerca de l'Hospital de la Sta Creu i Sant Pau and Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain.

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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The antiallodynic and antihyperalgesic effects of JWH-015 in WT and NOS1-KO mice.Effects of the subplantar administration of 150 µg of JWH-015 or vehicle in the contralateral and ipsilateral paw withdrawal latencies to a mechanical (A) or thermal (B) stimulus in WT and NOS1-KO mice, at 10 days after CFA injection. Data are expressed as mean values of the von Frey filaments strength (g) for mechanical allodynia and as the paw withdrawal latency (s) for thermal hyperalgesia ± SEM (5–6 animals per group). For each test, *** p<0.001, indicates significant differences vs. their contralateral paw (paired Student's t test), + indicates significant differences as compared with the ipsilateral paw of vehicle treated group (p<0.05, one way ANOVA followed by the Student-Newman-Keuls test) and # indicates significant differences as compared with the ipsilateral paw of WT group treated with JWH-015 (p<0.05, one way ANOVA followed by the Student-Newman-Keuls test).
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pone-0026688-g005: The antiallodynic and antihyperalgesic effects of JWH-015 in WT and NOS1-KO mice.Effects of the subplantar administration of 150 µg of JWH-015 or vehicle in the contralateral and ipsilateral paw withdrawal latencies to a mechanical (A) or thermal (B) stimulus in WT and NOS1-KO mice, at 10 days after CFA injection. Data are expressed as mean values of the von Frey filaments strength (g) for mechanical allodynia and as the paw withdrawal latency (s) for thermal hyperalgesia ± SEM (5–6 animals per group). For each test, *** p<0.001, indicates significant differences vs. their contralateral paw (paired Student's t test), + indicates significant differences as compared with the ipsilateral paw of vehicle treated group (p<0.05, one way ANOVA followed by the Student-Newman-Keuls test) and # indicates significant differences as compared with the ipsilateral paw of WT group treated with JWH-015 (p<0.05, one way ANOVA followed by the Student-Newman-Keuls test).

Mentions: The role played by nitric oxide synthesized by NOS1 in the local antinociceptive effects produced by JWH-015 during peripheral inflammation was evaluated by comparing the antiallodynic (Fig. 5A) and the antihyperalgesic (Fig. 5B) effects produced by a high dose of this agonist (150 µg) in WT and NOS1-KO mice at 10 days after CFA injection. Our results show that the subplantar injection of CFA induces a reduced mechanical allodynia (p<0.05; one way ANOVA, followed by Student Newman Keuls test) and a similar thermal hyperalgesia in the ipsilateral paw of NOS1-KO mice as compared to WT. The subplantar administration of JWH-015 only reversed these effects in WT mice, but not in NOS1-KO (p<0.001, paired Student's t test, comparing ipsilateral vs. contralateral paw). Moreover, the effects produced by JWH-015 in the ipsilateral paw of NOS1-KO mice are significantly lower to that those produced by this drug in the ipsilateral paw of WT mice (p<0.05; one way ANOVA, followed by Student Newman Keuls test). In both genotypes the subplantar administration of JWH-015 or vehicle did not have any significant effect on the contralateral paw of these animals.


The antinociceptive effects of JWH-015 in chronic inflammatory pain are produced by nitric oxide-cGMP-PKG-KATP pathway activation mediated by opioids.

Negrete R, Hervera A, Leánez S, Martín-Campos JM, Pol O - PLoS ONE (2011)

The antiallodynic and antihyperalgesic effects of JWH-015 in WT and NOS1-KO mice.Effects of the subplantar administration of 150 µg of JWH-015 or vehicle in the contralateral and ipsilateral paw withdrawal latencies to a mechanical (A) or thermal (B) stimulus in WT and NOS1-KO mice, at 10 days after CFA injection. Data are expressed as mean values of the von Frey filaments strength (g) for mechanical allodynia and as the paw withdrawal latency (s) for thermal hyperalgesia ± SEM (5–6 animals per group). For each test, *** p<0.001, indicates significant differences vs. their contralateral paw (paired Student's t test), + indicates significant differences as compared with the ipsilateral paw of vehicle treated group (p<0.05, one way ANOVA followed by the Student-Newman-Keuls test) and # indicates significant differences as compared with the ipsilateral paw of WT group treated with JWH-015 (p<0.05, one way ANOVA followed by the Student-Newman-Keuls test).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198780&req=5

pone-0026688-g005: The antiallodynic and antihyperalgesic effects of JWH-015 in WT and NOS1-KO mice.Effects of the subplantar administration of 150 µg of JWH-015 or vehicle in the contralateral and ipsilateral paw withdrawal latencies to a mechanical (A) or thermal (B) stimulus in WT and NOS1-KO mice, at 10 days after CFA injection. Data are expressed as mean values of the von Frey filaments strength (g) for mechanical allodynia and as the paw withdrawal latency (s) for thermal hyperalgesia ± SEM (5–6 animals per group). For each test, *** p<0.001, indicates significant differences vs. their contralateral paw (paired Student's t test), + indicates significant differences as compared with the ipsilateral paw of vehicle treated group (p<0.05, one way ANOVA followed by the Student-Newman-Keuls test) and # indicates significant differences as compared with the ipsilateral paw of WT group treated with JWH-015 (p<0.05, one way ANOVA followed by the Student-Newman-Keuls test).
Mentions: The role played by nitric oxide synthesized by NOS1 in the local antinociceptive effects produced by JWH-015 during peripheral inflammation was evaluated by comparing the antiallodynic (Fig. 5A) and the antihyperalgesic (Fig. 5B) effects produced by a high dose of this agonist (150 µg) in WT and NOS1-KO mice at 10 days after CFA injection. Our results show that the subplantar injection of CFA induces a reduced mechanical allodynia (p<0.05; one way ANOVA, followed by Student Newman Keuls test) and a similar thermal hyperalgesia in the ipsilateral paw of NOS1-KO mice as compared to WT. The subplantar administration of JWH-015 only reversed these effects in WT mice, but not in NOS1-KO (p<0.001, paired Student's t test, comparing ipsilateral vs. contralateral paw). Moreover, the effects produced by JWH-015 in the ipsilateral paw of NOS1-KO mice are significantly lower to that those produced by this drug in the ipsilateral paw of WT mice (p<0.05; one way ANOVA, followed by Student Newman Keuls test). In both genotypes the subplantar administration of JWH-015 or vehicle did not have any significant effect on the contralateral paw of these animals.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Grup de Neurofarmacologia Molecular, Institut de Recerca de l'Hospital de la Sta Creu i Sant Pau and Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain.

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.

Show MeSH
Related in: MedlinePlus