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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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Reversion of the antinociceptive effects of JWH-015.Effects of the subplantar administration of vehicle, AM630 (60 µg), NX-ME (150 µg) or AM251 (150 µg) on the inhibition of the mechanical allodynia (A) and thermal hyperalgesia (B) induced by the subplantar administration of JWH-015 (150 µg) in CFA-injected WT mice. 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 and drug, *** indicates significant differences when compared to their corresponding contralateral paw (p<0.001, paired Student's t test) and + indicates significant differences as compared with the ipsilateral paw of the vehicle treated group (p<0.05, one way ANOVA followed by the Student-Newman-Keuls test).
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pone-0026688-g002: Reversion of the antinociceptive effects of JWH-015.Effects of the subplantar administration of vehicle, AM630 (60 µg), NX-ME (150 µg) or AM251 (150 µg) on the inhibition of the mechanical allodynia (A) and thermal hyperalgesia (B) induced by the subplantar administration of JWH-015 (150 µg) in CFA-injected WT mice. 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 and drug, *** indicates significant differences when compared to their corresponding contralateral paw (p<0.001, paired Student's t test) and + indicates significant differences as compared with the ipsilateral paw of the vehicle treated group (p<0.05, one way ANOVA followed by the Student-Newman-Keuls test).

Mentions: The administration of CFA induced a significant mechanical allodynia (Fig. 2A) and thermal hyperalgesia (Fig. 2B) in the ipsilateral paw as compared to their corresponding contralateral paw (p<0.001; paired Student's t test). The antiallodynic (Fig. 2A) and antihyperalgesic (Fig. 2B) effects produced by a high dose of JWH015 in the ipsilateral paw of CFA-injected WT mice were completely reversed by their subplantar co-administration with a selective CB2R (AM630) or a peripheral opioid receptor (NX-ME) antagonist (p<0.001; paired Student's t test compared to their corresponding contralateral paw). The subplantar administration of AM251 (a selective CB1R antagonist) was unable to revert the local antiallodynic and antihyperalgesic effects produced by JWH-015 (p<0.05; one way ANOVA, followed by Student Newman Keuls, compared with the ipsilateral paw of the vehicle treated group). The subplantar administration of the agonist alone or combined with the different tested antagonists did not produce any significant effect in the contralateral paw as compared to vehicle. In addition, the subplantar administration of AM630, NX-ME, AM251 or vehicle alone in CFA-injected mice did not show any significant effect on the two different nociceptive responses evaluated in this study (data not shown).


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)

Reversion of the antinociceptive effects of JWH-015.Effects of the subplantar administration of vehicle, AM630 (60 µg), NX-ME (150 µg) or AM251 (150 µg) on the inhibition of the mechanical allodynia (A) and thermal hyperalgesia (B) induced by the subplantar administration of JWH-015 (150 µg) in CFA-injected WT mice. 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 and drug, *** indicates significant differences when compared to their corresponding contralateral paw (p<0.001, paired Student's t test) and + indicates significant differences as compared with the ipsilateral paw of the vehicle treated group (p<0.05, one way ANOVA followed by the Student-Newman-Keuls test).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198780&req=5

pone-0026688-g002: Reversion of the antinociceptive effects of JWH-015.Effects of the subplantar administration of vehicle, AM630 (60 µg), NX-ME (150 µg) or AM251 (150 µg) on the inhibition of the mechanical allodynia (A) and thermal hyperalgesia (B) induced by the subplantar administration of JWH-015 (150 µg) in CFA-injected WT mice. 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 and drug, *** indicates significant differences when compared to their corresponding contralateral paw (p<0.001, paired Student's t test) and + indicates significant differences as compared with the ipsilateral paw of the vehicle treated group (p<0.05, one way ANOVA followed by the Student-Newman-Keuls test).
Mentions: The administration of CFA induced a significant mechanical allodynia (Fig. 2A) and thermal hyperalgesia (Fig. 2B) in the ipsilateral paw as compared to their corresponding contralateral paw (p<0.001; paired Student's t test). The antiallodynic (Fig. 2A) and antihyperalgesic (Fig. 2B) effects produced by a high dose of JWH015 in the ipsilateral paw of CFA-injected WT mice were completely reversed by their subplantar co-administration with a selective CB2R (AM630) or a peripheral opioid receptor (NX-ME) antagonist (p<0.001; paired Student's t test compared to their corresponding contralateral paw). The subplantar administration of AM251 (a selective CB1R antagonist) was unable to revert the local antiallodynic and antihyperalgesic effects produced by JWH-015 (p<0.05; one way ANOVA, followed by Student Newman Keuls, compared with the ipsilateral paw of the vehicle treated group). The subplantar administration of the agonist alone or combined with the different tested antagonists did not produce any significant effect in the contralateral paw as compared to vehicle. In addition, the subplantar administration of AM630, NX-ME, AM251 or vehicle alone in CFA-injected mice did not show any significant effect on the two different nociceptive responses evaluated in this study (data not shown).

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