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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 role of the peripheral nitric oxide–cGMP–PKG-KATP signaling pathway in the antinociceptive effects of JWH-015.Mechanical antiallodynic (A, C, E) and thermal antihyperalgesic (B, D, F) effects of the subplantar co-administration of JWH-015 (150 µg) plus vehicle or different doses of ODQ (0.3 – 3.0 µg; A, B), Rp-8-pCPT-cGMPs (Rp-8; 0.3-5.0 µg; C, D) or glibenclamide (GC; 3.0–10 µg; E,F) in the ipsilateral paw of WT mice at 10 days after CFA injection. The effects of the subplantar administration of vehicle and the maximal doses of ODQ (3.0 µg), Rp-8 (5.0 µg) or glibenclamide (10.0 µg) administered alone are also shown. All drugs were administered 20 min before starting behavioral testing. 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 behavioral test and selective inhibitor assayed, * p<0.05 denotes significant differences vs. group treated with JWH-015 + vehicle (one way ANOVA followed by Student Newman Keuls test).
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pone-0026688-g006: The role of the peripheral nitric oxide–cGMP–PKG-KATP signaling pathway in the antinociceptive effects of JWH-015.Mechanical antiallodynic (A, C, E) and thermal antihyperalgesic (B, D, F) effects of the subplantar co-administration of JWH-015 (150 µg) plus vehicle or different doses of ODQ (0.3 – 3.0 µg; A, B), Rp-8-pCPT-cGMPs (Rp-8; 0.3-5.0 µg; C, D) or glibenclamide (GC; 3.0–10 µg; E,F) in the ipsilateral paw of WT mice at 10 days after CFA injection. The effects of the subplantar administration of vehicle and the maximal doses of ODQ (3.0 µg), Rp-8 (5.0 µg) or glibenclamide (10.0 µg) administered alone are also shown. All drugs were administered 20 min before starting behavioral testing. 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 behavioral test and selective inhibitor assayed, * p<0.05 denotes significant differences vs. group treated with JWH-015 + vehicle (one way ANOVA followed by Student Newman Keuls test).

Mentions: Our results showed that the local antiallodynic and antihyperalgesic effects produced by JWH-015 in the ipsilateral paw of CFA-injected WT mice were significantly inhibited by their peripheral co-administration with different doses of ODQ (Fig. 6, A-B), Rp-8-pCPT-cGMPs (Fig. 6, C-D) or glibenclamide (Fig. 6, E-F) in a dose-dependent manner (p<0.001, one way ANOVA followed by Student Newman Keuls test). While the local co-administration of JWH-015 plus ODQ, Rp-8-pCPT-cGMPs or glibenclamide did not have any significant effect on the contralateral paw of CFA-injected mice (data not shown). Our results also indicated that the subplantar administration of the highest tested doses of ODQ (3 µg), Rp-8-pCPT-cGMP (5 µg), glibenclamide (10 µg) did not produce any significant antiallodynic or antihyperalgesic effect in the ipsilateral or contralateral paw of CFA-injected WT mice.


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 role of the peripheral nitric oxide–cGMP–PKG-KATP signaling pathway in the antinociceptive effects of JWH-015.Mechanical antiallodynic (A, C, E) and thermal antihyperalgesic (B, D, F) effects of the subplantar co-administration of JWH-015 (150 µg) plus vehicle or different doses of ODQ (0.3 – 3.0 µg; A, B), Rp-8-pCPT-cGMPs (Rp-8; 0.3-5.0 µg; C, D) or glibenclamide (GC; 3.0–10 µg; E,F) in the ipsilateral paw of WT mice at 10 days after CFA injection. The effects of the subplantar administration of vehicle and the maximal doses of ODQ (3.0 µg), Rp-8 (5.0 µg) or glibenclamide (10.0 µg) administered alone are also shown. All drugs were administered 20 min before starting behavioral testing. 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 behavioral test and selective inhibitor assayed, * p<0.05 denotes significant differences vs. group treated with JWH-015 + vehicle (one way ANOVA followed by Student Newman Keuls test).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198780&req=5

pone-0026688-g006: The role of the peripheral nitric oxide–cGMP–PKG-KATP signaling pathway in the antinociceptive effects of JWH-015.Mechanical antiallodynic (A, C, E) and thermal antihyperalgesic (B, D, F) effects of the subplantar co-administration of JWH-015 (150 µg) plus vehicle or different doses of ODQ (0.3 – 3.0 µg; A, B), Rp-8-pCPT-cGMPs (Rp-8; 0.3-5.0 µg; C, D) or glibenclamide (GC; 3.0–10 µg; E,F) in the ipsilateral paw of WT mice at 10 days after CFA injection. The effects of the subplantar administration of vehicle and the maximal doses of ODQ (3.0 µg), Rp-8 (5.0 µg) or glibenclamide (10.0 µg) administered alone are also shown. All drugs were administered 20 min before starting behavioral testing. 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 behavioral test and selective inhibitor assayed, * p<0.05 denotes significant differences vs. group treated with JWH-015 + vehicle (one way ANOVA followed by Student Newman Keuls test).
Mentions: Our results showed that the local antiallodynic and antihyperalgesic effects produced by JWH-015 in the ipsilateral paw of CFA-injected WT mice were significantly inhibited by their peripheral co-administration with different doses of ODQ (Fig. 6, A-B), Rp-8-pCPT-cGMPs (Fig. 6, C-D) or glibenclamide (Fig. 6, E-F) in a dose-dependent manner (p<0.001, one way ANOVA followed by Student Newman Keuls test). While the local co-administration of JWH-015 plus ODQ, Rp-8-pCPT-cGMPs or glibenclamide did not have any significant effect on the contralateral paw of CFA-injected mice (data not shown). Our results also indicated that the subplantar administration of the highest tested doses of ODQ (3 µg), Rp-8-pCPT-cGMP (5 µg), glibenclamide (10 µg) did not produce any significant antiallodynic or antihyperalgesic effect in the ipsilateral or contralateral paw of CFA-injected WT mice.

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