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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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Related in: MedlinePlus

Dorsal root ganglia expression of NOS1.The relative mRNA (A) and protein (B) expression of NOS1 in the ipsilateral side of the dorsal root ganglia from naive and CFA injected WT mice are represented. A representative example of Western blot for NOS1 protein (155 kDa) in which β-actin (43 kDa) was used as a loading control is shown in C. Data are expressed as the mean values ± SEM of 5–6 samples per group. * indicates significant differences when compared CFA vs. naïve mice (p<0.05, Student's t test).
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pone-0026688-g004: Dorsal root ganglia expression of NOS1.The relative mRNA (A) and protein (B) expression of NOS1 in the ipsilateral side of the dorsal root ganglia from naive and CFA injected WT mice are represented. A representative example of Western blot for NOS1 protein (155 kDa) in which β-actin (43 kDa) was used as a loading control is shown in C. Data are expressed as the mean values ± SEM of 5–6 samples per group. * indicates significant differences when compared CFA vs. naïve mice (p<0.05, Student's t test).

Mentions: The mRNA and protein levels of NOS1 in the ipsilateral side of the dorsal root ganglia from WT mice with (CFA) and without (naive) inflammatory pain are shown in Figure 4A and 4B, respectively. Our results showed that inflammatory pain significantly enhanced the mRNA expression of NOS1, but not their protein levels, in the ipsilateral side of CFA injected mice as compared to naive (p<0.032, Student's t test).


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)

Dorsal root ganglia expression of NOS1.The relative mRNA (A) and protein (B) expression of NOS1 in the ipsilateral side of the dorsal root ganglia from naive and CFA injected WT mice are represented. A representative example of Western blot for NOS1 protein (155 kDa) in which β-actin (43 kDa) was used as a loading control is shown in C. Data are expressed as the mean values ± SEM of 5–6 samples per group. * indicates significant differences when compared CFA vs. naïve mice (p<0.05, Student's t test).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0026688-g004: Dorsal root ganglia expression of NOS1.The relative mRNA (A) and protein (B) expression of NOS1 in the ipsilateral side of the dorsal root ganglia from naive and CFA injected WT mice are represented. A representative example of Western blot for NOS1 protein (155 kDa) in which β-actin (43 kDa) was used as a loading control is shown in C. Data are expressed as the mean values ± SEM of 5–6 samples per group. * indicates significant differences when compared CFA vs. naïve mice (p<0.05, Student's t test).
Mentions: The mRNA and protein levels of NOS1 in the ipsilateral side of the dorsal root ganglia from WT mice with (CFA) and without (naive) inflammatory pain are shown in Figure 4A and 4B, respectively. Our results showed that inflammatory pain significantly enhanced the mRNA expression of NOS1, but not their protein levels, in the ipsilateral side of CFA injected mice as compared to naive (p<0.032, Student's t test).

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