Abstract
Both δ-opioid receptor (DOPr) and cannabinoid-2 receptor (CB2R) agonists attenuate neuropathic pain, but the precise mechanism implicated in these effects is not completely elucidated. We investigated whether nitric oxide synthesized by neuronal (NOS1) or inducible (NOS2) nitric-oxide synthases could modulate DOPr and/or CB2R antiallodynic and antihyperalgesic effects through the peripheral nitric oxide-cGMP-protein kinase G (PKG) pathway activation and affect their expression during neuropathic pain. In wild-type (WT) mice at 21 days after chronic constriction of sciatic nerve, we evaluated the effects of [d-Pen2,d-Pen5]-enkephalin (DPDPE); (2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone (JWH-015); and a NOS1 [N-[(4S)-4-amino-5-[(2-aminoethyl)amino]pentyl]-N′-nitroguanidine tris(trifluoroacetate) salt; NANT], NOS2 [l-N(6)-(1-iminoethyl)-lysine; l-NIL], l-guanylate cyclase [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; ODQ], or PKG [(Rp)-8-(para-chlorophenylthio)guanosine-3′,5′-cyclic monophosphorothioate; Rp-8-pCPT-cGMPs] inhibitor administered alone or combined. Expression of DOPr and CB2R mRNA in the spinal cord and dorsal root ganglia of naive and nerve-injured WT, NOS1-knockout (KO), and NOS2-KO mice, also was assessed. The subplantar administration of NANT, l-NIL, ODQ, or Rp-8-pCPT-cGMPs dose-dependently inhibited neuropathic pain and enhanced the local effects of DPDPE or JWH-015. Moreover, although the basal levels of DOPr and CB2R mRNA were similar between WT and NOS-KO animals, nerve injury only decreased (DOPr) or increased (CB2R) their expression in the dorsal root ganglia of WT and NOS2-KO mice, and not in NOS1-KO mice. Results suggest that inactivation of the nitric oxide-cGMP-PKG peripheral pathway triggered by NOS1 and NOS2 enhanced the peripheral actions of DOPr and CB2R agonists and that nitric oxide synthesized by NOS1 is implicated in the peripheral regulation of DOPr and CB2R gene transcription during neuropathic pain.
Footnotes
This work was supported by Fondo de Investigación Sanitaria, Madrid [Grants PI051604, PS0900968] and the Fundació La Marató de TV3 Barcelona [Grant 070810], Spain.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.167585.
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ABBREVIATIONS:
- DOPr
- δ-opioid receptor
- CB2R
- cannabinoid-2 receptor
- NOS1
- neuronal nitric-oxide synthase
- NOS2
- inducible nitric-oxide synthase
- PKG
- cGMP-dependent protein kinase
- WT
- wild type
- CCI
- chronic constriction of the sciatic nerve
- DPDPE
- [d-Pen2,d-Pen5]-enkephalin
- JWH-015
- (2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone
- AM630
- [6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)methanone
- NANT
- N-[(4S)-4-amino-5-[(2-aminoethyl)amino]pentyl]-N′-nitroguanidine tris(trifluoroacetate) salt
- l-NIL
- l-N(6)-(1-iminoethyl)-lysine
- ODQ
- 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one
- Rp-8-pCPT-cGMPs
- (Rp)-8-(para-chlorophenylthio)guanosine-3′,5′-cyclic monophosphorothioate
- KO
- knockout
- PCR
- polymerase chain reaction
- DMSO
- dimethyl sulfoxide
- ANOVA
- analysis of variance.
- Received February 23, 2010.
- Accepted May 20, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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