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 if 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 (CCI), we evaluated the effects of [d-Pen(2),d-Pen(5)]-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 a 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-KO and NOS2-KO mice, was also 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, but not in NOS1-KO. Results suggest that inactivation of 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.
- Received February 23, 2010.
- Revision received May 9, 2010.
- Accepted May 20, 2010.
- The American Society for Pharmacology and Experimental Therapeutics