The role of nitric oxide in the local antiallodynic and antihyperalgesic effects and expression of delta-opioid and cannabinoid-2 receptors during neuropathic pain in mice.
Both delta-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-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 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.
Hervera
Arnau
A
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.
Negrete
Roger
R
Leánez
Sergi
S
Martín-Campos
Jesús
J
Pol
Olga
O
D000818:Animals; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D010147:Pain Measurement / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy* / Q000378:metabolism*; D010812:Physical Stimulation; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020426:Sciatic Neuropathy / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000378:metabolism
D012333:RNA, Messenger; D043885:Receptor, Cannabinoid, CB2; D017465:Receptors, Opioid, delta; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C496321:Nos1 protein, mouse; C496317:Nos2 protein, mouse; D017869:Cyclic GMP-Dependent Protein Kinases