title: Peripheral effects of morphine and expression of μ-opioid receptors in the dorsal root ganglia during neuropathic pain: nitric oxide signaling.
abstract: BACKGROUND
  The local administration of μ-opioid receptor (MOR) agonists attenuates neuropathic pain but the precise mechanism implicated in this effect is not completely elucidated. We investigated if nitric oxide synthesized by neuronal (NOS1) or inducible (NOS2) nitric oxide synthases could modulate the local antiallodynic effects of morphine through the peripheral nitric oxide-cGMP-protein kinase G (PKG)-ATP-sensitive K+ (KATP) channels signaling pathway activation and affect the dorsal root ganglia MOR expression during neuropathic pain.
  
  
  RESULTS
  In wild type (WT) mice, the subplantar administration of morphine dose-dependently decreased the mechanical and thermal allodynia induced by the chronic constriction of the sciatic nerve (CCI), which effects were significantly diminished after their co-administration with different subanalgesic doses of a selective 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), PKG ((Rp)-8-(para-chlorophenylthio)guanosine-3',5'-cyclic monophosphorothioate; Rp-8-pCPT-cGMPs) inhibitor or a KATP channel blocker (glibenclamide). The evaluation of the expression of MOR in the dorsal root ganglia from sham-operated and sciatic nerve-injured WT, NOS1 knockout (KO) and NOS2-KO mice at 21 days after surgery demonstrated that, although the basal mRNA and protein levels of MOR were similar between WT and both NOS-KO animals, nerve injury only decreased their expression in WT mice.
  
  
  CONCLUSIONS
  These results suggest that the peripheral nitric oxide-cGMP-PKG-KATP signaling pathway activation participates in the local antiallodynic effects of morphine after sciatic nerve injury and that nitric oxide, synthesized by NOS1 and NOS2, is implicated in the dorsal root ganglia down-regulation of MOR during neuropathic pain.
authors.affiliation: Grup de Neurofarmacologia Molecular, Institut de Recerca de l'Hospital de la Sta Creu i Sant Pau & Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Arnau
authors.initials: A
authors.lastname: Hervera
authors.forename: Roger
authors.initials: R
authors.lastname: Negrete
authors.forename: Sergi
authors.initials: S
authors.lastname: Leánez
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Martín-Campos
authors.forename: Olga
authors.initials: O
authors.lastname: Pol
mesh_terms: D000818:Animals; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism*; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D009270:Naloxone / Q000031:analogs & derivatives / Q000494:pharmacology; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012584:Sciatic Nerve / Q000293:injuries; D015398:Signal Transduction / Q000187:drug effects; D013004:Somatostatin / Q000494:pharmacology
chemical_list: C529311:CTAP octapeptide; D010446:Peptide Fragments; D000644:Quaternary Ammonium Compounds; D017450:Receptors, Opioid, mu; D009569:Nitric Oxide; D009270:Naloxone; D013004:Somatostatin; C041269:N-methylnaloxone; D009020:Morphine