title: The peripheral administration of a nitric oxide donor potentiates the local antinociceptive effects of a DOR agonist during chronic inflammatory pain in mice.
abstract: Several works reveal that nitric oxide could enhance the peripheral antinociception induced by opioids during acute inflammation. Nonetheless, the role of nitric oxide in the local antinociceptive effects of delta-opioid receptor (DOR) agonists during chronic peripheral inflammation is not known. The aim of this study is to evaluate whether nitric oxide would enhance the local antinociceptive effects of a DOR agonist during chronic inflammatory pain in mice. Chronic inflammatory pain was induced by the subplantar administration of complete Freund's adjuvant (CFA; 30 microl) and thermal hyperalgesia assessed by plantar test. In C57BL/6J mice, we evaluated the local antinociceptive effects of a DOR agonist, [D-Pen2,5]-enkephalin (DPDPE) and a nitric oxide donor, DETA NONOate DETA/NO 2,2'-(hydroxynitrosohydrazino) Bis-Ethanamine (NOC-18) alone or combined (DPDPE plus NOC-18) at 1, 4, 7, and 10 days after CFA injection. The reversibility of the peripheral antinociceptive effects of DPDPE, alone or combined with NOC-18, was assessed with the local administration of selective (naltrindole) and non-selective (naloxone methiodide) DOR antagonists. The local administration of DPDPE or NOC-18 alone dose-dependently inhibited the thermal hyperalgesia induced by peripheral inflammation. Moreover, the co-administration of NOC-18 with DPDPE significantly increased the antinociceptive effects produced by DPDPE from 1 to 10 days of CFA-induced inflammatory pain (P < 0.05). These effects were completely blocked by naltrindole and naloxone methiodide. Our results demonstrate that nitric oxide might enhance the local antinociceptive effects of a DOR agonist during chronic inflammatory pain by interaction with peripheral DOR, representing a useful strategy for an efficient antinociceptive treatment of peripheral inflammatory pain.
authors.affiliation: Grup de Neurofarmacologia Molecular, Institut de Recerca, 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: Sergi
authors.initials: S
authors.lastname: Leánez
authors.forename: Roger
authors.initials: R
authors.lastname: Negrete
authors.forename: Olga
authors.initials: O
authors.lastname: Pol
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000008:administration & dosage*; D005620:Freund's Adjuvant; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives; D009292:Narcotic Antagonists / Q000008:administration & dosage; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000008:administration & dosage* / Q000378:metabolism; D009603:Nitroso Compounds / Q000008:administration & dosage* / Q000378:metabolism; D010147:Pain Measurement; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; C093285:NOC 18; D009292:Narcotic Antagonists; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D017465:Receptors, Opioid, delta; D009569:Nitric Oxide; D009271:Naltrexone; D020881:Enkephalin, D-Penicillamine (2,5)-; D005620:Freund's Adjuvant; C055382:naltrindole