title: Enhancement of μ-opioid receptor desensitization by nitric oxide in rat locus coeruleus neurons: involvement of reactive oxygen species.
abstract: It has previously been shown that nitric oxide (NO) synthase is involved in the development of opioid tolerance. The aim of the present work was to study the effect of NO on μ-opioid receptor (MOR) desensitization. Furthermore, we explored the possible role of reactive oxygen species (ROS) in this effect. Single-unit extracellular and whole-cell patch-clamp recordings were performed on locus coeruleus (LC) neurons from rat brain slices. Perfusion with high concentrations of Met(5)-enkephalin (ME) caused a concentration-related reduction of opioid effect, reflecting the induction of homologous MOR desensitization. The NO donors sodium nitroprusside and diethylamine NONOate markedly enhanced the ME-induced MOR desensitization, although the acute effect of ME on K(+) conductance was not affected by sodium nitroprusside. Continuous perfusion with the antioxidants melatonin, trolox, 21-[4-(2,6-di-1-pyrrolidinyl-4-pyrrimidinyl)-1-piperazinyl]-pregna-1,4,9(11)-triene-3,20-dione(Z)-2-butenedioate (U74389G), and diethyldithiocarbamate prevented the effect of sodium nitroprusside on MOR desensitization, but they did not themselves alter the desensitization. Like sodium nitroprusside, the ROS-generating molecule H(2)O(2) enhanced MOR desensitization induced by ME. However, α(2)-adrenoceptor desensitization induced by noradrenaline was not modified by H(2)O(2), suggesting a selective action of ROS on MOR. Our results suggest that elevated levels of NO, which may be reached in pathological processes, enhance homologous desensitization of MOR in the LC, probably through a mechanism involving ROS generation.
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Odontology, University of the Basque Country, Barrio Sarriena s/n, Leioa E-48940, Bizkaia, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Llorente
authors.forename: M T
authors.initials: MT
authors.lastname: Santamarta
authors.forename: G
authors.initials: G
authors.lastname: Henderson
authors.forename: J
authors.initials: J
authors.lastname: Pineda
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology; D004050:Ditiocarb / Q000494:pharmacology; D004744:Enkephalin, Methionine / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism; D008125:Locus Coeruleus / Q000378:metabolism* / Q000502:physiology; D008297:Male; D008550:Melatonin / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D009569:Nitric Oxide / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D002839:Chromans; D006834:Hydrazines; D017382:Reactive Oxygen Species; D018341:Receptors, Adrenergic, alpha-2; D017450:Receptors, Opioid, mu; D009599:Nitroprusside; D009569:Nitric Oxide; D004744:Enkephalin, Methionine; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; D004050:Ditiocarb; D006861:Hydrogen Peroxide; D008550:Melatonin; D011188:Potassium; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D009638:Norepinephrine