title: Contribution of nitric oxide-dependent guanylate cyclase and reactive oxygen species signaling pathways to desensitization of μ-opioid receptors in the rat locus coeruleus.
abstract: Nitric oxide (NO) is involved in desensitization of μ-opioid receptors (MOR). We used extracellular recordings in vitro to unmask the NO-dependent pathways involved in MOR desensitization in the rat locus coeruleus (LC). Perfusion with ME (3 and 10 μM) concentration-dependently reduced subsequent ME effect, indicative of MOR desensitization. ME (3 μM)-induced desensitization was enhanced by a NO donor (DEA/NO 100 μM), two soluble guanylate cyclase (sGC) activators (A 350619 30 μM and BAY 418543 1 μM) or a cGMP-dependent protein kinase (PKG) activator (8-pCPT-cGMP 30 μM). DEA/NO-induced enhancement was blocked by the sGC inhibitor NS 2028 (10 μM). A 350619 effect was also blocked by NS 2028, but not by the antioxidant Trolox. ME (10 μM)-induced desensitization was blocked by the neuronal NO synthase inhibitor 7-NI (100 μM) and restored by the PKG activator 8-Br-cGMP (100-300 μM). Paradoxically, ME (10 μM)-induced desensitization was not modified by sGC inhibitors (NS 2028 and ODQ), PKG inhibitors (H8 and Rp-8-Br-PET-cGMP) or antioxidant agents (Trolox, U-74389G and melatonin), but it was attenuated by a combination of NS 2028 and Trolox. In conclusion, MOR desensitization in the LC may be mediated or regulated by NO through sGC and reactive oxygen species signaling pathways.
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Odontology, University of the Basque Country (UPV/EHU), E-48940 Leioa, Bizkaia, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Pablos
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Odontology, University of the Basque Country (UPV/EHU), E-48940 Leioa, Bizkaia, Spain.
authors.forename: Aitziber
authors.initials: A
authors.lastname: Mendiguren
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Odontology, University of the Basque Country (UPV/EHU), E-48940 Leioa, Bizkaia, Spain. Electronic address: joseba.pineda@ehu.es.
authors.forename: Joseba
authors.initials: J
authors.lastname: Pineda
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008125:Locus Coeruleus / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008839:Microelectrodes; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D046509:Tissue Culture Techniques
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D017450:Receptors, Opioid, mu; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase
keywords: Cyclic guanosine monophosphate; Firing; Locus coeruleus; Nitric oxide; Reactive oxygen species; Slice; μ-Opioid receptor