title: Inhibition of neuronal nitric oxide synthase attenuates the development of morphine tolerance in rats.
abstract: Our previous results have shown the involvement of nitric oxide in acute opioid desensitization of mu-opioid receptors in vitro. In the present study, we investigated the effect of repeated administration of 7-nitroindazole (7-NI; 30 mg/kg/12 h, i.p., 3 days), an inhibitor of neuronal nitric oxide synthase in vivo, on mu-opioid receptor tolerance induced by subchronic treatment with morphine in rats. The inhibitory effect of the opioid agonist Met5-enkephalin (ME) on the cell firing rate was evaluated by single-unit extracellular recordings of noradrenergic neurons in the locus coeruleus from brain slices, and the antinociceptive effect of morphine was measured by tail-flick techniques. In morphine-treated animals, concentration-effect curves for ME in the locus coeruleus were shifted by 5-fold to the right as compared to those in sham-treated animals, which confirmed the induction of mu-opioid receptor tolerance. However, tolerance to ME in morphine-treated rats was fully prevented by co-administration of 7-NI when compared to the vehicle-morphine group. Likewise, the antinociceptive effect of morphine was reduced in morphine-treated animals as compared to the sham group, whereas the antinociceptive tolerance was partially prevented by co-administration of 7-NI in morphine-treated rats (when compared to the vehicle-morphine group). Finally, 7-NI administration in sham-treated rats failed to change the effect induced by ME on the locus coeruleus or by morphine in the tail-flick test as compared to vehicle groups. These results demonstrate that subchronic administration of a neuronal inhibitor of nitric oxide synthase attenuates the development of morphine tolerance to the cellular and analgesic effects of mu-opioid receptor agonists.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of the Basque Country, E-48940 Leioa, Bizkaia, Spain.
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Santamarta
authors.forename: Isabel
authors.initials: I
authors.lastname: Ulibarri
authors.forename: Joseba
authors.initials: J
authors.lastname: Pineda
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004361:Drug Tolerance; D004744:Enkephalin, Methionine / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007191:Indazoles / Q000494:pharmacology; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; D007191:Indazoles; D009419:Nerve Tissue Proteins; D004744:Enkephalin, Methionine; D009020:Morphine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; C080122:7-nitroindazole