Comparison of 7-nitroindazole with other nitric oxide synthase inhibitors as attenuators of opioid withdrawal.
Previously, we demonstrated that two nonselective inhibitors of nitric oxide synthase (NOS), L-NG-nitroarginine (L-NNA) and L-NG-nitroarginine methyl ester (L-NAME), reduced some signs of morphine withdrawal in rats. The present work extended these studies to include 7-nitroindazole (7-NI), an inhibitor specific for cerebral NOS, and N(5)-(1-iminoethyl)-L-ornithine (L-NIO), a potent inhibitor of endothelial NOS. Behavioral effects of these four NOS inhibitors and clonidine, an alpha 2-adrenoceptor, agonist, on morphine withdrawal in rats were assessed. Rats received one 75-mg morphine pellet subcutaneously (SC). Three days later, NOS inhibitors were administered IP 1 h before withdrawal was precipitated with naloxone (0.5 mg/kg, SC) and scored. 7-NI, L-NIO, L-NAME and L-NNA produced dose-related decreases in weight loss, diarrhea, wet dog shakes and grooming. 7-NI also reduced mastication, salivation and genital effects. Clonidine produced effects similar to 7-NI. In awake, morphine-naive and morphine-dependent rats not subjected to withdrawal, 7-NI was the only NOS inhibitor that did not increase blood pressure. Because 7-NI attenuated more signs of opioid withdrawal than L-NNA, L-NAME or L-NIO without causing hypertension, 7-NI appears to warrant further testing as a potential candidate for human use.
Vaupel
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DB
Neuroimaging and Drug Action Section, National Institute on Drug Abuse, Baltimore, MD 21224, USA.
Kimes
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AS
London
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ED
D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D007191:Indazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009293:Opioid-Related Disorders / Q000188:drug therapy*; D051381:Rats; D011916:Rats, Inbred F344; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D013997:Time Factors
D004791:Enzyme Inhibitors; D007191:Indazoles; D019001:Nitric Oxide Synthase; C080122:7-nitroindazole