Further in vivo studies on attenuating morphine withdrawal: isoform-selective nitric oxide synthase inhibitors differ in efficacy.
The N-methyl-D-aspartate (NMDA) receptor-nitric oxide (NO) pathway has been linked to opiate withdrawal. Pretreatments with four inhibitors of NO synthase, 7-nitro indazole, 3-bromo-7-nitro indazole, S-methyl-L-thiocitrulline and aminoguanidine, which exhibit different isoform selectivity in vitro, were evaluated for their ability to attenuate signs of naloxone-precipitated morphine withdrawal. In separate experiments, effects of NO synthase inhibitors on blood pressure were measured in naive and morphine-dependent rats. 7-Nitro indazole, 3-bromo-7-nitro indazole and S-methyl-L-thiocitrulline, which are specific inhibitors of the constitutive isoforms, produced dose-dependent reductions of several signs of withdrawal. Blood pressure was unaffected by the indazoles, whereas S-methyl-L-thiocitrulline produced a strong vasoconstrictor response. Aminoguanidine, which selectively inhibits inducible NO synthase, reduced fewer signs of opioid withdrawal, had a lower relative potency and exhibited no vasopressor activity. These data suggest that constitutive isoforms, but not the inducible isoform of NO synthase, have a primary role in NO-mediated processes that modulate the opioid withdrawal syndrome in the rat.
Vaupel
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DB
Brain Imaging 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; D002956:Citrulline / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006146:Guanidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D006339:Heart Rate / Q000187:drug effects; D007191:Indazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D007527:Isoenzymes; D008297:Male; D009020:Morphine / Q000009:adverse effects*; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy*; D013890:Thiourea / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
C106731:3-bromo-7-nitroindazole; D004791:Enzyme Inhibitors; D006146:Guanidines; D007191:Indazoles; D007527:Isoenzymes; D009292:Narcotic Antagonists; D002956:Citrulline; D009270:Naloxone; D009020:Morphine; D019001:Nitric Oxide Synthase; D013890:Thiourea; C086717:S-methylthiocitrulline; C004479:pimagedine; C080122:7-nitroindazole