Nitric oxide synthase inhibitors. Preclinical studies of potential use for treatment of opioid withdrawal.
Four inhibitors of nitric oxide synthase (NOS), administered as acute pretreatments, attenuated several signs of naloxone-precipitated opioid withdrawal in morphine-dependent rats. Profiles of these drugs for inhibiting the expression of withdrawal were similar to that of clonidine, a drug used clinically to treat opioid withdrawal. The nonselective NOS inhibitors, NG-nitro-L-arginine and NG-nitro-L-arginine methyl ester, and N(5)-(1-iminoethyl)-L-ornithine, a selective inhibitor of endothelial NOS, Increased blood pressure in awake, morphine-naive and morphine-dependent rats not undergoing withdrawal. 7-Nitroindazole, a selective inhibitor of neuronal NOS, did not elevate blood pressure. Insofar as hypertension is a component of opioid withdrawal in humans, the ability of 7-nitroindazole to attenuate morphine withdrawal in rats without eliciting a vasopressor response suggests that 7-nitroindazole may have human therapeutic potential. Research directions for the continued development of 7-nitroindazole as a therapeutic modality are discussed with respect to issues of physical dependence, tolerance, and safety.
Vaupel
D B
DB
Neuroimaging and Drug Action Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD USA.
Kimes
A S
AS
London
E D
ED
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000633:toxicity; D001794:Blood Pressure / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology; D003864:Depression, Chemical; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D006339:Heart Rate / Q000187:drug effects; D007191:Indazoles / Q000494:pharmacology / Q000633:toxicity; D009020:Morphine / Q000009:adverse effects / Q000494:pharmacology*; D019331:NG-Nitroarginine Methyl Ester; D009294:Narcotics / Q000009:adverse effects*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine; D009293:Opioid-Related Disorders / Q000188:drug therapy* / Q000378:metabolism; D009952:Ornithine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000633:toxicity; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000378:metabolism
D000316:Adrenergic alpha-Agonists; D004791:Enzyme Inhibitors; D007191:Indazoles; D009294:Narcotics; D019335:Nitroarginine; D009569:Nitric Oxide; C065027:N(G)-iminoethylornithine; D009020:Morphine; D001120:Arginine; D009952:Ornithine; D019001:Nitric Oxide Synthase; D003000:Clonidine; C080122:7-nitroindazole; D019331:NG-Nitroarginine Methyl Ester