Differences in delta- and mu-opioid receptor blockade measured by positron emission tomography in naltrexone-treated recently abstinent alcohol-dependent subjects.
Blockade of brain mu-opioid receptor (mu-OR) and delta-opioid receptor (delta-OR) was investigated in recently abstinent alcohol-dependent subjects (N=21) maintained on naltrexone. Subjects completed a 19-day inpatient protocol, which included alcohol abstinence followed by naltrexone treatment (50 mg) on days 15-19. Blood samples were collected after the first administration of naltrexone to evaluate serum levels of naltrexone and 6-beta-naltrexol. Regional brain mu-OR binding potential (BP) and delta-OR Ki was measured using [11C]carfentanil (CAR) positron emission tomography (PET) and [11C]methyl naltrindole ([11C]MeNTI) PET, respectively, before (day 5) and during naltrexone treatment (day 18). Naltrexone inhibition of [11C]CAR BP was near maximal across all brain regions of interest with little variability across subjects (mean+SD% inhibition=94.9+4.9%). Naltrexone only partially inhibited the [11C]MeNTI Ki and there was more variability across subjects (mean+SD% inhibition=21.1+14.49%). Peak serum levels of naltrexone were positively correlated with % inhibition of delta-OR Ki in neocortex and basal ganglia. Peak serum levels of naltrexone were not correlated with % inhibition of mu-OR BP. Peak levels of 6-beta-naltrexol were not significantly correlated with % inhibition of mu-OR BP or delta-OR Ki. Thus, the FDA recommended therapeutic dose of naltrexone was sufficient to produce near complete inhibition of the mu-OR in recently abstinent alcohol dependent subjects. The lower percent inhibition of delta-OR and greater variability in delta-OR blockade by naltrexone across subjects may contribute to individual differences in treatment outcomes to naltrexone. Further investigations on the relationship between individual differences in delta-OR blockade by naltrexone and clinical outcomes should be explored.
Weerts
Elise M
EM
Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA. eweerts@jhmi.edu
Kim
Yu Kyeong
YK
Wand
Gary S
GS
Dannals
Robert F
RF
Lee
Jae Sung
JS
Frost
J James
JJ
McCaul
Mary E
ME
D000328:Adult; D000437:Alcoholism / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D000701:Analgesics, Opioid; D003627:Data Interpretation, Statistical; D005260:Female; D005283:Fentanyl / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D008875:Middle Aged; D009271:Naltrexone / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009292:Narcotic Antagonists / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors*; D013375:Substance Withdrawal Syndrome / Q000000981:diagnostic imaging / Q000523:psychology; D013695:Temperance
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D019275:Radiopharmaceuticals; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D009271:Naltrexone; C017114:carfentanil; D005283:Fentanyl