The relationship between naloxone-induced cortisol and delta opioid receptor availability in mesolimbic structures is disrupted in alcohol-dependent subjects

Departments of Medicine Psychiatry and Behavioral Sciences Radiology Neuroscience Environmental Health Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Addiction Biology (Impact Factor: 5.36). 01/2013; 18(1):181-92. DOI: 10.1111/j.1369-1600.2011.00430.x


Hypothalamic-pituitary-adrenal (HPA) axis responses following naloxone administration have been assumed to provide a measure of opioid receptor activity. Employing positron emission tomography (PET) using the mu opioid receptor (MOR) selective ligand [(11) C] carfentanil (CFN), we demonstrated that cortisol responses to naloxone administration were negatively correlated with MOR availability. In this study, we examined whether naloxone-induced cortisol and adrenocorticotropin (ACTH) responses in 15 healthy control and 20 recently detoxified alcohol-dependent subjects correlated with delta opioid receptor (DOR) availability in 15 brain regions using the DOR-selective ligand [(11) C] methyl-naltrindole (MeNTL) and PET imaging. The day after the scan, cortisol responses to cumulative doses of naloxone were determined. Peak cortisol and ACTH levels and area under the cortisol and ACTH curve did not differ by group. There were negative relationships between cortisol area under curve to naloxone and [(11) C] MeNTL-binding potential (BP(ND) ) in the ventral striatum, anterior cingulate, fusiform cortices, temporal cortex, putamen and a trend in the hypothalamus of healthy control subjects. However, in alcohol-dependent subjects, cortisol responses did not correlate with [(11) C]MeNTL BP(ND ) in any brain region. Plasma ACTH levels did not correlate with [(11) C]MeNTL BP(ND) in either group. The study demonstrates that naloxone provides information about individual differences in DOR availability in several mesolimbic structures. The data also show that the HPA axis is intimately connected with mesolimbic stress pathways through opioidergic neurotransmission in healthy subjects but this relationship is disrupted during early abstinence in alcohol-dependent subjects.

Download full-text


Available from: Elise M Weerts, Feb 04, 2014
  • Source
    • "The present study shows that the blood glucose level in the dependent mice increased significantly in comparison with the independent negative control group, this increase correlates with cortisol level in dependent mice.[31] According to the previous studies, the blood glucose level in the opioid-dependent mice was significantly higher, because usage of opioids and injection of naloxone induce withdrawal signs and increase the blood glucose level.[31] Our data indicate that by treating the dependent animal with clonidine, exercise, and exercise in combination with clonidine, a significant reduction in the blood glucose level was revealed in comparison with the dependent positive control group, but in only results of groups under treatment by clonidine or exercise in combination with clonidine were statistically significant (P < 0.05). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Morphine withdrawal usually results in undesired outcomes, despite partial benefits of alternative medication such as methadone, because of the lack of mental sedation during the withdrawal period, may not lead to the desired result. In this study, forced exercise by treadmill is used to manage morphine dependence in animal model. Materials and Methods: Forty adult male mice were divided into 5 groups, from which 4 groups became dependent by increasing daily doses of morphine for 6 days (20-45 mg/kg, SC). Afterwards, the animals were treated for 21 days by either of the following protocol: Positive control (dependent) received once daily 45 mg/kg of morphine sulfate (SC) for 21 day, group under treatment by clonidine (0.4 mg/kg, SC) for 21 day group under treatment by forced exercise by treadmill for 21 day, group under treatment by combination of clonidine (0.4 mg/kg, SC) and forced exercise by treadmill for 21day and the negative control group(independent) received saline injection like other groups. Each of this administration was injected at 8 AM. Finally, in the test day (day 28), all animals received a single dose of naloxone (3 mg/kg, SC) at 8 AM and then were observed for withdrawal signs, and Total Withdrawal Score (TWS) was determined as described previously. After withdrawal sign evaluation for evaluation of stress level of dependent mice, blood cortisol and glucose level were measured in non-fasting situations well. Results: This study showed that TWS significantly decreased in all treatment groups in comparison with positive control group (P < 0.001). Moreover, blood cortisol and glucose level significantly decreased in group under treatment by clonidine (0.4 mg/kg) and group under treatment by combination of clonidine (0.4 mg/kg) and forced exercise by treadmill groups in comparison with control positive (dependent) (P < 0.05). Conclusion: This study suggested that forced exercise can be useful as adjunct therapy in dependent people and can ameliorate side effects and stress situation of withdrawal syndrome periods.
    08/2014; 3:171. DOI:10.4103/2277-9175.139181
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The mu opioid receptor system is altered in alcohol dependent (AD) subjects. Cortisol responses to opioid receptor antagonists are assumed to impart information about opioid receptor activity. In the present study we examined naloxone-induced cortisol responses in 18 healthy control (HC) and 25 recently detoxified AD subjects and then correlated the cortisol response with mu opioid receptor availability across 15 brain regions using positron emission tomography (PET) and the mu opioid receptor selective ligand [(11)C] Carfentanil (CFN). On average the AD subjects required twice the dose of naloxone to induce a peak cortisol response compared to the HC subjects. Using the rising slope of the cortisol curve (placebo to peak) as a metric we then went on to examine the relationship between cortisol responses to naloxone and [(11)C]CFN BP(ND). There were significant negative relationships between cortisol and [(11)C]CFN binding potential (BP(ND)) in multiple brain regions of HC subjects. However, cortisol responses did not correlate with [(11)C]CFN BP(ND) across any brain region in AD subjects. In summary, naloxone imparts information about individual differences in mu opioid receptor availability throughout the mesolimbic system in healthy individuals. However pathways governing the relationship between naloxone-induced cortisol and mu opioid receptor availability are disrupted during early abstinence in AD subjects.
    Alcohol (Fayetteville, N.Y.) 09/2012; 46(6):511-7. DOI:10.1016/j.alcohol.2012.04.006 · 2.01 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Objectives: Animal and clinical studies implicated opioid dysfunction in the pathogenesis of alcohol abuse and dependence. The π-opioid antagonist naltrexone reduces craving, eventually modulated by hypothalamic-pituitary-adrenal axis. Altered cortisol response to opioid receptor blockade not only in alcohol dependent persons, but also in persons with a family history of alcohol dependency was reported. Methods: Twenty patients with alcohol dependence who had undergone detoxification were recruited. Naloxone (3.2 mg/70 kg body weight) having a very similar receptor profile to naltrexone and placebo were administered in cross-over fashion on two separate days 48 h apart. Mood and craving was assessed with well-established instruments (Alcohol Craving Questionnaire (ACQ), Profile of Mood Scale (POMS)). Both patients and raters were blind to all treatments. Twelve patients were first treated with naloxone, eight were first treated with placebo. Results: No significant differences were found between the placebo and naloxone groups according to ACQ and POMS. Cortisol levels were significantly higher in naloxone group. Conclusions: We could not replicate the result, that blocking of the endogenous opioid system leads to reduced craving in alcohol-dependent individuals, while increase of cortisol after naloxone challenge is the expected biological effect of opioid receptor blockade on the hypothalamic-pituitary-adrenal (HPA) axis.
    The World Journal of Biological Psychiatry 09/2013; 14(7):539-46. DOI:10.3109/15622975.2013.812239 · 4.18 Impact Factor
Show more