Dysregulation of endogenous opioid emotion regulation circuitry in major depression in women

Department of Psychiatry, University of Michigan, Ann Arbor 48109-0720, USA.
Archives of General Psychiatry (Impact Factor: 13.75). 12/2006; 63(11):1199-208. DOI: 10.1001/archpsyc.63.11.1199
Source: PubMed

ABSTRACT There is extensive evidence implicating dysfunctions in stress responses and adaptation to stress in the pathophysiological mechanism of major depressive disorder (MDD) in humans. Endogenous opioid neurotransmission activating mu-opioid receptors is involved in stress and emotion regulatory processes and has been further implicated in MDD.
To examine the involvement of mu-opioid neurotransmission in the regulation of affective states in volunteers with MDD and its relationship with clinical response to antidepressant treatment.
Measures of mu-opioid receptor availability in vivo (binding potential [BP]) were obtained with positron emission tomography and the mu-opioid receptor selective radiotracer carbon 11-labeled carfentanil during a neutral state. Changes in BP during a sustained sadness challenge were obtained by comparing it with the neutral state, reflecting changes in endogenous opioid neurotransmission during the experience of that emotion.
Clinics and neuroimaging facilities at a university medical center.
Fourteen healthy female volunteers and 14 individually matched patient volunteers diagnosed with MDD were recruited via advertisement and through outpatient clinics.
Sustained neutral and sadness states, randomized and counterbalanced in order, elicited by the cued recall of an autobiographical event associated with that emotion. Following imaging procedures, patients underwent a 10-week course of treatment with 20 to 40 mg of fluoxetine hydrochloride.
Changes in mu-opioid receptor BP during neutral and sustained sadness states, negative and positive affect ratings, plasma cortisol and corticotropin levels, and clinical response to antidepressant administration.
The sustained sadness condition was associated with a statistically significant decrease in mu-opioid receptor BP in the left inferior temporal cortex of patients with MDD and correlated with negative affect ratings experienced during the condition. Conversely, a significant increase in mu-opioid receptor BP was observed in healthy control subjects in the rostral region of the anterior cingulate. In this region, a significant decrease in mu-opioid receptor BP during sadness was observed in patients with MDD who did not respond to antidepressant treatment. Comparisons between patients with MDD and controls showed significantly lower neutral-state mu-opioid receptor BP in patients with MDD in the posterior thalamus, correlating with corticotropin and cortisol plasma levels. Larger reductions in mu-opioid system BP during sadness were obtained in patients with MDD in the anterior insular cortex, anterior and posterior thalamus, ventral basal ganglia, amygdala, and periamygdalar cortex. The same challenge elicited larger increases in the BP measure in the control group in the anterior cingulate, ventral basal ganglia, hypothalamus, amygdala, and periamygdalar cortex.
The results demonstrate differences between women with MDD and control women in mu-opioid receptor availability during a neutral state, as well as opposite responses of this neurotransmitter system during the experimental induction of a sustained sadness state. These data demonstrate that endogenous opioid neurotransmission on mu-opioid receptors, a system implicated in stress responses and emotional regulation, is altered in patients diagnosed with MDD.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Recently μ opioid receptor (MOR) has been shown to be closely associated with depression. Here we investigated the action of Shuyu, a Chinese herbal prescription, on repeated restraint stress induced depression-like rats, with specific attention to the role of MOR and the related signal cascade. Our results showed that repeated restraint stress caused significant depressive-like behaviors, as evidenced by reduced body weight gain, prolonged duration of immobility in forced swimming test, and decreased number of square-crossings and rearings in open field test. The stress-induced depression-like behaviors were relieved by Shuyu, which was accompanied by decreased expression of MOR in hippocampus. Furthermore, Shuyu upregulated BDNF protein expression, restored the activity of CREB, and stimulated MEK and ERK phosphorylation in hippocampus of stressed rats. More importantly, MOR is involved in the effects of Shuyu on these depression-related signals, as they can be strengthened by MOR antagonist CTAP. Collectively, these data indicated that the antidepressant-like properties of Shuyu are associated with MOR and the corresponding CREB, BDNF, MEK, and ERK signal pathway. Our study supports clinical use of Shuyu as an effective treatment of depression and also suggests that MOR might be a target for treatment of depression and developing novel antidepressants.
    Evidence-based Complementary and Alternative Medicine 01/2015; 2015:1-11. DOI:10.1155/2015/452412 · 1.88 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: People who inject drugs (PWID) and have mental health conditions, such as major depression, an anxiety disorder, or antisocial or borderline personality disorder, may have elevated risk for HIV and HCV infection. This study examined the associations between psychiatric disorders and risky injection behavior in an out-of-treatment sample of young PWID. We recruited participants through outreach and respondent-driven sampling (RDS). Participants completed a computer-assisted self-interview and a psychiatric interview. Interviews took place at a community-based field site of the Community Outreach Intervention Projects. Participants were 570 young adults (18 to 25 years) who injected drugs in the previous 30 days. Psychiatric diagnoses were based on interviews using the Psychiatric Research Interview for Substance and Mental Disorders (PRISM). Injection behavior was classified into 3 categories: receptive syringe sharing, other equipment sharing only, and no sharing. Associations between injection risk behavior and psychiatric diagnoses were tested using RDS-weighted multinomial regressions. Substance-induced lifetime and past-year major depression, and borderline personality disorder, were significantly associated with a greater likelihood of receptive syringe sharing (p < .001). Substance-induced major depression in the past year was also associated with nonsyringe equipment sharing (p < .01). Primary major depression, antisocial personality disorder, and anxiety disorders other than posttraumatic stress disorder were slightly more prevalent among injectors who shared syringes; however, the associations were not statistically significant. Substance-induced major depression and borderline personality disorder are common among young PWID and are associated with risky injection behavior. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
    Psychology of Addictive Behaviors 08/2014; DOI:10.1037/a0036390 · 2.09 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background In a community sample of low-income African American adolescents, we tested the interactive effects of variation in the mu 1 opioid receptor (OPRM1) gene and the occurrence of stressful life events on symptoms of depression. Method Interactive effects of 24 OPRM1 simple nucleotide polymorphisms (SNP) and adolescent report of stressful life events on depression were tested using multilevel regressions. SNPs were dummy coded to test both additive and dominate forms of coding. Results Five OPRM1 SNPs showed significant evidence of interaction with stressful life events to alter depression risk (or symptoms) after adjusting for multiple testing and the correlated nature of the SNPs. Follow-up analyses showed significant differences based on OPRM1 genotype at both lower and higher frequencies of stressful life events, suggesting that participants with a copy of the minor allele on OPRM1 SNPs rs524731, rs9478503, rs3778157, rs10485057, and rs511420 have fewer symptoms in low stress conditions but more symptoms in high stress conditions compared to major allele homozygotes. Limitations The genetic variants associated with depression in African American adolescents may not translate to other ethnic groups. This study is also limited in that only one gene that functions within a complex biological system is addressed. Conclusions This current study is the first to find an interaction between OPRM1 and life stress that is associated with depression. It also addressed an understudied population within the behavioral genetics literature. Further research should test additional genes involved in the opioid system and expand the current findings to more diverse samples.
    Journal of Affective Disorders 06/2014; 162:12–19. DOI:10.1016/j.jad.2014.03.020 · 3.71 Impact Factor