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: 14.48). 12/2006; 63(11):1199-208. DOI: 10.1001/archpsyc.63.11.1199
Source: PubMed


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.

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    • "4.3. The N/OFQ-NOP system and suicide Previous post-mortem and imaging studies suggested that adaptations at the level of mu (Gabilondo et al., 1995; Gross-Isseroff et al., 1990; Kennedy et al., 2006; Scarr et al., 2012) or kappa (Hurd, 2002; Pietrzak et al., 2014) opioid receptors signaling may contribute to suicide pathophysiology . Extending on these findings, the present study shows that suicide completers exhibit decreased levels of N/OFQ mRNA in the dACC, compared to non-suicidal control subjects. "
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    • "Moreover, in subjects with Cluster B personality disorder (mostly with BPD), patients showing self-injury had significantly lower levels of β-endorphin and met-enkephalin in their cerebrospinal fluid (CSF) than individuals without self-injury (Stanley et al., 2010). However, a dysregulation of μopioid receptor binding was also found in PET studies in patients with depression (Kennedy et al., 2006). "
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    • "Recently, plentiful researches have discovered the important functions of MOR in emotional regulation, etiology, and treatment of some mood disorders. In patients with major depressive disorder, both neutral state and sustained sadness condition were associated with a statistically significant MOR activation [3]. Of note, both stressful life events on symptoms of major depression [4] and rates of response to antidepressants and consequent remission from major depressive disorder [5] are influenced by variation in the MOR gene. "
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