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.
"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 . Of note, both stressful life events on symptoms of major depression  and rates of response to antidepressants and consequent remission from major depressive disorder  are influenced by variation in the MOR gene. "
[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
"The pgACC, cytoarchitecturally and physiologically distinct subregion of the ACC, is involved in the processing of negative and positive emotions and affective component of pain and has anatomical connections to other core-emotional processing regions as amygdala, PAG, and hypothalamus (An et al. 1998; Beckmann et al. 2009). Imaging studies using the selective μ-opioid receptor agonist [ 11 C]carfentanyl, or nonselective opioid antagonist naloxone, identified a critical role of the EOS in control of these processes in the pgACC (Kennedy et al. 2006; Wager et al. 2007; Eippert et al. 2009). Analysis of the mechanisms underlying the neurochemical basis of lateralized function in the pgACC is clinically important, because abnormalities in this area are associated with depression, schizophrenia , borderline personality, and anxiety disorders (Fahim et al. 2005; Walter et al. 2009; Prossin et al. 2010; Pizzagalli 2011), and autism spectrum disorder including Asperger syndrome (Oner et al. 2007). "
[Show abstract][Hide abstract] ABSTRACT: Lateralization of the processing of positive and negative emotions and pain suggests an asymmetric distribution of the neurotransmitter systems regulating these functions between the left and right brain hemispheres. By virtue of their ability to selectively mediate euphoria, dysphoria, and pain, the μ-, δ-, and κ-opioid receptors and their endogenous ligands may subserve these lateralized functions. We addressed this hypothesis by comparing the levels of the opioid receptors and peptides in the left and right anterior cingulate cortex (ACC), a key area for emotion and pain processing. Opioid mRNAs and peptides and 5 "classical" neurotransmitters were analyzed in postmortem tissues from 20 human subjects. Leu-enkephalin-Arg (LER) and Met-enkephalin-Arg-Phe, preferential δ-/μ- and κ-/μ-opioid agonists, demonstrated marked lateralization to the left and right ACC, respectively. Dynorphin B (Dyn B) strongly correlated with LER in the left, but not in the right ACC suggesting different mechanisms of the conversion of this κ-opioid agonist to δ-/μ-opioid ligand in the 2 hemispheres; in the right ACC, Dyn B may be cleaved by PACE4, a proprotein convertase regulating left-right asymmetry formation. These findings suggest that region-specific lateralization of neuronal networks expressing opioid peptides underlies in part lateralization of higher functions, including positive and negative emotions and pain in the human brain.
"Emotion dysregulation is a common feature of psychiatric disorders. In particular, it is a defining feature of borderline personality disorder (American Psychiatric Association, 1994; Carpenter & Trull, 2013; Crowell, et al., 2009; Linehan, 1993), and is implicated in major depressive disorder (Gross & Muñoz, 1995; Kennedy, et al., 2006). Emotion dysregulation includes heightened emotional reactivity, high levels of negative affect, and inadequate and maladaptive emotion regulation strategies (Carpenter & Trull, 2013), leading to dysfunctional response patterns, such as self-injury (e.g. "
[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).
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