Endogenous opioid system dysregulation in depression: implications for new therapeutic approaches

Abstract

The United States is in the midst of an opioid addiction and overdose crisis precipitated and exacerbated by use of prescription opioid medicines. The majority of opioid prescriptions are dispensed to patients with comorbid mood disorders including major depressive disorder (MDD). A growing body of research indicates that the endogenous opioid system is directly involved in the regulation of mood and is dysregulated in MDD. This involvement of the endogenous opioid system may underlie the disproportionate use of opioids among patients with mood disorders. Emerging approaches to address endogenous opioid dysregulation in MDD may yield novel therapeutics that have a low or absent risk of abuse and addiction relative to µ-opioid agonists. Moreover, agents targeting the endogenous opioid system would be expected to yield clinical benefits qualitatively different from conventional monaminergic antidepressants. The development of safe and effective agents to treat MDD-associated endogenous opioid dysregulation may represent a distinct and currently underappreciated means of addressing treatment resistant depression with the potential to attenuate the on-going opioid crisis.

Fig. 1

Areas of opioid receptor gene expression (μ = OPRM1; δ = OPRD1; κ = OPRK1; NOP = ORL1) in the human brain (Donor: H0351.1015, 55 yrs, Male, White or Caucasian). The cortical gene expression patterns are displayed on an inflated cortical surface (outer and inner surfaces of the left hemisphere). Subcortical structures of the brain are represented from the frontal view, and subcortical as well as brainstem structures are shown in the side view. The color bar displays expression values using z-score normalization. Allen Institute; http://www.brain-map.org

Fig. 2

Positron emission tomography (PET) baseline measures of opioid receptor binding in humans [images averaged across a group of subjects (n < 20 for all groups)]. Images are color-coded according to the scale shown so that highest concentrations of the radiotracer are represented by red and lowest concentrations by black/purple. Binding maps in the coronal (top) and axial (bottom) view show greatest binding in the striatum and insular cortex for all radiotracers, except for the δ-opioid receptor antagonist: N1′-([11 C]methyl) Naltrindol. Left: μ-opioid receptor agonist: [¹¹C]; Carfentanil; δ-opioid receptor antagonist: N1′-([¹¹C]methyl) Naltrindol; κ-opioid receptor antagonist: [¹¹C] LY2795050; nociceptin receptor: [¹¹C]NOP-1A. Reproduced with permission [–139]. NOP receptor agonist: [¹¹C]NOP-1A, images provided by Rajesh Narendran

Fig. 3

Measure of changes in μ-opioid receptor availability in vivo with positron emission tomography (PET) during social rejection (not being liked by others) and acceptance (being liked by others). Compared to depressed patients, healthy controls showed greater rejection-induced opioid release in the nucleus accumbens, amygdala and midline thalamus. Reproduced with permission [82]