Opioid modulation of cognitive impairment in depression

Abstract

The failure of traditional antidepressant medications to adequately target cognitive impairment is associated with poor treatment response, increased risk of relapse and greater lifetime disability. Opioid receptor antagonists are currently under development as novel therapeutics for major depressive disorders (MDD) and other stress-related illnesses. Although it is known that dysregulation of the endogenous opioid system is observed in patients diagnosed with MDD, the impact of opioidergic neurotransmission on cognitive impairment has not been systematically evaluated. Here we review the literature indicating that opioid manipulations can alter cognitive functions in humans. Furthermore, we detail the preclinical studies that demonstrate the ability of mu opioid receptor (MOR) and kappa opioid receptor (KOR) ligands to modulate several cognitive processes. Specifically, this review focuses on domains within higher order cognitive processing, including attention and executive functioning, which can differentiate cognitive processes influenced by motivational state.

Activation of the G Protein-Coupled Estrogen Receptor Elicits Store Calcium Release and Phosphorylation of the Mu-Opioid Receptors in the Human Neuroblastoma SH-SY5Y Cells

“…Furthermore, E2 was found to rapidly desensitize µ-opioid receptor (MOR) in hypothalamic neurons in PLC, PKA, and PKC-dependent manners, suggesting that Ca 2+ signaling probably underlies estrogenic suppression of MOR function (Lagrange et al, 1997;Conde et al, 2016). MOR is best known for the regulation of pain and analgesia, but also plays important roles in regulation of reproductive behaviors, neuroprotection and cognition (Long et al, 2014;Jacobson et al, 2018;Liu et al, 2018;Vaidya et al, 2018). Therefore, it is of great interest to understand the identity of the receptor(s) which may mediate estrogenic suppression of MOR signaling.…”

Cognition and Pain: A Review

“…Mu opioid receptor and kappa-opioid receptor agonists have been shown to affect normal cognitive function; there is increased psychomotor retardation, decreased accuracy, and impaired recall. This bidirectional impact of pain and cognition has allowed researchers to test opioid antagonists as a potential cognitive-enhancing drug (Jacobson et al, 2018).…”

The role of the opioid system in decision making and cognitive control: A review

“…Likewise, no significant effects were reported by the earlier described study by Zacny and de Wit on impulsive action, which investigated the effect of 5, 10, and 20 mg PO of oxycodone in six females and six males participants on stop-signal performance and go/no-go performance (Zacny & de Wit, 2009). The absence of clear findings on overall measures of response inhibition resonates with rodent studies that often find no or mixed effects of opioid manipulations on premature responding (Jacobson et al, 2018).…”

“…By altering motivational processing and/or learning, opioid drugs could exert profound effects on cognitive control and reward-based decisions even after a single drug administration. Work in rodents indeed shows opioid-induced impairments in some measures of sustained attention and response inhibition (for an up-to-date review see, Jacobson, Wulf, Browne, & Lucki, 2018). Despite decades of nonhuman animal research, much less is known about acute opioid modulation of cognition and decision making in humans.…”

“…Opioids might help to downregulate stress responses under such conditions, perhaps improving sensorimotor gating relative to placebo. However, as reviewed elsewhere (Jacobson et al, 2018), effects of opioid drugs on prepulse inhibition in rodents are mixed, showing that additional systematic research is needed.…”