(2R,6R)-hydroxynorketamine (HNK) reverses mechanical hypersensitivity in a model of localized inflammatory pain.

The ketamine metabolite (2R,6R)-hydroxynorketamine, or (2R,6R)-HNK, was recently reported to evoke antinociception in response to a noxious thermal stimulus in healthy mice and reverse mechanical hypersensitivity in a murine model of neuropathic pain. This study reports the behavioral effects of (2R,6R)-HNK in male and female C57BL/6J mice exposed to a localized inflammatory pain condition and the broad pharmacological mechanism underlying this effect. Hind paw intraplantar injection of λ-carrageenan (CARR) caused inflammation and mechanical hypersensitivity in mice within 2 h, lasting at least 48 h. Administration of (2R,6R)-HNK (10-30 mg/kg i.p.) 2 h following CARR injection significantly reversed mechanical hypersensitivity within 1 h in male and female mice, and the effect persisted for 24 h following a single dose. The magnitude and timing of the analgesic effect of (2R,6R)-HNK were comparable to the non-steroidal anti-inflammatory drug carprofen. The reversal of hypersensitivity by (2R,6R)-HNK was blocked at 4 and 24 h after administration by pretreatment with the AMPA receptor antagonist NBQX and was not accompanied by changes in locomotor activity. These findings reinforce the growing evidence supporting (2R,6R)-HNK as a novel analgesic in multiple preclinical pain models and further support an AMPAR-dependent mechanism of action. SIGNIFICANCE: The ketamine metabolite (2R,6R)-HNK reversed mechanical hypersensitivity associated with localized inflammation with onset less than 1 h and duration greater than 24 h, an effect comparable to the NSAID carprofen. Reversal of mechanical hypersensitivity by (2R,6R)-HNK is AMPAR-dependent.

Buprenorphine as a Treatment for Major Depression and Opioid Use Disorder.

Rates of major depressive disorder (MDD) are disproportionally high in subjects with opioid use disorder (OUD) relative to the general population. MDD is often more severe in OUD patients, leading to compliance issues with maintenance therapies and poor outcomes. A growing body of literature suggests that endogenous opioid system dysregulation may play a role in the emergence of MDD. Buprenorphine, a mixed opioid receptor agonist/antagonist approved for the treatment of OUD and chronic pain, may have potential as a novel therapeutic for MDD, especially for patients with a dual diagnosis of MDD and OUD. This paper presents a comprehensive review of papers relevant to the assessment of buprenorphine as a treatment for MDD, OUD, and/or suicide compiled using electronic databases per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The principal goal of this literature review was to compile the clinical studies that have interrogated the antidepressant activity of buprenorphine in opioid naïve MDD patients and OUD patients with comorbid MDD. Evidence supporting buprenorphine's superiority over methadone for treating comorbid OUD and MDD was also considered. Finally, recent evidence for the ability of buprenorphine to alleviate suicidal ideation in both opioid-naïve patients and opioid-experienced patients was evaluated. Synthesizing all of this information, buprenorphine emerges as a potentially effective therapeutic for the dual purposes of treating MDD and OUD.

Antinociceptive and Analgesic Effects of (2R,6R)-Hydroxynorketamine.

Commonly used pain therapeutics, such as opioid medications, exert dangerous side effects and lack effectiveness in treating some types of pain. Ketamine is also used to treat pain, but side effects limit its widespread use. (2R,6R)-hydroxynorketamine (HNK) is a ketamine metabolite that potentially shares some beneficial behavioral effects of its parent drug without causing significant side effects. This study compared the profile and potential mechanisms mediating the antinociception activity of ketamine and (2R,6R)-HNK in C57BL/6J mice. Additionally, this study compared the reversal of mechanical allodynia by (2R,6R)-HNK with gabapentin in a model of neuropathic pain. Unlike the near-immediate and short-lived antinociception caused by ketamine, (2R,6R)-HNK produced late-developing antinociception 24 hours following administration. Pharmacological blockade of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors with 2,3-dioxo-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX) prevented the initiation and expressionof (2R,6R)-HNK antinociception, suggesting the involvement of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-dependent glutamatergic mechanisms in the pain reduction-like responses. Blockade of opioid receptors with naltrexone partially prevented the antinociceptive effect of ketamine but was ineffective against (2R,6R)-HNK. Furthermore, (2R,6R)-HNK did not produce dystaxia, even when tested at doses five times greater than those needed to produce antinociception, indicating a superior safety profile for (2R,6R)-HNK over ketamine. Additionally, (2R,6R)-HNK reversed mechanical allodynia in a spared nerve injury model of neuropathic pain with similar short-term efficacy to gabapentin (within 4 hours) while outperforming gabapentin 24 hours after administration. These findings support the further study of (2R,6R)-HNK as a potentially valuable agent for treating different types of pain and establish certain advantages of (2R,6R)-HNK treatment over ketamine and gabapentin in corresponding assays for pain. SIGNIFICANCE STATEMENT: The ketamine metabolite (2R,6R)-HNK produced antinociception in male and female mice 24 hours after administration via activation of AMPA receptors. The effects of (2R,6R)-HNK differed in time course and mechanism and presented a better safety profile than ketamine. (2R,6R)-HNK also reversed allodynia in SNI-operated animals within 4 hours of treatment onset, with a duration of effect lasting longer than gabapentin. Taken together, (2R,6R)-HNK demonstrates the potential for development as a non-opioid analgesic drug.

Mediation of the behavioral effects of ketamine and (2R,6R)-hydroxynorketamine in mice by kappa opioid receptors.

Emerging evidence has implicated the endogenous opioid system in mediating ketamine's antidepressant activity in subjects with major depressive disorder. To date, mu opioid receptors have been suggested as the primary opioid receptor of interest. However, this hypothesis relies primarily on observations that the opioid antagonist naltrexone blocked the effects of ketamine in humans and rodents. This report confirms previous findings that pretreatment with naltrexone (1 mg/kg) just prior to ketamine (10 mg/kg) administration effectively blocks the behavioral effect of ketamine in the mouse forced swim test 24 h post-treatment. Furthermore, pharmacological blockade of kappa opioid receptors prior to ketamine administration with the selective, short-acting antagonist LY2444296 successfully blocked ketamine's effects in the forced swim test. Likewise, the ability of the ketamine metabolite (2R,6R)-hydroxynorketamine to reduce immobility scores in the forced swim test was also blocked following pretreatment with either naltrexone or LY2444296. These data support a potential role of kappa opioid receptors in mediating the behavioral activity of ketamine and its non-dissociate metabolite (2R,6R)-hydroxynorketamine.

Long-term increase in sensitivity to ketamine's behavioral effects in mice exposed to mild blast induced traumatic brain injury.

Neurobehavioral deficits emerge in nearly 50% of patients following a mild traumatic brain injury (TBI) and may persist for months. Ketamine is used frequently as an anesthetic/analgesic and for management of persistent psychiatric complications. Although ketamine may produce beneficial effects in patients with a history of TBI, differential sensitivity to its impairing effects could make the therapeutic use of ketamine in TBI patients unsafe. This series of studies examined male C57BL/6 J mice exposed to a mild single blast overpressure (mbTBI) for indications of altered sensitivity to ketamine at varying times after injury. Dystaxia (altered gait), diminished sensorimotor gating (reduced prepulse inhibition) and impaired working memory (step-down inhibitory avoidance) were examined in mbTBI and sham animals 15 min following intraperitoneal injections of saline or R,S-ketamine hydrochloride, from day 7-16 post injury and again from day 35-43 post injury. Behavioral performance in the forced swim test and sucrose preference test were evaluated on day 28 and day 74 post injury respectively, 24 h following drug administration. Dynamic gait stability was compromised in mbTBI mice on day 7 and 35 post injury and further exacerbated following ketamine administration. On day 14 and 42 post injury, prepulse inhibition was robustly decreased by mbTBI, which ketamine further reduced. Ketamine-associated memory impairment was apparent selectively in mbTBI animals 1 h, 24 h and day 28 post shock (tested on day 15/16/43 post injury). Ketamine selectively reduced immobility scores in the FST in mbTBI animals (day 28) and reversed mbTBI induced decreases in sucrose consumption (Day 74). These results demonstrate increased sensitivity to ketamine in mice when tested for extended periods after TBI. The results suggest that ketamine may be effective for treating neuropsychiatric complications that emerge after TBI but urge caution when used in clinical practice for enhanced sensitivity to its side effects in this patient population.

Kappa Opioid Receptors in the Pathology and Treatment of Major Depressive Disorder.

The kappa opioid receptor (KOR) is thought to regulate neural systems associated with anhedonia and aversion and mediate negative affective states that are associated with a number of psychiatric disorders, but especially major depressive disorder (MDD). Largely because KOR antagonists mitigate the effects of stress in preclinical studies, KOR antagonists have been recommended as novel drugs for treating MDD. The purpose of this review is to examine the role of KORs and its endogenous ligand dynorphins (DYNs) in the pathology and treatment of MDD derived from different types of clinical studies. Evidence pertaining to the role of KOR and MDD will be reviewed from (1) post mortem mRNA expression patterns in MDD, (2) the utility of KOR neuroimaging agents and serum biomarkers in MDD, and (3) evidence from the recent Fast Fail clinical trial that established KOR antagonism as a potential therapeutic strategy for the alleviation of anhedonia, a core feature of MDD. These findings are compared with a focused evaluation of stress-induced alterations in OPRK and PDYN mRNA expression. Finally, the current status of the effects of KOR antagonists on behavioral phenotypes of stress in preclinical studies related to MDD is summarized.

Translational relevance of fear conditioning in rodent models of mild traumatic brain injury.

Mild traumatic brain injury (mTBI) increases the risk of posttraumatic stress disorder (PTSD) in military populations. Utilizing translationally relevant animal models is imperative for establishing a platform to delineate neurobehavioral deficits common to clinical PTSD that emerge in the months to years following mTBI. Such platforms are required to facilitate preclinical development of novel therapeutics. First, this mini review provides an overview of the incidence of PTSD following mTBI in military service members. Secondly, the translational relevance of fear conditioning paradigms used in conjunction with mTBI in preclinical studies is evaluated. Next, this review addresses an important gap in the current preclinical literature; while incubation of fear has been studied in other areas of research, there are relatively few studies pertaining to the enhancement of cued and contextual fear memory over time following mTBI. Incubation of fear paradigms in conjunction with mTBI are proposed as a novel behavioral approach to advance this critical area of research. Lastly, this review discusses potential neurobiological substrates implicated in altered fear memory post mTBI.

The kappa opioid receptor antagonist aticaprant reverses behavioral effects from unpredictable chronic mild stress in male mice.

RATIONALE: Major depressive disorder is a leading cause of disability worldwide and is likely precipitated by chronic stress. Although many antidepressants are currently available, these drugs require weeks to months of daily administration before reduction of symptoms occurs and many patients remain treatment-resistant despite several courses of treatment. There is a pressing need for new treatments for stress-related disorders. Kappa opioid receptors (KORs) are a promising new therapeutic target for major depressive disorder and anhedonia because acute KOR blockade prevents many effects of stress in rodents. OBJECTIVES: The following study assessed whether repeated treatment with the selective KOR antagonist aticaprant (also known as JNJ-67953964, and previously LY-2456302 and CERC-501) was effective in reversing behaviors in rodents following exposure to unpredictable chronic mild stress (UCMS). METHODS: Adult male C57BL/6J mice were exposed to 4 weeks of UCMS. After 3 weeks of stress, aticaprant (10 mg/kg) was administered daily for 11 treatments. Behavioral assessments included the sucrose preference test, nesting, forced swim test, hot plate test, light-dark test, and social interaction test. RESULTS: Aticaprant significantly reversed stress-induced deficits produced by UCMS on the SPT, nesting, FST, and hot plate test. The effects of aticaprant persisted through a stress and treatment recovery period. Aticaprant was not effective at reversing behavioral effects caused by stress in the light-dark and social interaction tests. CONCLUSIONS: The results support further study of the role of KORs in regulating circuits related to reward, self-care, and cognition when they are disrupted by chronic stress. They are also consistent with the clinical development of aticaprant as a therapeutic for stress-related disorders targeted at anhedonia, such as depression and post-traumatic stress disorder.

Vendor differences in anxiety-like behaviors in female and male Sprague Dawley rats.

Although Sprague Dawley outbred rats are commonly used in behavioral, physiological, and pharmacological studies, dramatic differences in responses may emerge from rats obtained from different suppliers even when sex, age, and environmental conditions are maintained constant. In the present study, we compared behavioral responses on three tests related to anxiety of Sprague Dawley female and male rats obtained from three different vendors in the United States: Charles River, Envigo, and Taconic. All rats were tested in the open field, light-dark box, and elevated zero maze. We found reduced time spent in the center area of the open field and decreased light compartment duration in the light-dark box test in female and male rats from Taconic compared to Charles River and Envigo rats, suggesting anxiety-like behaviors differ between the three vendors. No vendor differences were found on performance in the elevated zero maze. Furthermore, the contribution of stress hormones to vendor differences was examined by measuring serum corticosterone levels in rats 30 min after exposure to the elevated zero maze. There were no vendor differences in corticosterone levels, suggesting that endogenous levels of stress hormones most likely did not contribute to vendor differences in anxiety-like behaviors. Collectively, these findings highlight the importance of vendor selection of the Sprague Dawley stock for research involving behavioral tests related to anxiety.

Sex differences in the modulation of mouse nest building behavior by kappa opioid receptor signaling.

Emerging evidence suggests that females are less sensitive than males to the effects of kappa opioid receptor (KOR) ligands across multiple behavioral measures. The effects of the KOR agonist U50,488 and the KOR antagonist aticaprant were assessed on nest building behavior, an ethologically relevant indicator of overall well-being and affect, in adult male and female C57BL/6J mice. Females required a higher dose of U50,488 to suppress nesting, and a higher dose of aticaprant to restore U50,488-induced impairment of nesting. Females also required a higher dose of aticaprant to decrease immobility scores in the forced swim test. Pretreatment with the estrogen receptor modulator tamoxifen, at a dose which blocked estrogen receptors, augmented the effect of U50,488 on nesting in female mice, suggesting that estrogen receptors play a key role in attenuating the effects of KOR ligands in female mice. Together, these results suggest that females are less sensitive to KOR mediation, requiring a higher dose to achieve comparable results to males. This behavioral sensitivity, as measured by nesting, may be mediated by estrogen receptors. Together these studies highlight the importance of comparing sex differences in response to KOR regulation on behaviors related to affective states.

Behavioral effects of the kappa opioid receptor partial agonist nalmefene in tests relevant to depression.

Compounds with high affinity at kappa and mu opioid receptors may have clinical utility in treating major depressive disorder. Nalmefene (NMF) is a partial kappa opioid receptor agonist and potent mu opioid receptor antagonist, but there has been no preclinical evaluation of NMF in rodent tests relevant to depression and anxiety. To address this, the effects of NMF on neurochemical and behavioral endpoints in C57BL/6J mice were examined and contrasted with a structurally related analog, naltrexone (NTX). NMF exhibited kappa opioid receptor agonist activity, measured as a reduction in extracellular dopamine release in the nucleus accumbens using in vivo microdialysis following acute but not chronic administration. In the mouse forced swim test, female mice were more responsive to higher doses of NMF and NTX compared to male mice. The behavioral effects of NMF in the forced swim test were blocked in Oprk1-/- and Oprm1-/- mice. Conversely, the effects of NTX were blocked only in Oprm1-/- mice. These results indicate that both kappa and mu opioid receptors mediate the behavioral effects of NMF, but the effects of NTX in this test were modified only by mu opioid receptor engagement. Unlike NTX, NMF did not produce conditioned place aversion in either sex. Finally, NMF's activity in the marble burying test and forced swim test were retained following chronic administration. The sustained effects exerted by NMF on tests that are sensitive to antidepressant and anxiolytic compounds support further investigation of NMF as a potential therapeutic for depression.

Novel Targets to Treat Depression: Opioid-Based Therapeutics.

LEARNING OBJECTIVES: After participating in this activity, learners should be better able to:• Identify the effects of dysregulated opioid signalling in depression• Evaluate the use of opioid compounds and ketamine in patients with depression ABSTRACT: Major depressive disorder (MDD) remains one of the leading causes of disability and functional impairment worldwide. Current antidepressant therapeutics require weeks to months of treatment prior to the onset of clinical efficacy on depressed mood but remain ineffective in treating suicidal ideation and cognitive impairment. Moreover, 30%-40% of individuals fail to respond to currently available antidepressant medications. MDD is a heterogeneous disorder with an unknown etiology; novel strategies must be developed to treat MDD more effectively. Emerging evidence suggests that targeting one or more of the four opioid receptors-mu (MOR), kappa (KOR), delta (DOR), and the nociceptin/orphanin FQ receptor (NOP)-may yield effective therapeutics for stress-related psychiatric disorders. Furthermore, the effects of the rapidly acting antidepressant ketamine may involve opioid receptors. This review highlights dysregulated opioid signaling in depression, evaluates clinical trials with opioid compounds, and considers the role of opioid mechanisms in rapidly acting antidepressants.

Kappa Opioid Receptor Antagonists as Potential Therapeutics for Stress-Related Disorders.

Exposure to stressful stimuli activates kappa opioid receptor (KOR) signaling, a process known to produce aversion and dysphoria in humans and other species. This endogenous opioid system is dysregulated in stress-related disorders, specifically in major depressive disorder (MDD). These findings serve as the foundation for a growing interest in the therapeutic potential of KOR antagonists as novel antidepressants. In this review, data supporting the hypothesis of dysregulated KOR function in MDD are considered. The clinical data demonstrating the therapeutic efficacy and safety of selective and mixed opioid antagonists are then presented. Finally, the preclinical evidence illustrating the induction of behaviors relevant to the endophenotypes of MDD and KOR antagonist activity in stress-naïve and stress-exposed animals is evaluated. Overall, this review highlights the emergent literature supporting the pursuit of KOR antagonists as novel therapeutics for MDD and other stress-related disorders.

Addressing the Opioid Crisis: Medical Student Instruction in Opioid Drug Pharmacology, Pain Management, and Substance Use Disorders.

The marked increase in deaths related to opioid drugs after 1999 was associated with an increase in the number of prescriptions for opioid drugs. This was accompanied by increasing demand for improved management of chronically painful conditions. These factors suggest that improvements are needed in the education of physicians with regard to the management of chronic pain, the optimal therapeutic application of opioid drugs, and the avoidance of substance use disorders. In this article, we address the evidence that physician education can influence prescribing practices and we discuss approaches to enhance the preclinical and clinical education of medical students in pain management and substance use disorders.

Buprenorphine prevents stress-induced blunting of nucleus accumbens dopamine response and approach behavior to food reward in mice.

Alterations to the mesolimbic dopamine (DA) system are thought to underlie dysfunctional reward processing in stress-related psychiatric disorders. Using in vivio microdialysis in awake freely moving mice, we assessed the effects of stress on the motivational and neurochemical correlates underlying conditioned approach behavior for palatable food in the non-deprived mouse. Mice trained to approach and consume food in a familiar environment exhibited a 30% increase in nucleus accumbens shell (AcbSh) extracellular dopamine levels coincident with approach towards and consumption of the food reward. This effect was not observed in mice that were presented with the food in an unfamiliar environment or were exposed for the first time and were region specific. The addition of an acute environmental stressor (bright light and novel scent) during food exposure decreased DA release and delayed approach to the food. The disruptive impact of acute novelty stress on DA levels and approach behavior was reversed in animals pretreated with buprenorphine, an opioid drug with antidepressant-like and anxiolytic effects. Together, these data indicate that exposure to mild stress reduces incentive drive to approach palatable food via alterations in AcbSh dopamine responsiveness to food reward. Moreover, they implicate the brain opioid system as a potential pharmacological target for counteracting behavioral and neurochemical elements associated with stress.

Targeting opioid dysregulation in depression for the development of novel therapeutics.

Since the serendipitous discovery of the first class of modern antidepressants in the 1950's, all pharmacotherapies approved by the Food and Drug Administration for major depressive disorder (MDD) have shared a common mechanism of action, increased monoaminergic neurotransmission. Despite the widespread availability of antidepressants, as many as 50% of depressed patients are resistant to these conventional therapies. The significant length of time required to produce meaningful symptom relief with these medications, 4-6 weeks, indicates that other mechanisms are likely involved in the pathophysiology of depression which may yield more viable targets for drug development. For decades, no viable candidate target with a different mechanism of action to that of conventional therapies proved successful in clinical studies. Now several exciting avenues for drug development are under intense investigation. One of these emerging targets is modulation of endogenous opioid tone. This review will evaluate preclinical and clinical evidence pertaining to opioid dysregulation in depression, focusing on the role of the endogenous ligands endorphin, enkephalin, dynorphin, and nociceptin/orphanin FQ (N/OFQ) and their respective receptors, mu (MOR), delta (DOR), kappa (KOR), and the N/OFQ receptor (NOP) in mediating behaviors relevant to depression and anxiety. Finally, putative opioid based antidepressants that are under investigation in clinical trials, ALKS5461, JNJ-67953964 (formerly LY2456302 and CERC-501) and BTRX-246040 (formerly LY-2940094) will be discussed. This review will illustrate the potential therapeutic value of targeting opioid dysregulation in developing novel therapies for MDD.

Deletion of the vesicular monoamine transporter 1 (vmat1/slc18a1) gene affects dopamine signaling.

The vesicular monoamine transporter is involved in presynaptic catecholamine storage and neurotransmission. Two isoforms of the transporter exist, VMAT1 and VMAT2, and both are expressed in the brain, though VMAT2 expression is more robust and has been more widely studied. In this study we investigated the role of VMAT1 KO on markers of dopaminergic function and neurotransmission, and dopamine-related behaviors. Null-mutant VMAT1 mice were studied behaviorally using the tail suspension test, elevated zero maze and locomotor activity assessments. Tissue monoamines were measured both ex vivo and by using in vivo microdialysis. Protein expression of tyrosine hydroxylase and D2 dopamine receptors was measured using western blot analysis. Results show that VMAT1 KO mice have decreased dopamine levels in the frontal cortex, increased postsynaptic D2 expression, and lower frontal cortex tyrosine hydroxylase expression compared to WT mice. VMAT1 KO mice also show an exaggerated behavioral locomotor response to acute amphetamine treatment. We conclude that dopaminergic signaling is robustly altered in the frontal cortex of VMAT1 null-mutant mice and suggest that VMAT1 may be relevant to the pathogenesis and/or treatment of psychiatric illnesses including schizophrenia and bipolar disease.

Dysregulation of the Lateral Habenula in Major Depressive Disorder.

Clinical and preclinical evidence implicates hyperexcitability of the lateral habenula (LHb) in the development of psychiatric disorders including major depressive disorder (MDD). This discrete epithalamic nucleus acts as a relay hub linking forebrain limbic structures with midbrain aminergic centers. Central to reward processing, learning and goal directed behavior, the LHb has emerged as a critical regulator of the behaviors that are impaired in depression. Stress-induced activation of the LHb produces depressive- and anxiety-like behaviors, anhedonia and aversion in preclinical studies. Moreover, deep brain stimulation of the LHb in humans has been shown to alleviate chronic unremitting depression in treatment resistant depression. The diverse neurochemical processes arising in the LHb that underscore the emergence and treatment of MDD are considered in this review, including recent optogenetic studies that probe the anatomical connections of the LHb.

Ketamine Reverses Lateral Habenula Neuronal Dysfunction and Behavioral Immobility in the Forced Swim Test Following Maternal Deprivation in Late Adolescent Rats.

Mounting evidence suggests that the long-term effects of adverse early life stressors on vulnerability to drug addiction and mood disorders are related to dysfunction of brain monoaminergic signaling in reward circuits. Recently, there has been a growing interest in the lateral habenula (LHb) as LHb dysfunction is linked to the development of mental health disorders through monoaminergic dysregulation within brain reward/motivational circuits and may represent a critical target for novel anti-depressants, such as ketamine. Here, we show that maternal deprivation (MD), a severe early life stressor, increases LHb intrinsic excitability and LHb bursting activity, and is associated with the development of increased immobility in the forced swim test (FST) in late-adolescent male rats. A single in vivo injection of ketamine is sufficient to exert prolonged antidepressant effects through reversal of this early life stress-induced LHb neuronal dysfunction and the response in the FST. Our assessment of ketamine's long-lasting beneficial effects on reversal of MD-associated changes in LHb neuronal function and behavior highlights the critical role of the LHb in pathophysiology of depression associated with severe early life stress and in response to novel fast-acting antidepressants.

Opioid modulation of cognitive impairment in depression.

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 disorder (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 and kappa-opioid receptor 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.