Delta opioid receptors in brain function and diseases

Abstract

Evidence that the delta opioid receptor (DOR) is an attractive target for the treatment of brain disorders has strengthened in recent years. This receptor is broadly expressed in the brain, binds endogenous opioid peptides, and shows as functional profile highly distinct from those of mu and kappa opioid receptors. Our knowledge of DOR function has enormously progressed from in vivo studies using pharmacological tools and genetic approaches. The important role of this receptor in reducing chronic pain has been extensively overviewed; therefore this review focuses on facets of delta receptor activity relevant to psychiatric and other neurological disorders. Beneficial effects of DOR agonists are now well established in the context of emotional responses and mood disorders. DOR activation also regulates drug reward, inhibitory controls and learning processes, but whether delta compounds may represent useful drugs in the treatment of drug abuse remains open. Epileptogenic and locomotor-stimulating effects of delta agonists appear drug-dependent, and the possibility of biased agonism at DOR for these effects is worthwhile further investigations to increase benefit/risk ratio of delta therapies. Neuroprotective effects of DOR activity represent a forthcoming research area. Future developments in DOR research will benefit from in-depth investigations of DOR function at cellular and circuit levels.

Molecular Pharmacology ofδ-Opioid Receptors

“…The small number of plasma membrane-bound receptors is consistent with the observation that DOPr agonists have modest effects in modulating nociception and reward (Cahill et al, 2007;Pradhan et al, 2011); however, systemic administration of DOPr agonists such as SNC80 produces locomotor hyperactivity, anxiolytic effects, antidepressant effects, and absence seizures (Pradhan et al, 2011;Chu Sin Chung and Kieffer, 2013;Gendron et al, 2015). The fact that a low number of membrane-bound receptors are required for certain cellular functions, and that the majority of DOPrs are reserve receptors awaiting targeting to the plasma membrane, suggests that DOPrs are primarily engaged after specific physiologic stressors.…”

“…Both of these receptor types evoke effective analgesia (Kieffer and Gavériaux-Ruff, 2002;Chavkin, 2011;Gavériaux-Ruff and Kieffer, 2011), but stress and dysphoric responses associated with KOPr activation (Bruchas and Chavkin, 2010;Van't Veer and Carlezon, 2013) make DOPrs a more attractive alternative for analgesic drug development. In fact, DOPr agonists instead possess anxiolytic-and antidepressant-like actions (Chu Sin Chung and Kieffer, 2013). Their ability to evoke these emotional responses is highly desirable not only in terms of novel therapeutic applications but also because of the frequent association of anxiety and mood disorders with chronic pain (Goldenberg, 2010a,b).…”

“…Consequently, DOPr activation does not facilitate intracranial self-stimulation (Do Carmo et al, 2009), their agonists are not discriminated as morphine substitutes (Gallantine and Meert, 2005), and DOPrs do not display reinforcing properties (Banks et al, 2011). Despite these advantages, DOPr agonists display considerable potential for tolerance (Pradhan et al, 2010;Audet et al, 2012) and may increase forebrain excitability by reducing the threshold for seizures (Jutkiewicz et al, 2005(Jutkiewicz et al, , 2006Chu Sin Chung and Kieffer, 2013). Both of these are still outstanding issues in the search for safer and more effective opioid analgesics.…”

Molecular Targets of Cannabidiol in Neurological Disorders

“…Links between μ and δ OR function and a variety of brain disorders, including epilepsy, have been extensively investigated [149,150]. However, OR agonism and antagonism have each been confusingly associated with both pro-and anticonvulsant effects, and so make any antiepileptic therapeutic strategy involving OR targets uncertain.…”

Pharmacology of Opioids and their Effects on Gastrointestinal Function

“…Prolonged κ -opioid receptor signaling in response to chronic stress can lead to behavioral signs in animal models that are consistent with human depressive disorders ( 32 ). Th e precise role of δ -opioid receptors in brain function has only recently begun to be elucidated; however, they appear to decrease levels of anxiety and reduce depressive-like behaviors ( 30,33 ).…”