The delta opioid receptor: an evolving target for the treatment of brain disorders

Abstract

Compared to the better-known mu opioid receptor, delta opioid receptors have been relatively understudied. However, the development of highly selective delta opioid agonists, and the availability of genetic mouse models have extended our knowledge of delta opioid receptors in vivo. Here we review recent developments in the characterization of delta opioid receptor biology, and aspects of delta opioid receptor function that have potential for therapeutic targeting. Preclinical data have confirmed that delta opioid receptor activation reduces persistent pain and improves negative emotional states; clinical trials have been initiated to assess the effectiveness of delta opioid agonists in chronic pain and depression. Further, a possible role for these receptors in neuroprotection is being investigated. The usefulness of targeting delta opioid receptors in drug abuse remains open, and there is an emerging role of these receptors in impulse control disorders. Finally, the recent demonstration of biased agonism at the delta opioid receptor in vivo opens novel perspectives towards targeting specific therapeutic effects through drug design.

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.…”

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

“…Mu opioid analgesics, such as the canonical mu agonist morphine, are among the most effective and widely used drugs in the treatment of pain, but unwanted effects such as abuse liability limit their therapeutic potential (Gutstein and Akil, 2006). Kappa and delta opioid agonists have also been considered as candidate therapeutics for pain and other health problems, but their clinical deployment has been prevented by undesirable side effects that include psychotomimetic and convulsant effects, respectively (Chavkin, 2011;Pradhan et al, 2011). Table 4 shows illustrative data with selected opioids in ICSS procedures.…”

Network analysis of the genomic basis of the placebo effect

“…For example, OPRD1 (opioid receptor, δ1) is a member of the opioid family of G protein-coupled receptors that also includes μ, κ, and nociceptin (NOP) receptors and is associated with neurological diseases and disorders (15), including neonatal abstinence syndrome and morphine dependence. STX1A (syntaxin 1A) is a nervous system-specific protein implicated in the docking of synaptic vesicles with the presynaptic plasma membrane.…”