Delta Opioid Receptor and Peptide: A Dynamic Therapy for Stroke and Other Neurological Disorders

Abstract

Research of the opioid system and its composite receptors and ligands has revealed its promise as a potential therapy for neurodegenerative diseases such as stroke and Parkinson's Disease. In particular, delta opioid receptors (DORs) have been elucidated as a therapeutically distinguished subset of opioid receptors and a compelling target for novel intervention techniques. Research is progressively shedding light on the underlying mechanism of DORs and has revealed two mechanisms of DOR neuroprotection; DORs function to maintain ionic homeostasis and also to trigger endogenous neuroprotective pathways. Delta opioid agonists such as (D-Ala2, D-Leu5) enkephalin (DADLE) have been shown to promote neuronal survival and decrease apoptosis, resulting in a substantial amount of research for its application as a neurological therapeutic. Most notably, DADLE has demonstrated significant potential to reduce cell death following ischemic events. Current research is working to reveal the complex mechanisms of DADLE's neuroprotective properties. Ultimately, our knowledge of the DOR receptors and agonists has made the opioid system a promising target for therapeutic intervention in many neurological disorders.

Delta Opioid Receptor Activation with Delta Opioid Peptide [d-Ala2, d-Leu5] Enkephalin Contributes to Synaptic Improvement in Rat Hippocampus against Global Ischemia

“…The damaging events in global ischemic injury include acute injury (such as excitotoxicity and free radical injury) and prolonged damage (such as edema and inflammation), eventually leading to neuronal death after days of ischemia 3 . DADLE, a DOR agonist, has been proven to have therapeutic effects in stroke and many other neurological disorders including epilepsy, spinal cord injury, and neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, with poorly understood mechanisms 25 . In this study, we showed that DADLE-induced DOR activation promoted CA1 neuronal survival and astrocytic activation on day 7 post-ischemia ( Fig.…”

Opportunities and Challenges for In Silico Drug Discovery at Delta Opioid Receptors

“…Front and center have been the ability of δOR selective agonists to reduce chronic pain, be it inflammatory, neuropathic, or migraine [ 7 ]. δOR agonists have shown promise in preventing cardiac and cerebral ischemia [ 8 ], as a potential treatment for neurodegenerative diseases [ 9 , 10 , 11 , 12 , 13 ], and both δOR agonists and antagonists have been proposed as mechanisms for the treatment of alcohol use disorder [ 5 , 14 , 15 , 16 ]. Outside the central nervous system, δOR antagonism and positive allosteric modulation of δOR has been proposed as a treatment for gastrointestinal motility disorders, such as irritable bowel syndrome [ 17 , 18 ].…”

Exploration of beta-arrestin isoform signaling pathways in delta opioid receptor agonist-induced convulsions

“…The δ-opioid receptor (δOR) is a G-protein coupled receptor (GPCR) within the opioid family that has been considered as therapeutic target for the treatment of migraine, chronic pain, anxiety, and major depressive disorder ( Jutkiewicz, 2006 ; Perrine et al, 2006 ; Pradhan et al, 2011 ; Pradhan et al, 2014 ; Gendron et al, 2016 ; Cahill et al, 2022 ). δOR agonists have also been proposed as promising treatments for alcohol use disorder, ischemia, and stroke ( Schultz et al, 1997 ; Karck et al, 2001 ; Alongkronrusmee et al, 2018 ; Grant Liska et al, 2018 ; Sheng et al, 2018 ); particularly as δOR agonists generally display negligible abuse potential ( Van Rijn et al, 2012 ; Hudzik et al, 2014 ; Conibear et al, 2020 ; Gutridge et al, 2021 ) and thus, would be safer alternatives relative to µ-opioid receptor drugs. Yet, in contrast to the µ-opioid and κ-opioid receptor, no δOR selective compounds have been approved for clinical use.…”