The Delta-Opioid Receptor; a Target for the Treatment of Pain

Abstract

Nowadays, pain represents one of the most important societal burdens. Current treatments are, however, too often ineffective and/or accompanied by debilitating unwanted effects for patients dealing with chronic pain. Indeed, the prototypical opioid morphine, as many other strong analgesics, shows harmful unwanted effects including respiratory depression and constipation, and also produces tolerance, physical dependence, and addiction. The urgency to develop novel treatments against pain while minimizing adverse effects is therefore crucial. Over the years, the delta-opioid receptor (DOP) has emerged as a promising target for the development of new pain therapies. Indeed, targeting DOP to treat chronic pain represents a timely alternative to existing drugs, given the weak unwanted effects spectrum of DOP agonists. Here, we review the current knowledge supporting a role for DOP and its agonists for the treatment of pain. More specifically, we will focus on the cellular and subcellular localization of DOP in the nervous system. We will also discuss in further detail the molecular and cellular mechanisms involved in controlling the cellular trafficking of DOP, known to differ significantly from most G protein-coupled receptors. This review article will allow a better understanding of how DOP represents a promising target to develop new treatments for pain management as well as where we stand as of our ability to control its cellular trafficking and cell surface expression.

Methylene Blue Application to Lessen Pain: Its Analgesic Effect and Mechanism

“…Opioids are substances with similar effects to those of morphine and used primarily for lessening pain. Basically, opioids act by binding to opioid receptors (ORs), which show analgesia by reducing cyclic adenosine monophosphate (cAMP) and causing the resultant decrease in the excitatory ion channels (Quirion et al, 2020;Sun et al, 2020;Kaski et al, 2021).…”

Receptor and Molecular Targets for the Development of Novel Opioid and Non-Opioid Analgesic Therapies

“…The inhibition of presynaptic Ca2+ influx and stimulation of K+ efflux additionally hyperpolarizes neurons and inhibits pronociceptive neurotransmitter release ( 59). In the central nervous system, DORs have been implicated in the regulation of pain, anxiety, and depression (60). δ-opioid agonists have thus been pursued for their analgesic effect and desirable risk profile.…”

Biological Effects on μ-Receptors Affinity and Selectivity of Arylpropenyl Chain Structural Modification on Diazatricyclodecane Derivatives

“…Compounds 53-54 and 57-60 were synthesized as reported in Schemes 3 and 4, respectively. The amine intermediates 9-propionyl-9,10diazatricyclo[4.2.1.1 2,5 ]-decane ( 14) and 2-propionyl-2,7-diazatricyclo[4.4.0.0 3,8 ]decane (15), synthesized following the literature [25], were used as starting compounds. A first attempt to prepare derivatives 20-27 provided for a synthetic approach similar to that used for both DBO and DBN series, consisting of a simple alkylation of amines 14 and 15 with the required alkyl chlorides, but unexpectedly this condensation failed.…”

“…Indanones 32-35, 2-indolacetic acid and chloromethylquinoline hydrochloride (55) were purchased commercial products. The amine intermediates 9-propionyl-9,10-diazatricyclo [4.2.1.1 2,5 ]decane (14), and 2-propionyl-2,7-diazatricyclo[4.4.0.0 3,8 ]decane (15), the benzyl derivatives of 9,10-diazatricyclo[4.2.1.1 2,5 ]decane (44) and 2,7-diazatricyclo[4.4.0.0 3,8 ]decane were synthesized in accordance with [25] and bromomethyl quinoxaline (56) in accordance with [27].…”