Opioids are among the most effective analgesics available and are the first choice in the treatment of acute severe pain. However, partial efficacy, a tendency to produce tolerance, and a host of ill-tolerated side effects make clinically available opioids less effective in the management of chronic pain syndromes. Given that most therapeutic opioids produce their actions via µ-opioid receptors (MOPrs), other targets are constantly being explored, among which δ-opioid receptors (DOPrs) are being increasingly considered as promising alternatives. This review addresses DOPrs from the perspective of cellular and molecular determinants of their pharmacological diversity. Thus, DOPr ligands are examined in terms of structural and functional variety, DOPrs’ capacity to engage a multiplicity of canonical and noncanonical G protein–dependent responses is surveyed, and evidence supporting ligand-specific signaling and regulation is analyzed. Pharmacological DOPr subtypes are examined in light of the ability of DOPr to organize into multimeric arrays and to adopt multiple active conformations as well as differences in ligand kinetics. Current knowledge on DOPr targeting to the membrane is examined as a means of understanding how these receptors are especially active in chronic pain management. Insight into cellular and molecular mechanisms of pharmacological diversity should guide the rational design of more effective, longer-lasting, and better-tolerated opioid analgesics for chronic pain management.
This research was supported by the Natural Sciences and Engineering Research Council of Canada [Grants RGPIN-2015-05213 (to L.G.) and 311997 (to G.P.)], the Canadian Institutes of Health Research [Grants MOP 123399 and MOP 136871 (to L.G.), MOP 89716 (to P.W.S.), and MOP 79432 and MOP 324876 (to G.P.)], and the National Institutes of Health National Institute on Drug Abuse [Grants DA012864 and DA06511 (to M.v.Z.) and DA004443 and DA015353 (to P.W.S.)]. L.G. is the recipient of a Chercheur-boursier Senior from the Fonds de la Recherche du Québec-Santé.
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics