Molecular mechanisms of opioid receptor-dependent signaling and behavior

Abstract

Opioid receptors have been targeted for the treatment of pain and related disorders for thousands of years and remain the most widely used analgesics in the clinic. Mu (μ), kappa (κ), and delta (δ) opioid receptors represent the originally classified receptor subtypes, with opioid receptor like-1 (ORL1) being the least characterized. All four receptors are G-protein coupled and activate inhibitory G proteins. These receptors form homo- and heterodimeric complexes and signal to kinase cascades and scaffold a variety of proteins.The authors discuss classic mechanisms and developments in understanding opioid tolerance and opioid receptor signaling and highlight advances in opioid molecular pharmacology, behavioral pharmacology, and human genetics. The authors put into context how opioid receptor signaling leads to the modulation of behavior with the potential for therapeutic intervention. Finally, the authors conclude there is a continued need for more translational work on opioid receptors in vivo.

Figure 1. Sites of action of opioid analgesics

The grey pathway shows the sites of action on the pain transmission pathway from periphery to central nervous system. The red pathway shows the actions on pain modulating neurons in the mid brain and medulla. Abrevations: MOR- μ opioid receptor

Figure 2. Summary of Opioid Receptor Signaling

Cartoon depicting opioid receptor signal transduction and trafficking. In general, all four opioid receptor subtypes, μ, δ, κ, and ORL1 share these common pathways. New research indicates that selective-ligands at each opioid receptor can direct opioid receptors to favor one or more of these signaling events (biased agonism, or ligand directed signaling). Arrows refer to activation steps; T lines refer to blockade or inhibition of function. Abbreviations: α G-protein alphai subunit, arrestin phosphorylation- dependent GPCR scaffold, βγ- G-protein beta-gamma subunit, cAMP- cyclic adenosine monophosphate, ERK ½ - extra-cellular signal- regulated kinase, JNK - c-Jun N-terminal kinase, p38- p38 MAPK, P- phosphorylation

Figure 3. Opioid Dimerization

A cartoon depicting (A) Opioid receptor homodimers and opioid receptor heterodimers (B) Heterodimers between opioid receptors and other G-Protein coupled receptors (C) Protein-protein interactions involved in opioid receptor signal transduction. Abbreviations: βγ- G-protein beta-gamma subunit, μ- μ opioid receptor, δ- δ opioid receptor, CB1- Cannabinoid receptor type 1, κ- κ opioid receptor, ORL-1- opioid receptor like-1