Opioid Receptor Signal Transduction Mechanisms

Abstract

The myriad functions of morphine and its congeners are the consequences of the drug interacting with the three opioid receptors. In order to develop a perfect analgesic compound that mediates its function via these receptors, the mechanisms by which signaling occurs and the regulation of the signals must be fully elucidated. Since opioid receptors are members of the G protein-coupled receptor (GPCR) superfamily, many of their signaling processes mimic those of other GPCRs. However, it is apparent from recent proteomic and other studies that opioid receptors, similar to several GPCRs in the rhodopsin subfamily, exist in signaling complexes. These signaling complexes include the oligomerization of the opioid receptors with each other, with other GPCRs, or with other cellular proteins, such as b-arrestin or regulators of G protein signaling (RGS) that could alter or modulate the final receptor signals. In addition, accumulating evidence points to the presence of an agonist-selective signaling process with the opioid receptors. In this chapter, we will review the classical signaling mechanisms of opioid receptors, the various effectors that are regulated by opioid receptors, and their possible roles in the in vivo functions of drugs, and cellular regulators that could influence the amplitude and duration of the signals. We will examine recent data that support the existence of opioid receptor signaling complexes, or "receptosomes," in the transduction of opioid receptor signals. Finally, evidence for ligand-selective signaling and its implication in future drug development will be discussed.

Mu Opioids and Their Receptors: Evolution of a Concept

“…Similar to many receptors, phosphorylation is thought to be important in mu-opioid receptor regulation, having been implicated in a range of actions, including desensitization, tolerance, dependence, and internalization and biased agonism Law et al, 2000;Deng et al, 2001;Von Zastrow et al, 2003;Wang, 2003;Bohn et al, 2004;Waldhoer et al, 2004;Violin and Lefkowitz, 2007;International HapMap3 Consortium, 2010;Law, 2011;Reiter et al, 2012). Most phosphorylation sites are contained within the intracellular loops and C terminus in regions encoded by exons 2 and 3.…”

Functional Selectivity at the μ-Opioid Receptor: Implications for Understanding Opioid Analgesia and Tolerance

“…Activation of the OR can lead to the stimulation of a range of downstream effectors, including the activation of G protein-coupled inwardly rectifying potassium channels (e.g., Kir3) and the inhibition of voltage-gated calcium channels (Ca v ), as well as the activation of several second messenger systems, including protein kinase A (PKA), PKC, calcium/calmodulin kinase II (CaMKII), phospholipase C, extracellular regulated kinase 1/2 (ERK1/2), and c-jun N-terminal kinase (JNK) (for review, see Williams et al, 2001;Law, 2011). In addition to agonist-mediated differences in G protein coupling, ligands have also been shown to lead to distinct induction of some of these downstream signaling cascades.…”

“…At the cellular level, the OR traditionally has been described to mediate opioids drug effects by coupling to heterotrimeric G proteins (Fig. 1A), particularly pertussis toxin-sensitive G␣ i/o proteins, which act to inhibit adenylyl cyclases, modulate activity of certain ion channels, and signal through several second-messenger signal transduction cascades to promote signaling (for review, see Law, 2011).…”

Neuronal cytochrome P450 activity and opioid analgesia: relevant sites and mechanisms

“…In the PAG, μ stimulation inhibits pre-synaptic GABAergic activity, with the subsequent activation of descending, pain-relieving circuits, but details of these circuits remain unclear. At the neurochemical level, several cellular transduction mechanisms are used by μ opioid receptors (Williams, et al, 2013;Law, 2011), but opening of voltage-gated potassium channels in pre-synaptic GABAergic terminals (thereby reducing GABA release) is a favored hypothesis to account for the activation of descending, pain-relieving circuits (Vaughan, et al, 1997). As considered further below (see Discussion), both pre- and post-synaptic mechanisms are likely to be involved.…”