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Review
. 2012 Apr 10:14:e9.
doi: 10.1017/erm.2012.5.

Opioid receptor heteromers in analgesia

Cristina M Costantino  1 , Ivone Gomes, Steven D Stockton, Maribel P Lim, Lakshmi A Devi
Affiliations
Review

Opioid receptor heteromers in analgesia

Cristina M Costantino et al. Expert Rev Mol Med. .

Abstract

Opiates such as morphine and fentanyl, a major class of analgesics used in the clinical management of pain, exert their effects through the activation of opioid receptors. Opioids are among the most commonly prescribed and frequently abused drugs in the USA; however, the prolonged use of opiates often leads to the development of tolerance and addiction. Although blockade of opioid receptors with antagonists such as naltrexone and naloxone can lessen addictive impulses and facilitate recovery from overdose, systemic disruption of endogenous opioid receptor signalling through the use of these antagonistic drugs can have severe side effects. In the light of these challenges, current efforts have focused on identifying new therapeutic targets that selectively and specifically modulate opioid receptor signalling and function so as to achieve analgesia without the adverse effects associated with chronic opiate use. We have previously reported that opioid receptors interact with each other to form heteromeric complexes and that these interactions affect morphine signalling. Since chronic morphine administration leads to an enhanced level of these heteromers, these opioid receptor heteromeric complexes represent novel therapeutic targets for the treatment of pain and opiate addiction. In this review, we discuss the role of heteromeric opioid receptor complexes with a focus on mu opioid receptor (MOR) and delta opioid receptor (DOR) heteromers. We also highlight the evidence for altered pharmacological properties of opioid ligands and changes in ligand function resulting from the heteromer formation.

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Figures

Figure 1
Figure 1. A model for the role of MOR–DOR heteromer complex activity in the development of morphine tolerance
(a) Signalling of MOR in the absence of DOR (left pair), as found in Dor1 mutant mice, is not sufficient to the development of tolerance. The presence of DOR (centre pair) leads to the development of tolerance, but the occupancy of DOR (right pair) by agonist (+) or antagonist (−) in the context of MOR–DOR is sufficient to abrogate this effect. (b) Increased expression of MOR–DOR heteromer complexes produces a sustained increase in pERK that is associated with β-arrestin-dependent signalling and tolerance induction (dark green). Reduction of MOR–DOR pairs (blue/green) reduces the duration of pERK signalling and subsequent tolerance formation. When there is an abundance of MOR homomers (light blue), there is no secondary, sustained pERK generation over time and tolerance is not developed. Abbreviations: DOR, delta opioid receptor; MOR, mu opioid receptor; pERK, phosphorylated extracellular signal-regulated kinases.
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