The cross-talk between different G protein-coupled receptor signal-transduction pathways is an intriguing concept with important physiological implications . A recent study by Wang et al.  has discovered that the actions of opioid drugs on the μ-opioid receptor (MOR) are negatively regulated by an interaction with the undercharacterized GPR139 receptor . These findings implicate GPR139 as a potential target for increasing opioid safety.
The authors first identified opioid modulators using a transgenic C. elegans platform that were engineered to express the human MOR (tgMOR). Using a rapid behavioral readout to screen ∼2,500 mutagenized tgMOR worms, the authors identified ∼900 mutants with abnormal sensitivity to the opioid agonists morphine and fentanyl. In this paradigm, hypersensitive mutants recovered more rapidly from opioid-induced paralysis compared to the tgMOR animals. The authors focused on two mutants, one with homology to the L-type Ca2+ channel that is known to potentiate the nociceptive properties of opioids and the other frpr-13 that shares a phylogeny with the mammalian receptor GPR139. Furthermore, the opioid hypersensitivity in transgenic worms was reversed by the overexpression human GPR139, suggestive of a functional interaction between the receptors.
The authors then performed a variety of supporting in vitro functional assays in HEK293T cells that indicated GPR139 overexpression could attenuate or abolish MOR signaling and cell-surface expression. They also demonstrated that GPR139 and MOR were associating when co-expressed in this model system, although the relevance of this interaction in a native system awaits further investigation. Nevertheless, GPR139 and MOR were co-expressed in mouse neurons in brain regions implicated in opioid reward, analgesia and withdrawal. Moreover, a series of electrophysiological experiments using knockout mice indicated that GPR139 may offset the opioid-mediated inhibitory effects on neuronal firing.
On the basis of these compelling data, the authors then investigated the behavioural correlate of the GPR139 and MOR interaction. Although GPR139 knockout mice were ostensibly healthy, they exhibited consistently increased acute responses to morphine, including in a conditioned place preference paradigm as a measure of opioid reward, as well as in thermal and mechanical pain models. Equally, the GPR139 knockout mice exhibited fewer behavioural signs of withdrawal following the cessation of chronic opioid exposure. In a final set of experiments, the administration of a GPR139 surrogate agonist JNJ-63533054 led to a dose-dependent reduction in morphine analgesia in both pain paradigms in wild-type mice . JNJ-63533054 also markedly suppressed the self-administration of morphine these mice. Strikingly, these effects were absent in the Gpr139−/− mice, strongly implicating GPR139 as a negative regulator of opioid response in vivo.
Taken together, these findings suggest that GPR139 could be pharmacologically targeted in a strategy to increase the safety and efficacy of opioid treatment, which is currently an area of widespread public interest. Intriguingly, this study builds on the previous identification of α-Melanocyte Stimulating Hormone (αMSH) as a potential endogenous ligand for GPR139 . Given that αMSH is derived from the same precursor as another MOR ligand (β-endorphin), these findings may further indicate an important physiological interaction between these receptors. It will be of great interest to dissect the pharmacology of GPR139 activation, particularly in terms of potential therapeutic advantages over the direct inhibition of MOR.
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