Opioid Addiction and Opioid Receptor Dimerization: Structural Modeling of the OPRD1 and OPRM1 Heterodimer and Its Signaling Pathways

Abstract

Opioid addiction is a complex phenomenon with genetic, social, and other components. Due to such complexity, it is difficult to interpret the outcome of clinical studies, and thus, mutations found in individuals with these addictions are still not indisputably classified as opioid addiction-causing variants. Here, we computationally investigated two such mutations, A6V and N40D, found in the mu opioid receptor gene OPRM1. The mutations are located in the extracellular domain of the corresponding protein, which is important to the hetero-dimerization of OPRM1 with the delta opioid receptor protein (OPRD1). The hetero-dimerization of OPRD1–OPRM1 affects the signaling pathways activated by opioids and natural peptides and, thus, could be considered a factor contributing to addiction. In this study, we built four 3D structures of molecular pathways, including the G-protein signaling pathway and the β-arrestin signaling pathway of the heterodimer of OPRD1–OPRM1. We also analyzed the effect of mutations of A6V and N40D on the stability of individual OPRM1/OPRD1 molecules and the OPRD1–OPRM1 heterodimer with the goal of inferring their plausible linkage with opioid addiction. It was found that both mutations slightly destabilize OPRM1/OPRD1 monomers and weaken their association. Since hetero-dimerization is a key step for signaling processes, it is anticipated that both mutations may be causing increased addiction risk.

Polymorphisms in COMT and OPRM1 Collectively Contribute to Chronic Shoulder Pain and Disability in South African Breast Cancer Survivors’

“…The adenosyl homocysteinase enzyme (AHCY) and fibroblast growth factor 2 (FGF2) genes are responsible regulating methyltransferase (e.g., COMT activity), and fibroblasts activity, respectively [49,50]. Opioid receptor delta one (OPRD1) are related to-and can form a heterodimer with OPRM1, and proenkephalin (PENK) encodes the neuropeptide enkephalin, a strong agonist for the µ-opioid receptor [51,52]. Both AHCY and FGF2 share functional associated networks with PENK.…”

The Skin–Brain Axis: From UV and Pigmentation to Behaviour Modulation

“…OPRM1 partakes in endogenous and exogenous opioid response regulation in the central nervous system [ 125 ], ultimately inhibiting neurotransmitter release and, thus, the transmission of nervous stimuli upon binding [ 126 ]. While β-endorphin, a POMC-derivative and endogenous OPRM1 ligand [ 127 ], was not found to affect nociceptive thresholds in MC1R wild-type animals directly, OPRM1 loss-of-function decreased nociceptive thresholds of MC1R mutant animals, suggesting that MC1R modulates nociception in an OPRM1-dependent manner [ 116 ]. However, the plasma levels of another derivative of POMC, α-MSH, are also decreased in MC1R variant yellow-furred (equivalent to red-haired) mice.…”

Proteome-Informed Machine Learning Studies of Cocaine Addiction

“…Their mutual interactions in the network also indicate DAT is the most important node, which connects the upper and lower parts of the network. Network analysis shows that DAT has the highest degree (11) among all of the nodes and is a hub of the core network. Additionally, the closeness centrality of DAT is as high as 1.000, which also suggests its full connection to all of the other proteins in the core network.…”

“…Cocaine also blocks the serotonin transporter and norepinephrine transporter, inhibiting the reuptake of serotonin and norepinephrine and thus increasing the level of the activation of serotonin and norepinephrine receptors. Additionally, cocaine exposure could regulate opioid receptors and endogenous opioid peptides and may also affect the selection of G-protein versus β-arrestin pathways. , Repeated use of psychostimulants alters gene expression throughout the brain, including in the nucleus accumbens, a critical center for reward processing. Frequent cocaine exposure increases the level of expression of the transcription factor ΔFosB and brain-derived neurotrophic factor (BDNF), which in turn regulate gene expression to alter both dendritic and synaptic morphology and function in the nucleus accumbens and prefrontal cortex, likely driving the long-term compulsion for drug seeking and taking that underlies addiction …”