Genetic and epigenetic studies of opioid abuse disorder - the potential for future diagnostics

Abstract

Introduction: Opioid use disorder (OUD) is a global problem that often begins with prescribed medications. The available treatment and maintenance plans offer solutions for the consumption rate by individuals leaving the outstanding problem of relapse, which is a major factor hindering the long-term efficacy of treatments.

Areas covered: Understanding the neurobiology of addiction and relapse would help identifying the core causes of relapse and distinguish vulnerable from resilient individuals, which would lead to more targeted and effective treatment and provide diagnostics to screen individuals who have a propensity to OUD. In this review, we cover the neurobiology of the reward system highlighting the role of multiple brain regions and opioid receptors in the development of the disorder. We also review the current knowledge of the epigenetics of addiction and the available screening tools for aberrant use of opioids.

Expert opinion: Relapse remains an anticipated limitation in the way of recovery even after long period of abstinence. This highlights the need for diagnostic tools that identify vulnerable patients and prevent the cycle of addiction. Finally, we discuss the limitations of the available screening tools and propose possible solutions for the discovery of addiction diagnostics.

Keywords: Opioid; addiction; brain; circuitry; epigenetics; reward.

Figure.1:. Neurocircuitry of addiction.

Dopaminergic signalling is an important element in motivation and goal seeking behaviour which plays a critical role in addiction. Establishment of the rewarding effect starts with disinhibition of dopaminergic neurons in the VTA which results in a steep release of dopamine in the NAc. The motivation and learning systems facilitate dependence by pairing the rewarding experience with contextual and drug-associated cues. Maintenance of the addictive behaviour involves glutamatergic inputs from PrL and the BLA to the NAc core alongside projections from the IL and ventral hippocampus to the NAc shell to mediate drug seeking. The motivation to obtain reward is further signalled by inhibitory GABA projections from the NAc shell to the VP. Anticipation and craving are mediated via dopaminergic projections from the VTA to the PFC, NAc, amygdala and the hippocampus all of which are context- and cue-induced. Abstinence results in a hypodopaminergic state associated with reduced uptake of dopamine [9] [49] in the NAc which mediates withdrawal.

Figure.2:. Intracellular signalling cascade following the activation of opioid receptors.

Activation of the G protein-coupled opioid receptors results in the dissociation of G_α and G_βγ. Acute activation of the receptor recruits G_αi/o leading to inhibition of AC I, V and VI, and recruits G_βγ resulting in the stimulation of AC II. The analgesic effect of opioid receptor is the product of inhibition of presynaptic VGCC and activation of GIRK via G_βγ. Dependency is regulated by cAMP signalling where prolonged activation of the receptors results in superactivation of AC leading to a rapid increase of cAMP. B-raf is activated by cAMP via Rap-1, which forms a dimer with Raf-1 and subsequently activate ERK via MEK. Intracellular Ca²⁺ is increased following the activation of IP3. Dissociated G_βγ activates PLCβ leading to the production of IP3 which mobilises Ca²⁺ from the endoplasmic reticulum. Free Ca²⁺ bind to calmodulin (CAM) and modulate the function of multiple Ca²⁺/calmodulin-dependent protein kinase (CaMKs) amongst them is CaMK IV which is the only CaMK with the ability to phosphorylate cAMP response element-binding protein (CREB). Activation of CREB can also be achieved via p90 ribosomal S6 kinase (p90RSK). Activation of PKC can be activated by the dissociated G_βγ or the free intracellular Ca²⁺ which results in the activation of the MAPK signalling cascade resulting in the activation of p90RSK. Opioid induced signalling cascades converge on the activation of the transcription factor CREB which is a crucial element of synaptic plasticity.