Molecular and Epigenetic Aspects of Opioid Receptors in Drug Addiction and Pain Management in Sport

Abstract

Opioids are substances derived from opium (natural opioids). In its raw state, opium is a gummy latex extracted from Papaver somniferum. The use of opioids and their negative health consequences among people who use drugs have been studied. Today, opioids are still the most commonly used and effective analgesic treatments for severe pain, but their use and abuse causes detrimental side effects for health, including addiction, thus impacting the user's quality of life and causing overdose. The mesocorticolimbic dopaminergic circuitry represents the brain circuit mediating both natural rewards and the rewarding aspects of nearly all drugs of abuse, including opioids. Hence, understanding how opioids affect the function of dopaminergic circuitry may be useful for better knowledge of the process and to develop effective therapeutic strategies in addiction. The aim of this review was to summarize the main features of opioids and opioid receptors and focus on the molecular and upcoming epigenetic mechanisms leading to opioid addiction. Since synthetic opioids can be effective for pain management, their ability to induce addiction in athletes, with the risk of incurring doping, is also discussed.

Keywords: dopaminergic system; drug addiction; epigenetics; ncRNAs; neuron excitability; nociception; opioid receptors; opioids.

Figure 1

(Top) Schematic representation of a parasagittal rat brain section with depicted the main dopaminergic pathways, originating from the ventral midbrain nuclei, the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNpc). The mesocorticolimbic pathway (green arrows) originate mainly from the VTA and represents the major reward system in the brain. (Bottom) Functional connections between VTA and its target areas are strongly affected by inhibitory (GABAergic) inputs to VTA originating from different brain areas. The most robust effect of opioids is linked to inhibition of GABAergic neuron firing and consequent disinhibition of VTA DA neurons that increase firing rate and DA release.

Figure 2

(A) Main histone tail changes caused by long-term opioid exposure on specific brain areas in rodents and humans. (B) Main deregulated miRNA and targets in specific brain areas following long-term opioid exposure in mouse models. Basolateral and central amygdala (BLA and CeA, respectively), dorsal stiatum (dStri), hippocampus (HPC), locus coeruleus (LC), nucleus accumbens (NAcc), ventral stiatum (dStri), ventral tegmental area (VTA), ventrolateral orbitofrontal cortex (VLO). Data extracted from [12]. -, stable levels; ↑, increased levels; ↓, decreased levels.