Gene Number: 4988

Location: 6q25.2

Key Functions: Pain perception, opioid response, reward system regulation, addiction susceptibility, mood modulation

OPRM1 encodes the μ-opioid receptor (MOR), a G protein–coupled receptor (GPCR) that serves as the primary molecular target for endogenous opioid peptides (such as endorphins and enkephalins) and exogenous opioid drugs (such as morphine, fentanyl, and heroin). The receptor plays a central role in mediating the effects of both naturally occurring and pharmacological opioids on analgesia, reward, mood regulation, and stress adaptation.

Upon activation by an agonist, the μ-opioid receptor inhibits adenylyl cyclase activity, reduces cAMP levels, and promotes the opening of G-protein–coupled inwardly rectifying potassium (GIRK) channels while inhibiting voltage-gated calcium channels. This cascade leads to neuronal hyperpolarization and decreased neurotransmitter release, resulting in analgesia and euphoria. The receptor is highly expressed in brain regions integral to pain modulation and reward processing, including the periaqueductal gray (PAG), thalamus, nucleus accumbens, amygdala, and locus coeruleus, as well as the dorsal horn of the spinal cord.

Key physiological and neurobiological functions of OPRM1 include:

1. Pain perception and analgesia:OPRM1 activation suppresses nociceptive transmission within ascending pain pathways. Endogenous opioids such as β-endorphin bind to the receptor to reduce pain perception during stress or injury. Pharmacological activation through opioid analgesics further amplifies this effect but also carries a risk of tolerance and dependence through receptor desensitization and downregulation mechanisms mediated by β-arrestins.

   
   

2. Reward and addiction:The receptor is a crucial component of the mesolimbic dopamine system. Activation of OPRM1 in the ventral tegmental area (VTA) inhibits GABAergic interneurons, thereby disinhibiting dopaminergic neurons projecting to the nucleus accumbens, which leads to enhanced dopamine release and the subjective experience of reward. Chronic overstimulation induces neuroadaptive changes that underlie tolerance, craving, and dependence.

   
   

3. Mood regulation and stress response:Beyond pain and reward, OPRM1 modulates affective processes and stress resilience. Its activation reduces the hypothalamic–pituitary–adrenal (HPA) axis response to stress and contributes to feelings of calmness and social bonding. Dysregulation of OPRM1 signaling has been linked to depressive phenotypes and altered stress coping.

   
   

4. Individual variation and pharmacogenomics:The most studied polymorphism, A118G (rs1799971), results in an Asn40Asp amino acid substitution in the receptor’s N-terminal region, altering its glycosylation and ligand-binding properties. The G allele is associated with reduced receptor expression and lower binding affinity for endogenous opioids, leading to decreased analgesic response, increased pain sensitivity, and altered susceptibility to addiction. Individuals carrying the G allele often require higher opioid doses for effective pain control but may experience blunted euphoric effects. Moreover, this variant has been implicated in differential response to naltrexone treatment in alcohol and opioid dependence.

   
   

5. Neuroadaptive plasticity and tolerance:Repeated OPRM1 activation induces receptor internalization and coupling changes involving G-protein uncoupling and β-arrestin recruitment, leading to tolerance and physical dependence. These cellular adaptations modify downstream signaling pathways (e.g., ERK/MAPK, PI3K/Akt), contributing to the chronic effects observed in opioid use disorder (OUD).

   
   

In summary, OPRM1 is a central regulator of pain, reward, and affective processes. Its function bridges the physiological domains of nociception, emotion, and motivation. Genetic and epigenetic variations in this gene significantly influence an individual’s pain threshold, emotional resilience, vulnerability to addiction, and pharmacological response to opioids, making it a critical locus in both clinical pharmacogenomics and neurobehavioral research.