Introduction: Nicotine and morphine are two well-known substances that influence pain regulation, reward processing, and addiction-related behaviors. While their effects have traditionally been studied from a neurochemical perspective—especially regarding the dopaminergic, opioidergic, and glutamatergic systems—recent advances have revealed a crucial role for epigenetic mechanisms in mediating these effects. Epigenetic processes such as histone acetylation, methylation, and regulation by non-coding RNAs can produce lasting changes in gene expression and neural function, even long after drug exposure ends. This review aims to explore how nicotine and morphine impact neurotransmitter signaling pathways through epigenetic modifications, and how these interactions contribute to long-term neurobehavioral outcomes, including addiction and pain sensitivity.
Methods: To gather relevant data, we performed a structured search across three major scientific databases: PubMed, Scopus, and Web of Science. Our inclusion criteria were peer-reviewed original articles and review papers published between 2015 and 2023. We used a combination of keywords, including "nicotine," "morphine," "epigenetic regulation," "histone modifications," "dopamine," "neurotransmission," and "conditioned place preference (CPP)." Both animal-based and in vitro studies were included if they examined how nicotine or morphine affected neurotransmitter systems through epigenetic alterations.
Results: The literature suggests that both nicotine and morphine can trigger epigenetic changes in brain areas associated with emotion, reward, and pain—including the nucleus accumbens, prefrontal cortex, amygdala, and ventral tegmental area. These substances influence the activity of key enzymes that modify histones, such as G9a (a histone methyltransferase), HDACs (histone deacetylases), and CBP/p300 (histone acetyltransferases). Nicotine, for example, enhances histone H3 acetylation in the nucleus accumbens, promoting the expression of dopamine-related genes and reinforcing addictive behavior. Similarly, morphine alters histone methylation patterns that reduce GABAergic inhibition in the VTA, thereby amplifying reward sensitivity. In addition, both substances regulate non-coding RNAs such as miR-132 and miR-212, which influence synaptic plasticity and receptor availability. These epigenetic changes are not limited to the individual exposed but may also be passed on to offspring through modifications in germ cells, contributing to inherited vulnerability to addiction or altered pain sensitivity
Conclusion: The interaction between epigenetic regulation and neurotransmitter signaling is a key factor in the long-term behavioral and physiological responses to nicotine and morphine. Histone modifications and non-coding RNAs provide a biological bridge between short-term drug effects and persistent changes in brain function. Understanding these processes opens new possibilities for therapeutic interventions aimed at reversing or preventing the adverse outcomes of drug exposure—including addiction, chronic pain, and even intergenerational transmission of risk. Targeting the epigenetic machinery may become a promising approach in the development of novel treatments for substance use disorders and pain management.