Opioid addiction is a massive problem worldwide, leading to fractured families, struggling health care systems, and destroyed communities . What often begins as a prescription can develop into a potentially fatal addiction to opioids, whether in the form of heroin or prescription drugs . Indeed, nearly 50,000 Americans die every year because of opioid consumption . The necessity of understanding opioid addiction and its principal mechanism cannot be understated. Only by understanding how opioids trap people into a cycle of intake and withdrawal can addiction be treated.
The endogenous opioid system is highly integrated, interacting with many other crucial neurotransmitter networks in the body . It consists of three canonical opioid receptors (ORs): mu (MOR), delta (DOR), and kappa (KOR) . These receptors all promote analgesia in the brain, and they can be simultaneously activated by the same polypeptides, as well as individually activated by distinct ones [2, 3]. From the use of second- and third-messenger systems, to G protein-dependent pathways, to possibly even ligand-directed signaling, their principle signaling mechanisms vary .
Unfortunately, this system is also extremely vulnerable to disturbances, which explains how opioids can produce long-lasting outcomes in the body . Drug-based opioids, such as painkillers and heroin, interact with the endogenous opioid system by activating the various types of opioid receptors and thus creating a disequilibrium . For instance, opioids can activate MORs, which promote disinhibited dopamine neuron firing and, as a result, elevate rates of dopamine transmission . Meanwhile, KOR activation affects dysphoria (a sense of unease), while DOR activation reduces anxiety . By repeatedly consuming opioids, users alter their OR-mediated intracellular signaling cascades that, ultimately, produce the rewarding and reinforcing effects that promote further consumption of opioids .
Opioid addiction is also sustained by the epigenetic modifications that the drug produces in affected neurons . Repeated opioid use results in a wide variety of DNA changes, such as histone acetylation, chromatic structure modification, and demethylation . Together, these changes reinforce the linkage between the rewarding experience of consuming drugs with the bodily cues producing craving and encouraging relapse [1, 4].
On a broader level, genetics factor into individuals’ addictive responses to opioid consumption. For one, men are more likely than women to be addicted to opioids, likely owing to female subjects’ lower sensitivity to the analgesic effects of MOR . Furthermore, various genes are associated with opioid addiction . For instance, researchers have found an association between certain single nucleotide polymorphisms (SNPs) located on potassium signaling pathways and opioid dependence . Predispositions to certain psychological disorders have long been known to affect opioid dependence, and having SNPs that code for those disorders also increases an individual’s chance of becoming addicted to opioids [2, 3]. While the connection between these SNPs and opioids requires further investigation, the knowledge that they are linked is certainly valuable for prevention purposes.
Another mechanism through which opioid addiction occurs is the gut-brain axis . The gut-brain axis and opioid use are mutually reinforcing . Gut bacteria can promote or reduce one’s propensity to succumb to opioid-related behaviors, while opioids can alter the gut microbiome to produce abnormalities that help sustain addiction . This is an area that requires more research, particularly concerning how the specific molecular interactions that occur in the gut modulate opioid reinforcement . Regardless, the observed connection between gut dysbiosis and neuroinflammation, impaired reward, and enhanced stress strongly promotes the connection between the gut-brain axis and opioid addiction .
The aforementioned pathways are just part of the mechanism which opioid addiction operates. The complexity of the opioid system suggests that there may be more addiction mechanisms to discover .
 C. J. Browne et al., “Epigenetic Mechanisms of Opioid Addiction,” Biological Psychiatry, vol. 87, no. 1, p. 22-23, January 2020. [Online]. Available: https://doi.org/10.1016/j.biopsych.2019.06.027.
 M. A. Emery and H. Akil, “Endogenous Opioids at the Intersection of Opioid Addiction, Pain, and Depression: The Search for a Precision Medicine Approach,” Annual Review of Neuroscience, vol. 43, p. 355-374, February 2020. [Online]. Available: https://doi.org/10.1146/annurev-neuro-110719-095912.
 S. C. Wang et al., “Opioid Addiction, Genetic Susceptibility, and Medical Treatments: A Review,” International Journal of Molecular Science, vol. 20, no. 17, p. 1-17, January 2019. [Online]. Available: https://doi.org/10.3390/ijms20174294.
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 G. F. Koob, “Neurobiology of Opioid Addiction: Opponent Process, Hyperkatifeia, and Negative Reinforcement,” Biological Psychiatry, vol. 87, no. 1, p. 44-53, January 2020. [Online]. Available: https://doi.org/10.1016/j.biopsych.2019.05.023.
 M. Ren and S. Lotfipour, “The Role of the Gut Microbiome in Opioid Use,” Behavioral Pharmacology, vol. 31, no. 2, p. 131-121, April 2021. [Online]. Available: https://doi.org/10.1097/FBP.0000000000000538.