Understanding Oxycodone Addiction: How Genetics and Sex Shape Behavior

The opioid epidemic remains a critical public health crisis, fueled in part by the widespread prescription of medications like oxycodone. While these drugs are effective for pain, they carry a high risk for addiction and dangerous side effects like respiratory depression. In our recent study with the de Guglielmo lab, we explored how genetic background and sex influence the way the body processes oxycodone and the development of addiction like behaviors.

The Big Question

We set out to understand why only a subset of individuals who use opioids develop an Opioid Use Disorder (OUD). By using four different inbred rat strains (ACI/N, BN/NHsd, F344/N, and WKY/N), we investigated how genetic differences contribute to drug metabolism, the escalation of drug use, motivation, and physical symptoms like pain sensitivity and breathing difficulties.

Exploring the Role of Genetics and Sex

To mirror the human experience of addiction, we gave rats extended access to oxycodone for 12 hours a day over three weeks. This allowed them to "self administer" the drug by pressing a lever. Throughout the study, we measured several key factors:

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  Escalation: How quickly the rats increased their drug intake over time.

  
  
  
  
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  Motivation: How hard they were willing to work for a single dose.

  
  
  
  
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  Metabolism: How fast their bodies broke down oxycodone into other substances.

  
  
  
  
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  Physical Effects: Changes in pain sensitivity (hyperalgesia) and lung function (respiratory depression).

  
  
  
  
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  Seeking: Their urge to find the drug even after four weeks of being clean.

  
  
  
  

What We Discovered

Our findings revealed that a rat's genetic strain plays a major role in its response to opioids:

• Metabolism vs. Behavior: The BN/NHsd strain stood out. These rats processed oxycodone into oxymorphone(a much more potent substance) much faster than other strains. This led them to acquire the drug taking habit much more quickly, though it did not change the total amount they took in the long run.

  
  
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  Escalation Patterns: The F344/N strain showed the steepest increase in drug use, suggesting they might be more vulnerable to the transition from casual use to addiction.

  
  
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  Relapse Risk: Even after a month of abstinence, BN/NHsd rats showed the highest levels of drug seeking behavior when they saw cues associated with their past use.

  
  
  
  
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  Respiratory Sensitivity: Most strains experienced significant breathing suppression when given oxycodone. However, the BN/NHsd strain remained uniquely insensitive to this dangerous side effect.

  
  
  
  
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  Minimal Sex Differences: Within each strain, males and females behaved very similarly. The main differences were in metabolism, where females generally processed the drug faster than males, except in the BN/NHsd strain where the pattern was reversed.

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Why This Matters

This research proves that there is no "one size fits all" experience with opioid use. Genetic variations significantly change how the body feels the "reward" of the drug and how it handles withdrawal. By identifying these specific genetic traits, we can move toward more personalized medicine. We believe that understanding these biological blueprints is essential for developing better prevention strategies and more effective treatments for those struggling with opioid addiction.

Reference: Doyle, M.R., Martinez, A.R., Qiao, R., Dirik, S., Di Ottavio, F., Pascasio, G., Martin-Fardon, R., Benner, C., George, O., Telese, F., & de Guglielmo, G. (2023). Strain and sex-related behavioral variability of oxycodone dependence in rats. Neuropharmacology, 237, 109635. https://doi.org/10.1016/j.neuropharm.2023.109635