Oxycodone self-administration in rats differentially alters IL-1R1 and IL-1R2 expression in the brain

Pharmacol Biochem Behav. 2026 Sep 18:174271. doi: 10.1016/j.pbb.2026.174271. Online ahead of print.

ABSTRACT

Interleukin 1β (IL-1β) is a proinflammatory cytokine that binds to two receptors, IL-1R1 and IL-1R2. IL-1R1 activation initiates neuroinflammation, and IL-1R2 is a decoy receptor that reduces IL-1R1 signaling by sequestering IL-1β. Emerging evidence links IL-1β to substance use disorders. Methamphetamine and ethanol increase IL-1β levels in the brain, and antagonism of IL-1β signaling reduces negative affective behaviors caused by methamphetamine and ethanol. However, effects of chronic opioid exposure on the IL-1β system in the brain and blocking IL-1β signaling on rewarding effects of opioids are unknown. We determined if oxycodone self-administration (SA) causes brain-region specific changes in IL-1β, IL-1R1, and IL-1R2 levels (mRNA and protein) and if antagonizing IL-1β signaling affects oxycodone SA behaviors. Following 14 days of oxycodone SA (0.056 mg/kg/inf), IL-1R2 mRNA levels were increased in the basolateral amygdala (BLA) and IL-1R1 mRNA levels in the BLA were decreased. For IL-1β itself, oxycodone SA did not affect mRNA levels. Oxycodone SA also did not alter protein levels of IL-1R2, IL-1R1, pro-IL-1β, mature-IL-1β, or the relative expression ratios between pro- and mature-IL-1β. Systemic administration of anakinra, an IL-1R1 antagonist, did not block acquisition of oxycodone SA. Intracerebroventricular (ICV) administration of anakinra following oxycodone acquisition did not reduce oxycodone SA and infusions. Our results show that oxycodone SA induces notable changes in IL-1 receptor mRNA in the BLA but is not affected by pharmacological antagonism of IL-1β signaling.

PMID:42759895 | DOI:10.1016/j.pbb.2026.174271