Chronic inflammatory pain reduces fentanyl intake during early acquisition of fentanyl self-administration, but does not change motivation to take fentanyl in male and female rats

The co-occurrence of chronic pain and opioid misuse has led to numerous preclinical investigations of painopioid interactions to examine how pain manipulations alter the reinforcing properties of opioids. However, preclinical investigations of chronic pain effects on opioid drug self-administration have produced inconsistent results. Our previous work demonstrated that established fentanyl self-administration is resistant to change by induction of chronic inflammatory pain (Complete Freund's Adjuvant; CFA) in male and female rats, while other laboratories have shown that CFA increased fentanyl self-administration in male but not female rats when pain induction precedes self-administration, which may be a critical factor in determining the effects of chronic pain on self-administration. The present study was designed similarly to Higginbotham et al. (2022) to test the effects of CFA on fentanyl self-administration in rats that underwent pain prior to acquisition of fentanyl selfadministration. Male and female rats treated with hindpaw CFA or saline were trained to intravenously selfadminister (IVSA) fentanyl for 3 weeks under limited access to fentanyl (2 h per day) conditions. After 3 weeks of fentanyl IVSA acquisition, we tested motivation to take fentanyl using progressive ratio testing and dose-response testing. CFA male and female rats self-administered less fentanyl than saline-treated controls during week 1 of acquisition, but not during weeks 2-3 of acquisition. Intra-session analysis of week 1 data demonstrated that chronic inflammatory pain suppressed fentanyl intake towards the end of week 1 and at the end of each operant session. We also report no effects of chronic inflammatory pain on motivation to take fentanyl. We discuss potential methodological explanations for differences between these results and prior reports. Our findings demonstrate that CFA temporarily suppresses fentanyl IVSA in animals without changing motivation to take fentanyl or promoting escalation of opioid use, suggesting that chronic inflammatory pain is unlikely to promote long-term risk of opioid misuse.