Impact of morphine dependence and withdrawal on economic demand for fentanyl, cocaine, and methamphetamine in rats.

Abstract

Stimulant-opioid co-use has surged in the United States, with methamphetamine use among people who use opioids increasing 82.6 % from 2015 to 2017. This trend contributes to rising overdose deaths, marking a "fourth wave" of the opioid epidemic. This study examined how opioid dependence and withdrawal affect the reinforcing effects of opioids and stimulants. Male Sprague-Dawley rats (8-12 per group) were trained to self-administer fentanyl (3.2µg/kg/inf), cocaine (0.32mg/kg/inf), or methamphetamine (0.1mg/kg/inf) under fixed ratio (FR) schedules. Opioid dependence was established through escalating twice-daily morphine injections (10-40mg/kg) over four days, then maintained with daily doses of 40mg/kg morphine. Rats exhibited stable signs of withdrawal (somatic signs, weight loss, hyperalgesia) following 20h but not 12h of morphine deprivation. Demand curves were generated by progressively increasing work requirements (FR 3, 5, 10, 18, 32, 56, 100, etc.) across sessions conducted 12 (morphine dependent) or 20 (morphine withdrawn) hours after morphine or saline (non-dependent controls). Morphine withdrawal (20-hour deprived group) increased demand for fentanyl but decreased demand for cocaine and methamphetamine. Morphine dependence (12-hour deprived group) had minimal effects, but did reliably decrease demand for cocaine. Morphine dependence increased demand intensity (Q₀) only for the small dose of fentanyl; all other conditions were unaffected. These results demonstrate that opioid withdrawal increases motivation for opioid use while reducing motivation for stimulants, particularly at higher costs. Understanding these dynamics is crucial for developing effective polysubstance treatments addressing both opioid dependence and stimulant co-use.