Abstract
Recent estimates suggest increased popularity of the concurrent use of opioids and stimulants, with over 50% of treatment-seeking opioid users reporting regular stimulant use. The goal of the current study was to determine how opioid dependence and withdrawal affect the reinforcing effects of fentanyl, cocaine, and methamphetamine. Male Sprague-Dawley rats were allowed to self-administer fentanyl under a progressive ratio (PR) schedule of reinforcement. Baseline evaluations of reinforcing effectiveness of fentanyl, cocaine, and methamphetamine were determined. Opioid dependence was then established by administering escalating doses of morphine (10–40 mg/kg) twice-daily for four days and subsequently maintained by once-daily injections of 40 mg/kg morphine. To evaluate the impact of opioid dependence and withdrawal on the self-administration of fentanyl, cocaine, and methamphetamine, sessions occurred either 12 or 20 h after the morphine, respectively. During opioid withdrawal, the fentanyl dose-response curve was shifted rightward with an increase in maximal effectiveness, whereas it was shifted rightward with a reduction in maximal effectiveness when evaluated in rats currently dependent on opioids, relative to baseline. The reinforcing effects of cocaine and methamphetamine were unchanged by either condition. The current studies provide direct evidence that the reinforcing effects of fentanyl are increased in opioid-withdrawn rats and reduced in opioid-dependent rats, relative to rats that are not physically dependent on opioids. These findings suggest that motivations to use opioids are dependent on the state of the individual whereas stimulants retain their reinforcing effects regardless of whether the individual is in an opioid-dependent or withdrawn state.
Highlights
The opioid crisis continues to pose a significant health burden, as evidenced by approximately 50 million people reported to have misused opioids worldwide in 2018 (United Nations Office on Drugs and Crime, 2019)
There were three main findings 1) signs of morphine withdrawal: were apparent following 20 h of morphine deprivation, but not 12 h, suggesting that rats cycled through states of morphine dependence and withdrawal on a daily basis; 2) morphine withdrawal produced a rightward shift in the fentanyl doseresponse curve with an increase in the maximal effect, whereas morphine dependence produced a greater rightward shift with a reduction in the maximal effect of fentanyl; and 3) the reinforcing effectiveness of the doses of cocaine and methamphetamine evaluated were unaffected by states of morphine dependence and withdrawal
These data are consistent with previous studies demonstrating that induction of morphine dependence produces a decrease in body weight that fluctuates as a function of time since prior morphine injection (Cooper et al, 2008; Cooper et al, 2010), with increases of approximately 20 g 12 h after an injection of morphine, and reductions of approximately 20 g observed by 20 h after a morphine injection
Summary
The opioid crisis continues to pose a significant health burden, as evidenced by approximately 50 million people reported to have misused opioids worldwide in 2018 (United Nations Office on Drugs and Crime, 2019). One major hurdle in treating opioid use disorder and preventing opioid-induced overdose is the relatively high rate of relapse following a period of abstinence, with one study reporting that ∼60% of individuals relapse in the first week of abstinence and ∼80% relapse in the first month (Smyth et al, 2010). One proposed contributor to the relatively high relapse rates in individuals with opioid use disorder is the ability of opioids to reverse/terminate symptoms associated with withdrawal from opioids (Solomon and Corbit, 1974; Koob and Le Moal, 2001; Colpaert et al, 2006; Koob, 2020). The cessation of opioid use in an individual that is physically dependent on opioids results in the emergence of a withdrawal syndrome comprising of psychological (e.g., anxiety, craving) and physiological (e.g., nausea, diarrhea) symptoms with varying intensities which together can culminate in a highly aversive state for the individual. While the reinforcing effects of fentanyl have been previously characterized in rats (Lal et al, 1977; van Ree et al, 1978; Awasaki et al, 1997; Morgan et al, 2002; Wade et al, 2015; Wager et al, 2017), much less is known about how opioid dependence and withdrawal impact the reinforcing effects of fentanyl (Townsend et al, 2019), or other commonly coabused drugs
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