Impact of Morphine Dependence and Withdrawal on the Reinforcing Effectiveness of Fentanyl, Cocaine, and Methamphetamine in Rats

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 The current studies provide direct evidence that the reinforcing effects of fentanyl are increased in opioid-withdrawn rats and reduced in opioid-dependent rats, relative to rats that are not physically dependent on opioids.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whereas stimulants retain their reinforcing effects regardless of whether the individual is in an opioid-dependent or withdrawn state.

Opioid and Sucrose Craving Are Accompanied by Unique Behavioral and Affective Profiles after Extended Abstinence in Male and Female Rats

“…The lack of 22-kHz USVs is consistent with the idea that somatic withdrawal symptoms are not driving craving behavior. Although rats may experience withdrawal-like behavior in early abstinence following chronic opioid self-administration ( Gipson et al, 2021 ; Seaman and Collins, 2021 ), withdrawal symptoms subside within the first few days of abstinence ( Welsch et al, 2020 ). Yet, craving continues to intensify for several weeks.…”

Sex- and Dose-Dependent Differences in the Development of an Addiction-Like Phenotype Following Extended-Access Fentanyl Self-Administration

“…Thus, in the current study, we examined fentanyl self-administration across a broad range of fentanyl doses (0.25, 0.75, 1.5, and 3.0 µg/kg/infusion) and hypothesized that relapse vulnerability would be highest following high-dose fentanyl self-administration. We also expanded our model to include an additional key feature of OUD in humans, physical dependence ( American Psychiatric Association, 2013 ), as assessed by spontaneous weight loss during early withdrawal, a highly predictive single factor of withdrawal ( Cicero and Meyer, 1973 ; Gellert and Holtzman, 1978 ; Nickel and Aledter, 1987 ; Maldonado et al, 1992 ; Houshyar et al, 2004 ; Navarro-Zaragoza et al, 2010 ; Pintér-Kübler et al, 2013 ; Bobzean et al, 2019 ; Seaman and Collins, 2021 ; Townsend et al, 2021 ). Physical dependence is a defining feature of OUD in humans ( American Psychiatric Association, 2013 ), and women experience a more severe withdrawal syndrome than men ( Huhn and Dunn 2020 ).…”

Modeling Stimulant and Opioid Co-use in Rats Provided Concurrent Access to Methamphetamine and Fentanyl

“…These studies lay the groundwork for a deeper evaluation of the interactions between the reinforcing effects of methamphetamine and fentanyl using drug-vs.-drug choice. For instance, previous studies from our laboratory and others have demonstrated that the reinforcing effects of opioids, but not stimulants, are enhanced when subjects are in a state of opioid withdrawal (47,55,56). However, the degree to which opioid withdrawal would impact preference for and/or economic interactions between methamphetamine and fentanyl is an important and underexplored aspect of the current epidemic of polysubstance use.…”

“…Rats were anesthetized with 2–3% isoflurane and prepared with chronic indwelling catheters in the left and right femoral veins using procedures similar to those described previously ( 37 , 47 , 48 ). Catheters were tunneled under the skin and attached to a vascular access button placed in the mid-scapular region.…”

“…Behavior was initially maintained by either 0.1 mg/kg/infusion of methamphetamine or 0.0032 mg/kg/infusion of fentanyl under a fixed ratio (FR) 1: timeout (TO) 5-s schedule of reinforcement during daily 90-min sessions. Doses were chosen based on their relative positions (peak) on their respective progressive ratio dose-response curves ( 47 , 48 ). Two sets of conditioned stimuli (discriminative and infusion-paired) were used in these studies.…”