Divergent profiles of fentanyl withdrawal and associated pain in mice and rats

Abstract

Opioid abuse has devastating effects on patients, their families, and society. Withdrawal symptoms are severely unpleasant, prolonged, and frequently hinder recovery or lead to relapse. The sharp increase in abuse and overdoses arising from the illicit use of potent and rapidly-acting synthetic opioids, such as fentanyl, highlights the urgency of understanding the withdrawal mechanisms related to these drugs. Progress is impeded by inconsistent reports on opioid withdrawal in different preclinical models. Here, using rats and mice of both sexes, we quantified withdrawal behaviors during spontaneous and naloxone-precipitated withdrawal, following two weeks of intermittent fentanyl exposure. We found that both mice and rats lost weight during exposure and showed increased signs of distress during spontaneous and naloxone precipitated withdrawal. However, these species differed in their expression of withdrawal associated pain, a key contributor to relapse in humans. Spontaneous or ongoing pain was preferentially expressed in rats in both withdrawal conditions, while no change was observed in mice. In contrast, withdrawal associated thermal hyperalgesia was found only in mice. These data suggest that rats and mice diverge in how they experience withdrawal and which aspects of the human condition they most accurately model. These differences highlight each species’ strengths as model systems and can inform experimental design in studies of opioid withdrawal.

Lipophilic analogues of D-cysteine prevent and reverse physical dependence to fentanyl in male rats

“…We show here that the injection of NLX elicited pronounced withdrawal syndrome consisting of behavioral and cardiorespiratory responses, and falls in body temperature and body weight, in male rats that received twice-daily co-injections of fentanyl (125 μg/kg, IV) + vehicle. These withdrawal phenomena seen in this study are strongly suggestive of the rats having become physically-dependent on fentanyl, and are consistent with reports on the patterns of NLXprecipitated withdrawal signs seen in a variety of fentanyladministration protocols (Bartoletti et al, 1987;Adams and Wooten, 1994;De Kock and Meert, 1995;Thornton and Smith, 1997;Fendt and Mucha, 2001;Lohmann and Smith, 2001;Chen and Pan, 2006;Bruijnzeel et al, 2007;Liu et al, 2008;Mitzelfelt et al, 2011;Mitzelfelt et al, 2014;Gyawali et al, 2020;Uddin et al, 2021), and in other protocols used to induce physical dependence to opioids (Laska et al, 1976;Laska et al, 1977;Hutchinson et al, 2007;Lopez-Gimenez and Milligan, 2010;Morgan and Christie, 2011;Nielsen and Kreek, 2012). Moreover, the lack of behavioral responses elicited by the injection of NLX in rats that received co-injections of vehicle + vehicle, vehicle + D-CYSee or vehicle + D-CYSea suggests that the behavioral phenomena that occurred upon the injection of NLX in fentanyl-injected rats were indeed withdrawal phenomena (due to the development of physical dependence to the opioid), rather than other potential issues (e.g., multiple injection protocols) that would lead NLX to cause behavioral reactions.…”

Effects of sub-lethal doses of fentanyl on vital physiologic functions and withdrawal-like behaviors in adult goats

“…Each of these behaviors were greatest at the beginning of the observation period and waned by 3-4h, where the duration of the increases in each behavior was dose-dependent. These behaviors are similar to that observed in rodents and pigs following abstinence (Varshneya et al, 2019;Digranes et al, 2023) or naloxone-precipitated withdrawal from fentanyl (Uddin et al, 2021), suggesting that the adult goat may also be a useful model to study mechanisms or other unique aspects of withdrawal from fentanyl and its relevance to human withdrawal symptomatology.…”

Morphine-induced side effects can be differentially modulated by cannabidiol in male and female rats

“…Studies have also reported that withdrawal behavior can vary from protocols investigating precipitated or spontaneous withdrawal [59]. Evaluating animals in observation chambers, for instance, is one factor that can play a role in the differences in withdrawal behavior, as space constraint might limit the number of wet dog shakes, abdominal constrictions and writhing behavior observed during a determined time of testing [58]. In addition, jumping behavior might be impacted by the height of observation chambers, as rats in withdrawal have shown to jump less as the height of the chamber increases [60].…”

“…Precipitated withdrawal behavior can be expressed in humans and laboratory animals as affective and emotional symptoms, as well as somatic signs. A spectrum of behavior occurs in both rats and mice in a similar manner, as shown by only few studies that investigated potential differences between species[58]. Studies have also reported that withdrawal behavior can vary from protocols investigating precipitated or spontaneous withdrawal[59].…”