Spontaneous withdrawal in intermittent morphine administration in rats and mice: effect of clonidine coadministration and sex-related differences

Abstract

Background/aim: Treating animals repeatedly with intermittent and increasing morphine doses has been suggested to allow some withdrawal during each dosing interval, which causes repeated stress. The present study aimed to test this hypothesis and assess sexrelated differences in withdrawal signs and their suppression by clonidine.Materials and methods: Male and female rats and mice were administered with increasing doses of morphine twice daily at different dosing intervals. Rats were given clonidine in drinking water (5 µg/mL). Spontaneous and naloxone-precipitated withdrawal signs and novelty-induced grooming were evaluated.Results: Male rats and male and female rats displayed manifestations of morphine withdrawal at the end of 14-h and 24-h dosing intervals, respectively. Clonidine attenuated the severity of the withdrawal signs. Male but not female mice displayed withdrawal signs at the end of 12-h and 17-h dosing intervals. Female mice exhibited less pronounced naloxone-precipitated withdrawal syndrome. Grooming did not reflect a "stress-like state" in morphine-treated animals. Conclusion:These findings indicate intermittent morphine treatment-induced spontaneous withdrawal in rats and mice and sexrelated differences in spontaneous and naloxone-precipitated withdrawal signs in mice. Since the treatment protocol closely parallels the drug use pattern in opioid addicts, further experiments are needed to clarify the stress associated with the treatment and the efficacy of sedatives.

Preliminary evidence of different and clinically meaningful opioid withdrawal phenotypes

“…These results support additional research on this topic, particularly since only a limited number of studies examining sex-based differences in opioid withdrawal exist (Papaleo and Contarino. 2006;Allahverdiyev et al 2015). The results from this study also provide support for more focused evaluation of opioid withdrawal phenotypes to tailor OUD treatment.…”

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

“…However, few studies directly compare the withdrawal nuances in different rodent species within the same report. The few studies that do use both species find mostly overlapping withdrawal signs 58 .…”

Depression of home cage wheel running is an objective measure of spontaneous morphine withdrawal in rats with and without persistent pain

“…The difference is that we studied voluntary running on a wheel as opposed to movement around the rat’s home cage. Spontaneous opioid withdrawal has also been shown to cause somatic withdrawal symptoms (Koga and Inukai, 1981; Cicero et al, 2002; Papaleo and Contarino, 2006; Allahverdiyev et al, 2015), although these tend to be mild and are not evident in all studies (Palma et al, 2015). Wheel running improves on home cage monitoring and assessment of somatic symptoms by continuously assessing withdrawal-induced decreases in voluntary behavior, a common clinical phenomenon observed in patients undergoing opioid withdrawal (Wesson and Ling, 2003).…”