Gender- and morphine dose-linked expression of spontaneous somatic opiate withdrawal in mice

The opiate withdrawal syndrome powerfully motivates opiate seeking and abuse. Development of effective medications for opiate withdrawal symptoms is thus a primary research goal and heavily relies on improved experimental models. This study was carried out to establish a clinically relevant paradigm to assess somatic opiate withdrawal in mice. Female and male C57BL/6J mice were treated with saline or increasing morphine doses (10–50 mg/kg or 20–100 mg/kg) during 6 consecutive days and tested for the spontaneous expression of somatic opiate withdrawal signs 8, 32, 56 and 80 h after last drug administration. Contrary to opioid receptor antagonist-precipitated procedures, the spontaneous opiate withdrawal paradigm used here revealed interesting gender- and morphine dose-linked differences. In particular, 56 h after last morphine administration elevated global opiate withdrawal scores were still evident in female but not in male mice treated with 20–100 mg/kg. The severity of somatic opiate withdrawal directly correlated with the prior cumulative morphine exposure. Timing of expression of somatic opiate withdrawal signs also varied as a function of both gender and morphine dose. For example, expression of paw tremors and wet dog shakes was earlier in opiate-withdrawn male than in female mice. Overall, these findings highlight the possibility to detect gender- and opiate dose-linked differences in the expression and duration of somatic opiate withdrawal using a clinically relevant research model. The behavioral paradigm described here may represent a more appropriate tool to investigate the neurobiological bases of opiate withdrawal as opposed to opioid receptor antagonist-precipitated opiate withdrawal procedures.