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 (10-50mg/kg or 20-100mg/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 20-100mg/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 For example, expression of paw tremors and wet dog shakes was earlier in opiate-withdrawn male than in female mice.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.
Dipartimento di Farmacologia e Anestesiologia, Largo Meneghetti 2, 35131 Padova, Italy.
Francesco
F
Papaleo
Angelo
A
Contarino
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000008:administration & dosage / Q000633:toxicity*; D009021:Morphine Dependence / Q000503:physiopathology*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D051381:Rats; D012737:Sex Factors; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*
D009020:Morphine