Barbiturate physical dependence and thermoregulatory dysfunction in mice

Body temperature, as monitored by radio telemetry, was observed in C57BL/6J males during six days of chronic phenobarbital (PB) intoxication and subsequent withdrawal, at an ambient temperature of 21-22°C. Control animals, not exposed to PB, were also monitored. Marked hypothermia was seen initially, followed by gradual functional tolerance development. Upon withdrawal, marked hypothermia was again seen, reaching a maximum at a time when the milder symptoms of withdrawal (tremor, convulsions on handling, Straub tail) were at their maximum frequency. The more severe and later-developing symptoms (seizures) occurred when hypothermia was much less. In a second experiment, PB-dependent mice exposed to 34°C during withdrawal, which completely prevented hypothermia, exhibited markedly reduced withdrawal symptomatology compared to mice at 22°C, but only with respect to the milder symptoms. These results suggest that the milder symptoms of PB withdrawal may be adaptive in that they may generate body heat (thermogenesis) to partially offset withdrawal hypothermia. Thus, the withdrawal-induced hypothermia may causally contribute to some aspects of the withdrawal syndrome.