Neurotensin analog NT77 induces regulated hypothermia in the rat

The potential use of hypothermia as a therapeutic treatment for stroke and other pathological insults has prompted the search for drugs that can lower core temperature. Ideally, a drug is needed that reduces the set-point for control of core temperature (T_c) and thereby induces a regulated reduction in T_c. To this end, a neurotensin analog (NT77) that crosses the blood brain barrier and induces hypothermia was assessed for its effects on the set-point for temperature regulation in the Sprague-Dawley rat by measuring behavioral and autonomic thermoregulatory responses. Following surgical implanation of radiotransmitters to monitor T_c, rats were placed in a temperature gradient and allowed to select from a range of ambient temperatures (T_a) while T_c was monitored by radiotelemetry. There was an abrupt decrease in selected T_a from 29 to 16°C and a concomitant reduction in T_c from 37.4 to 34. 0°C 1 hr after IP injection of 5.0 mg/kg NT77. Selected T_a and T_c then recovered to control levels by 1.5 hr and 4 hr, respectively. Oxygen consumption (M) and heat loss (H) were measured in telemetered rats housed in a direct calorimeter maintained at a T_a of 23.5°C. Injection of NT77 initially led to a reduction in M, little change in H, and marked decrease in T_c. H initially rose but decreased around the time of the maximal decrease in T_c. Overall, NT77 appears to induce a regulated hypothermic response because the decrease in T_c was preceded by a reduction in heat production, no change in heat loss, and preference for cold T_a's. Inducing a regulated hypothermic response with drugs such as NT77 may be an important therapy for ischemic disease and other insults.