Heat stroke: opioid-mediated mechanisms.

In our previous study in guinea pigs, intensive and prolonged intraperitoneal heating (IPH) caused heat stroke characterized by high mortality and accompanied by two paradoxical phenomena: ear skin vasoconstriction at a high body temperature (Tb) (hyperthermia-induced vasoconstriction) and a post-IPH Tb fall at an ambient temperature (Ta) below thermoneutrality (hyperthermia-induced hypothermia). In this study, we tested the hypothesis that the mechanisms of the two phenomena involve endogenous opioid agonists. Experiments were conducted in 24 unanesthetized, lightly restrained guinea pigs, each chronically implanted with an intraperitoneal thermode and intrahypothalamic thermocouple. The thermoregulatory effects of a wide-spectrum opioid-receptor antagonist, naltrexone (NTX; 50 or 0 mumol/kg sc), were studied in IPH-induced heat stroke and under normal conditions. IPH was accomplished by perfusing (50 ml/min; 80 min) water (45 degrees C) through the thermode. Ta was maintained at approximately 24 degrees C. Skin vasodilation occurred at the onset of IPH but later changed to vasoconstriction despite high Tb and continuing IPH. IPH-induced hyperthermia (1.8 +/- 0.1 degrees C) was followed by a post-IPH Tb fall (-5.1 +/- 0.7 degree C; calculated for the survivors only). The 48-h mortality rate was 50%. NTX prevented the hyperthermia-induced vasoconstriction and attenuated the hyperthermia-induced hypothermia (-1.8 +/- 0.4 degree C). None of the NTX-treated animals died. The effects of NTX on Tb regulation under normal conditions were minor. These results indicate that the phenomena of both hyperthermia-induced vasoconstriction and hyperthermia-induced hypothermia are opioid dependent. The latter is speculated to reflect opioid-mediated inhibition of metabolism; the former is thought to result from opioid-induced hemodynamic alterations. Because both phenomena did not occur in the NTX-treated survivors, the skin vasoconstriction at high Tb and the posthyperthermia Tb fall may be viewed as markers of the severity of heat stroke. It is suggested that opioid antagonists may have therapeutic potential in heat-induced disorders.