Activation of Neurokinin 3 Receptors in the Median Preoptic Nucleus Decreases Core Temperature in the Rat

Estrogens have pronounced effects on thermoregulation, as illustrated by the occurrence of hot flushes secondary to estrogen withdrawal in menopausal women. Because neurokinin B (NKB) gene expression is markedly increased in the infundibular (arcuate) nucleus of postmenopausal women, and is modulated by estrogen withdrawal and replacement in multiple species, we have hypothesized that NKB neurons could play a role in the generation of flushes. There is no information, however, on whether the primary NKB receptor neurokinin 3 receptor (NK(3)R) modulates body temperature in any species. Here, we determine the effects of microinfusion of a selective NK(3)R agonist (senktide) into the rat median preoptic nucleus (MnPO), an important site in the heat-defense pathway. Senktide microinfusion into the rat MnPO decreased core temperature in a dose-dependent manner. The hypothermia induced by senktide was similar in ovariectomized rats with and without 17β-estradiol replacement. The hypothermic effect of senktide was prolonged in rats exposed to an ambient temperature of 29.0 C, compared with 21.5 C. Senktide microinfusion also altered tail skin vasomotion in rats exposed to an ambient temperature of 29.0 but not 21.5 C. Comparisons of the effects of senktide at different ambient temperatures indicated that the hypothermia was not secondary to thermoregulatory failure or a reduction in cold-induced thermogenesis. Other than a very mild increase in drinking, senktide microinfusion did not affect behavior. Terminal fluorescent dextran microinfusion showed targeting of the MnPO and adjacent septum, and immunohistochemical studies revealed that senktide induced a marked increase in Fos-activation in the MnPO. Because MnPO neurons expressed NK(3)R-immunoreactivity, the induction of MnPO Fos by senktide is likely a direct effect. By demonstrating that NK(3)R activation in the MnPO modulates body temperature, these studies support the hypothesis that hypothalamic NKB neurons could be involved in the generation of menopausal flushes.