Effects of endocrine disrupter chemicals on a novel G-protein-coupled neurosteroid receptor

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The intraplantar injection of dehydroepiandrosterone sulfate (DHEAS), a representative neurosteroid, showed hyperalgesia in the Hargreaves' thermal or automatic paw-pressure mechanical nociception test. The Diphenhydramine (DPH), an H_1 histamine (His) receptor antagonist, blocked the hyperalgesia induced by DHEAS as well as the hyperalgesia induced by His or compound 48/80, a mast cell degranulating agent. The DHEAS-induced hyperalgesia was also blocked by progesterone (PROG), another type of neurosteroid and a putative neurosteroid receptor antagonist. Neither DPH nor PROG showed any changes in the thermal threshold. In the algogenics-induced nociceptive flexor responses test in mice, the flexor responses induced by intraplantar injection of DHEAS were blocked by p,p'-DDE, an endocrine disrupting chemical (EDC) as well as by PROG. P,p'-DDE also blocked the DHEAS-induced hyperalgesia in Hargreaves' thermal nociception test. Besides the hyperalgesic actions, DHEAS increased vascular pe … More rmeability as measured with Evans blue plasma extravasation. Consistent with behavioral studies, it was blocked by DPH, PROG and p,p'-DDE. These results suggest that DHEAS has significant hyperalgesic and vasodilatory actions through His release, and these actions were reversible by PROG and an EDC, p,p'-DDE. Moreover, we demonstrated the presence and characterization of a novel neurosteroid receptor underlying such rapid algogenic actions. In the measurements of β-hexosaminidase release from a mast cell line, RBL-2H3, some agonistic neurosteroids, including DHEAS caused rapid degranulation, and it was blocked by PROG. Pharmacological analyses revealed that the stimulation of putative membrane receptor leads to activation of novel G_<q/11> and phospholipase C, which is followed by [Ca^<2+>]_i increase. We further found that many representative EDCs showed antagonistic actions for DHEAS-induced [Ca^<2+>]_i increase, degranulation and nociception. All these results suggest that the G_<q/11>-coupled neurosteroid receptor may regulate the neuroimmunological activity related to sensory stimulation, and EDCs may exert neuronal actions through a disturbance of this mechanism. Less