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2001年薬理学会抄録 英文

Endocrine disruptors suppress peripheral nociception through metabotropic neurosteroid receptors

Akira Yoshida and Hiroshi Ueda

Endocrine disruptors disturb endocrine system by affecting steroid hormone receptor actions. Neurosteroids which are steroid hormones generated in nervous system influence various neuronal events through cell surface metabotropic sigma receptors. Here we characterized the effects of endocrine disruptors on the neurosteroid-induced actions through G protein coupled receptors. We observed that dehydroepiandrosterone sulfate (DHEAS), a neurosteroid stimulated G protein derived from Gi1 in reconstitution experiments, and the stimulation was blocked by progesterone, another neurosteroid and NE-100, a sigma receptor antagonist. In the peripheral nociception test in mice, intraplantar injection of DHEAS in low doses caused pertussis toxin (PTX)-insensitive and diphenhydramine, histamine antagonist-sensitive flexor responses, indicating the nociception caused by histamine released from peripheral mast cells. The neurosteroid-induced responses were completely blocked by endocrine disruptors such as methoxychlor and 4,4ユ-DDE. On the other hand, DHEAS in high doses in the presence of diphenhydramine for blockade of the histamine action still showed PTX-sensitive nociception which was also partially blocked by methoxychlor. These findings suggest that there exist two types of novel neurosteroid receptors sensitive to endocrine disruptors, neuronal NS1/sigma type which mediates activation of Gi1, and NS2 type which mediates histamine release.