xestospongin-a and Pain

1 Agonistic neurosteroids, including pregnenolone, dehydroepiandrosterone and its sulfate (DHEAS), caused rapid degranulation in measurements of beta-hexosaminidase (beta-HEX) release from a mast cell line, RBL-2H3. This degranulation was blocked by BSA-conjugated progesterone (PROG-BSA) or 17beta-estradiol, both of which are antagonistic neurosteroids. 2 DHEAS-induced beta-HEX release was blocked by U-73122 or xestospongin C, but not by PTX or EGTA. DHEAS-induced beta-HEX release was also abolished by G(q/11)-AS, but not by G(q/11)-MS. Pharmacological analyses revealed that the neurosteroids stimulated a putative membrane receptor through activation of the novel G(q/11) and phospholipase C. 3 While representative endocrine-disrupting chemicals (EDCs) did not show any degranulation or nocifensive actions by themselves, they blocked the DHEAS-induced degranulation. 4 The binding of a PROG-BSA-fluorescein isothiocyanate conjugate (PROG-BSA-FITC) to cells was inhibited by neurosteroids and EDCs. 5 In the algogenic-induced biting and licking responses test, DHEAS caused agonistic nocifensive actions in a dose-dependent manner between 1 and 10 fmol (i.pl.). DHEAS-induced nocifensive actions were abolished by PROG-BSA or nonylphenol. 6 Taken together, these results suggest that a G(q/11)-coupled neurosteroid receptor may regulate the neuroimmunological activity related to sensory stimulation and that some EDCs have antagonistic actions for this receptor.

Topics: Animals; Behavior, Animal; beta-N-Acetylhexosaminidases; Binding, Competitive; Cattle; Cell Line, Tumor; Cell Membrane; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Dose-Response Relationship, Drug; Estradiol; Estrenes; Fluorescein-5-isothiocyanate; GTP-Binding Protein alpha Subunits, Gi-Go; Leukemia, Basophilic, Acute; Macrocyclic Compounds; Male; Mast Cells; Mice; Nociceptors; Oligonucleotides, Antisense; Oxazoles; Pain; Pertussis Toxin; Phenols; Phosphodiesterase Inhibitors; Pregnenolone; Pyrrolidinones; Receptors, Steroid; Serum Albumin, Bovine; Type C Phospholipases