Brain Research, 298 (1984) 21%224 219 Elsevier Thyrotropin-Releasing Hormone (TRH) Improves Survival in Anaphylactic Shock: A Central Effect Mediated by the Sympatho-Adrenomedullaryfl-Adrenoceptive System SHIMON AMIR, MICHAL HAREL and AMIR SCHACHAR Department of lsotope Research, Weizmann Institute of Science, Rehovot (Israel) (Accepted September 6th, 1983) Key words: thyrotropin-releasing hormone - - anaphylactic shock - - sympatho-medullary system - - fl-adrenoceptive sites - - endorphins - - mice Treatment with thyrotropin-releasing hormone (TRH) significantly improved survival following induction of fatal systemic anaphyl- axis in mice. The protective effect was mediated centrally since survival was increased by intracerebroventricular (i.c.v.) administra- tion of TRH at doses which had no effect when given systemically (5-25 ktg). Acid-TRH, a deomidated metabolite of TRH which lacks hypophysiotropic influences, was as effective as TRH when administered i.c.v., but it was inactive following intravenous (i.v.) admin- istration. The protective effect of TRH in anaphylaxis was reversed by treatments which diminished sympathetic outflow to the adren- al medulla, i.e. ganglionic blockade by chlorisondamine chloride or surgical denervation of the adrenal glands. Destruction of sympa- thetic nerve endings by the catecholamine neurotoxin 6-hydroxydopamine did not alter the response to TRH. Finally, selective block- ade of fl-adrenoceptive sites by propranolol diminished the effect of TRH. Blockade of a-adrenoceptors by phentolamine or dopa- minergic receptors by domperidone did not alter the protective effect of TRH in anaphylaxis. Collectively, these results indicate that the beneficial effect of TRH in anaphylactic shock involves central nervous system actions which are mediated peripherally through in- teraction of sympatho-adrenomedullarycatecholamines with fl-adrenoceptive effectors. The possibilitythat TRH exerts its protective actions in shock by acting centrally to functionally antagonize the pathophysiologic effects of endogenous opiate peptides (endor- phins) will be discussed. INTRODUCTION Circulatory shock following endotexemia24, 25, hemorrhage a4 or spinal cord trauma 17 can be re- versed by thyrotropin-releasing hormone (TRH). The protective effect involves changes in cardiovas- cular and respiratory functions; it is mediated by cen- tral autonomic actions of TRH as well as by peripher- al influences and it appears to be independent of TRH's ability to release thyrotropin and prolactin from the pituitary gland z6. Recent studies in the unanesthesized guinea pig have shown that TRH can reverse the hypotensive effect of leukotriene D435,36, a constituent of slow-re- acting substance of anaphylaxis (SRS-A) 33, impli- cated in the mechanism of anaphylactic shock 10,34. In these experiments TRH reversal of SRS-A leuko- triene D 4 hypotension was associated with enhanced sympatho-adrenomedullary discharge 35. Moreover, TRH has been demonstrated to reverse anaphylactic shock in the guinea pig modeP 7. The present investigation evaluated the effect of TRH upon survival in a controlled model of anaphyl- actic shock in the mouse8, and examined the role of the sympatho-adrenomedullary system in the re- sponse to TRH following induction of anaphylaxis in this species. MATERIALS AND METHODS Male ICR mice (28-30 g body weight) were immu- nized intraperitoneally (i.p.) with 2 mg bovine serum albumin (BSA) in 0.2 ml aluminum hydroxide gel (prepared by mixing equal volumes of 2 N AI2 (504) 3 and 2 N NaOH and washing the collected precipitate 3 times with saline). Fatal shock was induced by chal- lenging the mice intravenously (i.v.) with 25/tg BSA in 0.2 ml saline 10 days after immunization. Correspondence: S. Amir, Department of Isotope Research, Weizmann Institute of Science, Rehovot, Israel. 0006-8993/84/$03.00 © 1984 Elsevier Science Publishers B.V.