Acción analgésica de la T.R.H. Contribución al estudio de su mecanismo de acción.

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(1)Acción analgésica de la T.R.H. Contribución al estudio de su mecanismo de acción. Daniel Palop Palop. ADVERTIMENT. La consulta d’aquesta tesi queda condicionada a l’acceptació de les següents condicions d'ús: La difusió d’aquesta tesi per mitjà del servei TDX (www.tesisenxarxa.net) ha estat autoritzada pels titulars dels drets de propietat intel·lectual únicament per a usos privats emmarcats en activitats d’investigació i docència. No s’autoritza la seva reproducció amb finalitats de lucre ni la seva difusió i posada a disposició des d’un lloc aliè al servei TDX. No s’autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant al resum de presentació de la tesi com als seus continguts. En la utilització o cita de parts de la tesi és obligat indicar el nom de la persona autora.. ADVERTENCIA. La consulta de esta tesis queda condicionada a la aceptación de las siguientes condiciones de uso: La difusión de esta tesis por medio del servicio TDR (www.tesisenred.net) ha sido autorizada por los titulares de los derechos de propiedad intelectual únicamente para usos privados enmarcados en actividades de investigación y docencia. No se autoriza su reproducción con finalidades de lucro ni su difusión y puesta a disposición desde un sitio ajeno al servicio TDR. No se autoriza la presentación de su contenido en una ventana o marco ajeno a TDR (framing). Esta reserva de derechos afecta tanto al resumen de presentación de la tesis como a sus contenidos. En la utilización o cita de partes de la tesis es obligado indicar el nombre de la persona autora.. WARNING. On having consulted this thesis you’re accepting the following use conditions: Spreading this thesis by the TDX (www.tesisenxarxa.net) service has been authorized by the titular of the intellectual property rights only for private uses placed in investigation and teaching activities. Reproduction with lucrative aims is not authorized neither its spreading and availability from a site foreign to the TDX service. Introducing its content in a window or frame foreign to the TDX service is not authorized (framing). This rights affect to the presentation summary of the thesis as well as to its contents. In the using or citation of parts of the thesis it’s obliged to indicate the name of the author..

(2) ACCIÓN ANALGÉSICA DE LA TRH. CONTRIBUCIÓN AL ESTUDIO DE SU MECANISMO DE ACCIÓN.. Tesis que presenta D. Daniel Palop y Palop, Licenciado en Medicina y Cirugía, para optar al grado de Doctor.. Facultad de Medicina Universidad de Barcelona Junio de 1982..

(3) 177. I B L I O G R A F I A. ALAMO,. C. SERRANO, M.J., ARAGON A. y CUENCA E.. ( 1979 ). Neuromodulación aminêrgica y acción antinociceptiva de la morfina y de la T.R.H. ARCH, de Farmacol y Toxicol V,. 172 - 175. ALAMO, C. ARIAS, A. y CUENCA, E.. ( 1981 ). Intervención de mecanismos serotoninêrgicos en la actividad analgésica de la T.R.H.. Arch, de Farmacol y Toxîcol VII - 39-44.. ANDERSSON, S. CHANG, D. FOLKERS, K. y ROSSELL, S.. ( 1976 ). Inhibition of gastric secretion in dogs by neurotensin Life Sei 19, 367 - 370. ARNOLD, R y CREUTZ-FELDT W. ( 1975 ). Hemmung der pentagastrininduzierten säure Sekretion des magens beim menschendurch somatostatin. Deutsche Medizinische Wochenschrift. 100 ; 1014 - 1016. BADANY, A. A. B. ( 1982 ) Mechanisms of elevation of rat brain triptophan concentration by various doses of salicylate. BR. J. Pharmac '. 76 : 211 - 213. BARNEA, A. BEN-JOHNATHAN, N. COLSTON, C. JOHNSTON, Ü.M. y PORTER, S.C. ( 1975 ) Differential sub-cellular compartmentalization of T.R.H. and Gonadotropin releasing hormone ( L.R.H. ) in hypothalamic tissue. Proc Nat Acad Sei, U.S.A.. 72,. 3153 - 3159.

(4) 178 BASSIRI, R y UTIGER, R.D.. ( 1972 ). Serum inactivation of the immunological and biological activity of T.R.H. Endocrinology, 91. (s) 657. BARLOW, T.S., COOPER, B.R., BRÉESE, G.R. PRANGE, A.J. Jr., YLIPTON, M.A. ( 1975 ) Effects of T.R.H. on behavior : Evidence for an anorexic - like action. Neurosci. ABS, 1 : 334. BATTAINI, F. y PETERKOFSKY, A ( 1980 ) Histidyl-proline-Diketopiperazine, an endogenous brain peptide that inhibits { Na4"- K4) A T Pase Biochen. Biophys. Research Communs. 94 : 240 - 247. BAUER, K. ( 1976 ). Regulation of degradation of T.R.H. by thyroid hormones Nature, 259 : 591 - 593. BAUER, K., GARF, K.J., FAIVRE, A. - BÄUMEN, A., BEIER, S.A., TIXIER VIDAL, y KLEIN KAUF, H. { 1978 ) Inhibition of prolactin secretion zine.. by Histidyl-Proline-Diketopipera-. Nature, 274, 174. BEALE, J.S., WHITE, R.P. y SHANGPO HUANG. ( 1977. ). EEC and blood pressure effects of T.R.H. in rabbits Neuropharmacology, 16 : 499 - 506.

(5) 179. BENKERT, 0. ( 1975 ) Studies on pituitary hormones and releasing hormones in depression and sexual impotence. En Hormones, Homeostasis and the Brain, W.H. Gispen, Tj. B. Van Wimersma Greidanus, B. Bonus and de Wied (E.D.S.) pp. 25-36, Progress In Brain Research vol. 42, Elsevier, AMSTERDAM.. BENNET, G.W., EDWARDSDN, J.A., HOLLAND, D., JEFFCOATE, S.L. y WHITE, N. ( 1975 ) Release of immunoreactive luteinizing hormone-releasing hormone and T.R.H. from hypothalamic synaptosomas. Nature, 257 : 323 - 334. BEN-SRETI, M.M. y SEWELL, R.D.E.. ( 1981 ). Centrally-mediated hyperalgesia ihimice produced by the antimuscarinic agents atropine and tlyoscine. J. Pharm. Pharmacol, 33 : 390 - 391.. BERENDSEN, H. LEONARD, B.E. y RIGTER, H.. ( 1976 ). The action of psychotropic drugs on dopa induced behavioural responses in mice. Arzneimittel - Forsch. 26 : 16. BHANDARU, L. y EMERSON, OH.. ( 1980 ). Evidence for the presence of the putative T.R.H. metabolite, deamido T.R.H., in human urine. J. Clin Endocrinol. Metab 51, 410 - 412. BHARGAVA, H.N.. ( 1980 ). The effects of the T.R.H. and Histidyl-Proline Diketopiperazine on delta-9-Tetrahydrocannabinol-induced hypothermia. Life. Sei 26 : 845 - 850.

(6) 180. BHARGAVA, H.N.. ( 1981 ). Dissociation of tolerance títthe analgesic and hypothermie Effects of friorfine by using T.R.H. Life Sei. 29 : 1015 - 1020. BIGELOW, L.G., GILLIN, U.C., SEMAL, C. y WYATT, R.J. T.R.H. in chronic Lancet, ii,. ( 1975 ). schizophrenia.. 869 -870. BIGGIO, G. y GUIDOTTI, A.. ( 1979 ). Regulation of cyclic G.M.P. in cerebellum by a striatal dopaminergic maechanism. Nature, 265 : 240 - 242. BILLER, B.J., BOYO, A., MOLICTH, N.E., POST, K.D., WOLPERT, S.M. y REICHLIN, S. ( 1980 ) Galactorrea syndromes. En : The pituitary adenoma. Post, K.D., Packson, I.M.D., Reichlin, S. Eds. Plenum Press: 65 - 90. BISETTE, G. , NEMEROFF, C.B., LOOSEN, P.T., PRANGE, A.J., Jr., y LIPTON, M.A. ( 1976 a ) Comparison of the analeptic activity of T.R.H., LH RH, ACTH 4-10 and related peptides Pharmacol. Biochem. Behav ( Suppl, I ), 5 : 135 - 138. BISSETTE, G. NEMEROFF, C.B., LOOSEN, P.T., PRANGE, A.J. Jr., y LIPTON, M.A. ( 1976 b ) Hypothermia and intolerance to cold induced by intracisternal administration of the hypothalamic peptide neurotensin Nature. 262 : 607 - 609.

(7) 181. BISSETTE, G., NEMEROFF, C.B., PRANGE, A.J. Jr., LOOSEN, P.T., BRÉESE, G.R., BURNETT, G.B.y LIPTON, M.A. ( 1978 ) Modification of pentobarbital induced sedation by natural and synthetic peptides Neuropharmacology, 12 : 229 - 237. BLADE-FONT, A, ESCARTIN, P, ANGLADA, J y PALOP, D. ( 1980 ). Synthesis and analgesic activity of some analogs and derivatives of L-Histidyl-L-Prolinamide Comunicación presentada al VII International Symposium on Medicinal Chemistry. Torremolinos. Spain. 2 - 5 September.. BOLER. J., ENZMANN, F., FOLKERS, K., BOWERS, C.Y. y SCHALLY, A.V. ( 1969 ) The identity of chemical and hormonal properties of T.R.H. and Pyroglutamyl-histidyl proline-amide Biochem. Biophys. Res. Comm,. 37 : 705 - 710. BORSY, J., KIRALI, I. y BUJVSZ, S. ( 1974. ). Behavioral and antidepressant effects of T.R.H. J. Pharmacol. ( Paris ) , 5 , Suppl,. 2 : 10. BOSCHI, G., LAUNAY, N. y RIPS, R. ( 1980 ) Induction of Wet-Dog Shakes by intracerebral "Acid" T.R.H. in rats. Neuroscience Letters. 16 : 209 - 212. BOWERS, C.Y., FRIESEN, H.G., HWANG, P., GUYDA, H.J. y FOLKERS, K. ( 1971 ) Prolactin and thyrotropin release in man by synthetic T.R.H. Biochem. Biophys. Res. Commun. 45 , 1003 - 1041. BRÉESE, G. R., COTT, Ü.M., COOPER, B.R., PRANGE, A.J., Jr. y LIPTON, M.A. ( 1974 a ) Antagonism of ethanol narcosis by T.R.H. Life Sei., 14 : 1053 - 1063.

(8) 182. BRÉESE, G.R., COOPER, B.R., PRANGE, A.J., Jr., COTT, J.M. y LIPTON M.A. ( 1974 b ) Interactions of T.R.H. with centrally acting drugs. En : The Thyroid Axis, Drugs and Behavior, Prange, A.J., Jr., (Ed], 115 - 127 Raven-Press, New York.. BRÉESE, G.R., COTT, J.M., COOPER, B.R. PRANGE, A.J., Jr., LIPTON M.A. y PLOTNIKOFF, N.P. ( 1975 ) Effects of T.R.H. on the actions of pentobarbital and other centrally acting drugs J. Pharmacol. Exp. Ther., 193 : 11-22. BREWSTER, D. y WALTHAM, K. ( 1981 ) T.R.H. degradation rates vary widely between different animal species Biochem. Pharmacology, 30 : 619 - 622. BROWN, M. y VALE, W. ( 1975 a ) Growth hormone release in the rat: effects of somatostatin and T.R.F. Endrocrinology. : 97 : 1151 - 1156. BROWN, M. y VALE, W. ( 1975 b ) Central nervous system effects of hypothalamic peptides Endocrinology, 96 : 1333 - 1335. BROWN, M. RIVIER, J. y VALE, W. ( 1977 a ) Bombesin: Potent effects on Thermorégulation in the rat, Science, 196 : 998 - 1000. BROWN, M., RIVIER, J. y VALE, W. ( 1977 b ) Actions of Bombesin, T.R.H., PGE2 and Naloxone on thermorégulation in the rat. Life Sei. 20 : 1681 - 1688.

(9) is: BROWNSTEIN, M.S.., PALKQVITS, M. SAAVEDRA, J.M., BASSIRI, R.M. y UTIGER, R.D. ( 1974 ) T.R.H. in specific nuclei of rat brain Science, 185 : 267 - 269. BROWNSTEIN, M.J., UTIGER, R.D., PALKGVITS, M. y KIZER, U.S. ( 1975 ) Effects of hypothalamic deafferentation on T.R.H. levels in rat brain. Proc. Nati. Acad. Sei. U.S.A.. BURGER, M. G. y PATEL, Y=C.. 72: 4177 - 4179. ( 1977 ). T.R.H. - T.S.H. Clin. Endocrinol. Metab, 6 : 63 - 100. BURGUS, R., DUNN, T.F., DESIDERIO, D. y GUILLEMIN, R. ( 1969 ) Structure meléculaire de le facteur hypothalamique hypophysiotrope T.R.F. d'origine bovine: mise en évidence par spectromètre de masse de la séquence : PGN-HIS-PRD-NH2 C.R. Acad. Sei. ( Paris ) 269 : 1870 - 1873. BURROWS, G.E., ROBINSON, E.S. y HENDLEY, E.D. ( 1976. ). Effect of T.R.H. on Norepinephrine uptake in rat cerebral cortical homogenates Neurosci, Abst.,. 2 : 667. CAMPBELL, M. ( 1975 ) Clinical Trials of T.R.H. Psychopharmac Serv Cent Bull. 11, 19-20. CARINO, M.A., SMITH, J.R., WEICK, B.B. y HORITA, A. ( 1976 Effects of T.R.H. microinjected into various brain areas of conscious and pentobarbital-pretreated rabbits. Life. Sei., 19 : 1687 - 1692. ).

(10) 184 CARRAWAY, R.E. y LEEMAN, B.E. ( 1973 ) The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalamus. J. Biol. Chem. 248,. 6854-- 6861. CARRAWAY, R.E. y LEEMAN, S.E. ( 1976 a ) Radioimnunoassay for neurotensin, a hypothalamic peptide J. Biol. Chem. 251, 7035 - 7044. CARRAWAY, R. E. y LEEMAN, S.E. ( 1976 b ) Characterization of radioimmunoassayable neurotensin in the rat, J. Biol. Chem. 251, 7045 - 7052. CHASE, T.N., WOODS, A.C., LIPTON, M.A. y MORRIS, C.E. ( 1974 ) Hypothalamic releasing factors and Parkinson's disease Archs Neurol 31, 55-56. CHIMARA, K., KATO, y MAEDA, K., ABE, H., FURUMOTO, M. y IMURA, H. ( 1977 ) Effects of T.R.H. on sleep and sleep-related growth hormone release in normal subjects J. Clin. Endocrinol Metab. 44 : 1094 - 1100. CHILDS, G.V., COLE, D.E., KUBEK, M., TOBIN, R.B. y WILBER, J.F. ( 1978 ) Endogenous T.R.H. in the anterior pituitary: sites of activity as identified by immunocytochemical staining. J. Histochern Cytochem, 26 : 901 - 908.

(11) 185. CLARK, M.S., PARADES, A., COSTILOE, J.P. y WOOD, F. ( 1975 ) Synthetic T.R.H. administered orally to chronic schizophrenic patients Psychopharmacol commun : 1 : 191 - 200. COLLU, R., CLERMQNT, M.J., LETERTE, J., LEBOEF, G. y DUCHARNE, S.R. ( 1975 ) Inhibition of pentobarbital-induced release of growth hormone by T.R.H. Endocrine Res. Comm, 2 : 123 - 135. CONSTANTINIDIS, S., GEIS BUHLER, F., GAILLARD, Ü.M., HOVAGUIMIAN, Th y TISSOT, R. ( 1974 ) Enhancement of cerebral noradrenaline turnover by T.R.H.: Evidence by fluorescence histochemistry Experientia, 30 : 1182. COOPER, S.R., BLOOM, F.E. y ROTH, R.H., (EDS) (1978) The biochemical basis of neuropharmacology 3 d Ed. New-York : Oxford University Press. 259 -264. COTT, J.M., BRÉESE, G.R., COOPER, B.R., BARLOW, T.S. y PRANGE, A.J. Jr. ( 1.976 ) Investigations into the mechanism of reduction of ethanol sleep by T.R.H. J. Pharmacol Exp. Ther., 196 : 594 -604. COTT, J.M. y ENGEL, J. ( 1977 ) Antagonism of the analeptic activity of T.R.H. by agents wich enhance gaba transmission Psychopharmacol 52 : 145 - 149.

(12) 186. COX, B.M., OPHEIM, K., TESCHEMACHER, H. y GOLDSTEIN, A. ( 1975 ) A peptide-like substance from pituitary that acts like morphine. 2 purification and properties. Life Sei. 16. 1777 - 1782. CROWLEY, T.J. y HYDINGER, M. ( 1976 ) Mif, T.R.H. and simian social and motor behavior Pharmacol Biochem Behav ( Suppl. 5 ) 1 : 79 -88. CSEH, G., BARAT, E., PATTHY, A. y GRAFF ( 1972 ) Citado por Hughes y Cols ( 1975 ) FEBS. Lett, 21, 344 - 346. CUENCA, E., SERRANO, M.I., GIBERT-RAHOLA, J. y GALIANA, S. ( 1975 ) Enhancement of noradrenaline responses by T.R.H. J. Pharm. Pharmacol, 27 : 199 - 200. CUENCA, E. ( 1976 ) El T.R.H. en Psicofarmacología En Avances en Terapéutica 7 : 100 - 113. CUENCA, E., SERRANO, M.I., GIBERT-RAHOLA, J. CARRASCO, M.S. y ESTEBAN,S.M. ( 197B ) Estudio de la actividad analgésica de la T.R.H. y del M.I.F. Arch, de Farmacol y Toxicol, IV,. 71 - 76. DAVIS, K.L., HOLLISTER, L.E. y BERGER, P.A. ( 1.975 T.R.H. in schizophrenia AM. J. Psychiat. 132 (9) 951 - 953. ).

(13) 187. DEBEIJUK, L., REDDING, T.W., ARIMURA, A. y SCHALLY, A.V. ( 1973 ) Effect of T.R.H. and triiodothyronine on prolactine release in sheep Proc. Soc. Exp. Biol. Med. 142, 421 - 423. DELBARRE, B. , SENOIM, D. y SCHMITT, H.. ( 1.978). Further attempts to characterize the action of C.A.M.P. and T.R.H. in control blood pressure regulation. En : Molecular Biology and Pharmacology Of Ciclic Nucleotides, G, Fol co And R. Paoletti Eds. Elsevier/North Holland Biomédical Press.. DEWEY, W.L., HARRIS, L.S., HOWES, J.F. y NUITE, U.A. (1.970) The effect of various neurohumoral modulators on the activity of morphine and the narcotic antagonists in the tail flick and phenilquinone tests. J. Pharmacol. Exp. Ther: 175 : 435. DODSON, R.A. y JOHNSON, W.E. (1.979) Effects of ethanol, arecoline, atropine and nicotine, alone and in various combinations on rat cerebellar cyclic guanosine 3* - S1 monophosphate. (Meuropharmacology, 18 : 871 - 876. DÖHLER, K.D., VON-ZUR MÜHLEN, A., DÖHLER, J. y FRICKE, E. (1977) Development of the pituitary-thyroid axis in male and female rats Acta Endocrinologica 84, Suppl : 208, 2 - 3. DOLVA, L., HANSSEN, K.F. y FREY, H.M.M. (1978) Action of T.R.H. on gastrointestinal functioninman : inhibition of glucose and xylose absorption from the gut. Scand. J. Gastroenterol 13 : 599 - 604..

(14) 188. DOLVA, L.O., HANSSEN, K.F., BERSTAD, A. y FREY, H.M.. (1979). T.R.H. inhibits the pentagastrin stimulated gastric secretion in man: a dose response study. Clin-Endocrinol 10, 281 - 286. DRAYSON, A.M. (1.974) T.R.H. in cyclical psychoses Lancet, ii, 312. EDDY, N.B. y LEIMBACH, D. (1.953) Synthetic analgesics II Dithienylbutenyl and Dithienylbutylamines. J. Pharmacol. Exp. Ther. 107, 385. EMERSON, C.H., VOGEL, W. y CURRIE, B.L. (19SO) Concentrations of T.R.H. and deamido-T.R.H. and T.R.H.-deamidase activity in brain. Endocrinology : 107 : 443 - 449. ENGLER, D., SCANLON, M.F. y JACKSON, I.M.D. (1981) T.R.H. in the systemic circulation of the neonatal rats is derived from the pancreas and the extraneuronal tissues J. Clin. Invest. 67 : 800 - 80S. ENJALBERT, A., RUBERG, M., ARANCIBIA, S., PRIAM, M., BAUER, K. y KORDON, C. ( 1979 ) Inhibition of in vitro prolactin secretion by histidyl-prolinediketopiperazine, a degradation product of T.R.H. European J. Pharmacol,. 58 ,. 97-98. ESCARTIN, P., ANGLADA, J., CASALS, T., FERRER, G. y PALOP, D. (1977) Toxicidad crónica de la T.R.H.. : aspectos bioquímicos. Comunicación presentada en la III Reunión de la Asociación Española de Farmacólogos (Madrid)..

(15) 189 ESCARTIN, P., ANGLADA, J. y PALOP, D. (1979. a). Efecto de la T.R.H. administrada por via I.C.V. frente a un agente nociceptivo físico y otro químico. Comunicación presentada en la IV Reunión de la A.E.F. y 1§ Reunion Hispano - Portuguesa de Farmacología (Santiago de Compostela).. ESCARTIN, P., PALOP, D., RODRIGUEZ, L., y VALDECASAS, F.G, (1979 b) Comparación de dos métodos analgesimétricos. Influencia de la modificación del comportamiento al valorar analgésicos. Comunicación presentada en la IV Reunión de la A.E.F. y 1§ Reunión Hispano-Portuguesa de Farmacología (Santiago Compostela). FADEN, A.I. y HOLADAY, J.W. ( 1979 ) Opiate antagonists : A role in the treatment of hypovolemic shock. Science. 205,. 317 - 318.. FADEN, A.I. y HOLADAY, J.W.. ( 1980 ). Naloxone treatment of endotoxin shock : Stereospecificity of physiologic and pharmacological effects in the rat. J. Pharmacol. Exp. Ther. 212 :. FADEN, A.I., JACOBS, T.P. y HOLADAY, J.W.. ( 1981 a). Opiate antagonist improves neurologic recovery after spinal injury Science 211,. 493 - 494. FADEN, A.I., JACOBS, T.P. y HOLADAY, J.W. ( 1981 b) T.R.H. improves neurologic recovery after spinal trauma in cats N. Engl. J. Med. 305, 1063 - 1067.

(16) 190. FENNESY, M. R. y LEE, U.R. ( 1970 ) Modification of morphine analgesia by drugs affecting and tryptaminergic mechanisms. adrenergic. J. Pharm Pharmac, 22 : 930 - 935. FURLONG, F.W., BROWN, G.M. Y BEECHING, U.E. ( 1976 ) T.R.H.: Differential antidepressant and endocrinological effects. Am. J. Psychiatry : 133 : 1187 - 1190. GASCOIGNE, A.D., HIRST, B.H., REED, J.S. y SHAW, D.B. ( 1980 ) Effects of T.R.H. and methionine-enkefalin on gastric acid and pepsin secretion in the cat. Br. J. Pharmac 69, 527 - 534. GAUTWIK, K.M., TASHJIAN, A.H. Jr., KOURIDES, F.A. (1974 ) T.R.H. is not sole physyologic mediator of prolactin release during suckling N. Engl J. Med. 290 : 1162 - 1165. GOLD, P.W., GOODWIN, F.K., WEHR, T. y REBAR, R. ( 1978 ) Pituitary thyrotropin response to T.R.H. in affective illness. Relationship to spinal fluid amine metabolites. Am. J. Psychiatry, 134 : 1028 - 1031. GOUJET. M.A., SIMON, P., CHERMAT, A. y BOISSIER, U.R. (1.975). Profil de la T.R.H. en Psychopharmacologie expérimentale Psychopharmacologia: 45 : 87. GREEN, A.F. y YOUNG, P.A. (1.951) A comparison! of heat and pressure analgesiometric methods in rats. Br. J. Pharmacology, 6 : 572 - 585.

(17) 191. GREEN, A.R. y GRAHAME-SMITH, D.G. (1974) T.R.H. potentiates behavioral changes following increased brain 5-hydroxytryptamine accumulattion in rats. Nature 251. : 524 - 526. GREEN, A.R., HEAL, D.J., GRAHAME-SMITH, D.G. y KELLY, P.H. (1976) The contrasting action of T.R.H. and cycloheximide in altering the effects of centrally acting drugs: evidence for the non-involvement of dopamine sensitive adenylate cyclase. Neuropharmacology 15, 591 - 599.. GUILLEMIN, R., BURGUS, R. y VALE, W. (1974) The Hypothalamic Hypophysiotropic Thyrotropin - Releasing Factor. En: Current Studies on Thyrotropin M.S.S. Information Corporation.. : I. Ormston, B-J. - La Bella, F.S.. GUILLEMIN, R., LING, N. y BURGUS, R.. (l976). C.R. Acad. Sei. 282, 783. HALL, R. y GOMEZ PAN, A. (1976) The hipothalamic regulatory hormones and their clinical applications En advances in Clinical Chemistry, Vol. 18, 173-212. Academic Press. New—York.. HARRIS, A.C., CHRISTIANSON, D., SMITH, M.S., FANG, S.L., BRAVERMAN, L.E. y VAGENAKIS, A.G. ( 1978 ). The phisiological role of T.R.H. in the regulation of T.S.H. and prolactin secretion in the rat. J. Clin. Invest. 61 : 441 -448. HARRIS, L.S., DEWEY, W.L., HOWES, J.F., KENNEDY, J.S. y PARS, H. (1969) Narcotic-antagonist analgesics : Interactions with cholinergic J. Pharmacol. Exp. Ther. 169 : 17 - 22.. systems..

(18) 192. HENDERSHOT, L.C. y FORSAITH, J. ( 1959 ) Antagonism of the frequency of phenylbenzoquinone induced writhing in the mouse by weak analgesics and non analgesics. J. Pharm Exp. Therap. 125, 237 - 240. HERSHMAN, S.M. ( 1974 ) Clinical Application of T.R.H. N. Engl. J. Med., 290 : 886 - 890. HIÑE, B., SANGHVI, I., y GERSHON, S. ( 1973 ) Evaluation of T.R.H. as a potential antidepressant agent in the conscious dog. Life Sei., 13 : 1789 - 1797. HIRSCHMANN, R. F. (1977) Some recent developments in the synthesis of biologically-active peptides En : Matthieu J. ( Ed ) Proc. 5 T.H. Int. Symp. Med. Che. Paris July 1976. HO, IK, LU, S.E., STOLMAN, S., LOH, H.H. y WAY, L. ( 1972 ) Influence of p-Chlorophenylalanine on Morphine tolerance and physical dependence and regional brain serotonin turnover studies in Morphine tolerant-dependent mice. J. Pharmacol Exp. Ther. 182, 155 ( 1972 ). HOKFELT, T., FUXE, K., JOHANSSON, 0., JEFFCOATE, S. y WHITE, N. (1975 T.R.H. containing nerve terminals in certain brain stern nuclei and in the spinal cord. Neurosci Lett. 1 : 133 - 139. a).

(19) 1S3. HOKFELT, T., EFENDIC, S., HELLERSTROM, C., JOHANSSON, 0., LUFT, R. y ARIMURA, A. ( 1975 b } Cellular localization of somatostatin in Endocrine—Like cells and neurons of the rat with special reference to the A-pcells of the pancreatic islets and the hypothalanus Acta Endocrinológica, 80, Suppl. 200. HÓKFELT, T., LUNDBERG, Ü.M., SCHULTZBERG, M. JOHANSSON, O., LJUNGDAHL, A. y REHFELD, J. (i960) Co-existence of peptides and putative transmitters in neurons En : Neural Peptides And Neuronal Communication« Costa, E. Trabucchi, M. Eds, Raven-Press New-York, 1 - 2 3. HOLADAY, J.W. y FADEN, A.J. ( 1978. ). Naloxone reversal of endotoxin hypotension suggests role of endorphins in shock Nature 275, 450 - 451. HOLADAY, J.W., TSENG, L.F., y LOH, H.H. ( 1978 ) T.R. antagonizes beta—endorphin hypothermia and catalepsy Life Sei, 22, 1537 - 1543. HOLADAY, J. W., D'AMATO, R.J., y FADEN, A.I. ( 1981. ). T.R.H. improves cardiovascular function in experimental endotoxic and hémorragie shock Science: 213, 216 - 218. HORITA, A. y CARINO, M.A. ( 1975 ) T.R.Hinduced hyperthermia and behavioral excitation in rabbits Psychopharmacol Commun I : 403 - 414.

(20) 194. HORITA, A., CARINO, M.A. y CHESNUT, R.M. ( 1976. ). Influence of T.R.H. on drug-induced narcosis and hypothermia in rabbits Psychopharmacology ( Berlin ) 49 : 57-62. HORST, W.D. y SPIRIT, N. ( 1974 ) A possible mechanism for the antidepressant activity of T.R.H. Life. Sei., 15 : 1073 - 1082. HOWES, J.F.,HARRIS, L.S., DEWEY, W.L. y VUYDA, C.A. ( 1969) Brain acetylcholine levels and inhibition in mice J. Pharmacol. Exp. Ther., 169:. of the thail flick reflex. 23 - 28. HUEY, L.Y., JANOWSKY, D.S., MANDELA-, A.J., JUDD, I.L., y PENDERY, M. ( 1975 ) Preliminary studies on the use of T.R.H. in manic states, depression and the dysphoria of alcohol withdrawal. Psychopharmac Serv. Cent. Bull, 11 (l), 24 - 27. HUGHES, J. ( 1975 ) Isolation of an endogenous compound from the forain with pharmacological properties similar to morphine Brain Res 88 : 295 - 308. HUGHES, J.N., SMITH, T., KOSTERLITZ, H., FOTHERGILL, L., MORGAN, B. y MORRIS, H. ( 1975 ) Identificaction of two related pentapeptides from the brain with potent opiate agonist activity. Nature, 258 : 577 - 579.

(21) 195. HUIDOBRO - TORO, J.P., SCOTTI DE CAROLIS y LONGO, V.G. ( 1974 ) Action of two hypothalamic factors ( T.R.H., MIF ) and of angiotensin II on the behavioral effects of L-Dopa and 5-hydroxytryptophan in mice. Pharmacol. Biochem. Behav. 2 : 105 - 109. HUNT, W.A., REDDS, J.D., DALTON, T.K. y CATRAVAS, G.N. ( 1977 ) Alterations in brain cyclic guanosine 31 - 51 Monophosphate levels affter acute and chronic treatment with ethanol. J. Pharmacol. Exp. Ther. 201 : 103 - 109. MUTTON, S.W., PARENT, M.K., SILVIS, S.E. MORLEY, J.E. JOHNSON, G.J. ( 1981 ) T.R.H. suppressed gastric acid outpout in patients with ZollingerEllison Syndrome and systemic mastocytosis The American Journal of Medicine; 71 , 957 - 960. INANAGA, K., NAKANO, T. y NAGATO, T. ( 1975 ) Effects of T.R.H. in schizophrenia Kurume. Med. J., 22 : 159 - 168. INANAGA, K. NAKANO, T. TANAKA, M. y OGAWA, N. ( 1978 ) Behavioral effects of Protirelin in schizophrenia. Arch. Gen. Psychiatry., 35 : 1011 - 1014. IRESON, J.D. ( 1970 ) A comparison of the antinociceptive actions of cholinomimetic and morphine-like grugs Br. J. Pharmac. 40 : 92 - 101.

(22) 196. JACKSON, I.M.D. y REICHLIN, S. ( 1977 a ) Brain T.R.H. hormone is independent of the hypothalamus. Nature, 267 : 853 - 854. JACKSON, I.M.D., y REICHLIN, S. ( 1977 b ) T.R.H. : Abundance in the skin of the frog rana pipiens Science 198 : 414 - 415. JACKSON, I.M.D., ( 1979 ) The releasing factors of the hyphotalamus. En : Barrington E.J.W. (ED) Hormones and evolution, New York, Academic Press 723 - 789. JACKSON, I.M.D. y REICHLIN, S.. ( 1979. ). Distribution and biosynthesis of T.R.H. in the nervous system. En : Central noernous system effects of hyphotalamic hormones and other peptides. Collu, R., Barbeau, A., Ducharme, J.R., Rochefort, J.G. (ED) Raven Press, New York.. JACKSON., I.M.D. ( 1980 a ) T.R.H. in the rat nervous system: Identity with synthetic T.R.H. on high performance liquid chromatography following affinity chromatography Brain. Res. 201 : 245 - 248. JAKSON., I.M.D. ( 1980 b ) Diagnostic tests for the evaluation of pituitary tumors En : The Pituitary Adenoma. Post. K.D., Jackson, I.M.D., Reichlin, S. (ED) Plenum Press, New York..

(23) 197. JACKSON., I.M.D. ( 1982 ) T.R.H. N. Engl. J. Med. 306 : 145 - 155. JACOBS, L., SNYDER, P., WILBER, J., UTIGER, R. y DAUGHADAY, W. (1971) Increased serun Prolactin after administration of synthetic T.R.H. in man J. Clin. Endocrinol. Metab. 33 : 996 - 998. JOHANSSON, 0. y HOKFELT, T. ( 1980 ) T.R.H., Somatostatin and Enkephalin : Distribution studies using immunohistochemical techniques. J. Histochem. Cytochem. : 364 - 366. JONES, C.N., GRANT, L.D. y PRANGE, A.J. Jr. ( 1978 ) Stimulus properties of T.R.H. Psychopharmacology, 59 : 217 - 224. KALIVAS, P.W. y HORITA, A. ( 1980 ] T.R.H. : Neurogenesis of actions in the pentobarbital narcotized rat J. Pharmacol Exp. Ther. 212:. KATO, G., AGID, I. ( 1979. 203 - 210. ). Les récepteurs de l'acetylcholine La Nouvelle Presse Médicale, 8 : 2407 - 2411. KELLER, H.H., BARTHOLINI, C. y PLETSCHER, A. ( 1974 ) Enhacement of cerebral noradrenaline turnover by T.R.H. Nature, 248 : 528 - 529.

(24) 198. KELLOKUMPU, S., VUQLTEENAHO, O., LEPPALUOTQ, J. ( 1980 ) Behavior of rat hypothalamic and extrahypothalamic immunoreactive T.R.H. in thin-layer chromatography (TLC) and high pressure liquid chromatography (HPLC) Life Eci. 475 - 480. KING, C.D. ( 1975 ) Inhibition of slow wave sleep and rapid eye movement sleep by T.R.H. in cats Pharmacologist, 17 : 211. KIRKEGAARD, C., FABER, J., HUMMER, L., y ROGOWSKI, P. ( 1979 ) Increased levels of T.R.H. in cerebrospinal fluid from patients with endogenus depresión. Psychoneuroendocrinology, 4 : 227 - 235. KLEINBERG, D.L., NOEL, G.L., y FRANTZ, A.G. ( 1977 ) Galactorrhea : A study of 235 cases including 48 with pituitary tumors. N. Engl. J. Med. 296 : 589 - 600. KOCH y OKQN, E. ( 1979 ) Localization of releasing hormones in the human brain Int. Rev. Exp. Pathol. 19 : 45 - 62. KORANYL, L., TAMASY, V., KIRALY, I. y BORSY ( 1976. ). Effect of T.R.H. and antidepressant agents on brain stem and hypothalamic multiple unit activity in the cat Psychopharmacology, 49 : 197 - 200.

(25) 199. KOSTER, R., ANDERSON, M. y DE BEER, E.J. ( 1959 ) Acetic acid for analgesic screening Fed. Proc. 18 : 412. KOSTERLITZ, H.W., LYDON, R.J. y WATT, A.J. ( 1970 ) The effects of noradrenaline, adrenaline and isoprenaline on inhibition and beta adrenoceptors in the longitudinal muscle of the guinea pig ileum. Brit. J. Pharmacol. 39 : 398 - 413. KRAEMER, G.W., MUELLER, R., BRÉESE, G.R., PRANGE, A.J., Jr., LEWIS, U.K., MORRISON, H. y Me KINNEY, W.T. Jr. (l976) T.R.H. : Antagonism of pentobarbital narcosis in the monkey Pharmacol. Biochem. Behav. 4 : 709 - 712.. KREIDER, M.S., WINQKUR, A. y UTIGER, R.D. (1.979) T.R.H. immunoreactivity in rat hypothalamus and brain : Assessment by gel filtration and thin layer chromatography. Brain. Res. 171 : 161 - 165. KRIEGER, D.T. y CONDON, E.M. (197S) Ciproheptadine treatment of Nelson's syndrome restoration of plasma A.C.T.H. circadian periodicity and reversal of response to T.R.F. J. Clin. Endocrinol Metab. 46 : 349 - 352. KRUSE, K. (1975) T.R.H. : Interaction with chlorpromazine in mice, rats and rabbits J. Pharmacol. (Paris) 6 : 249 -268. KELLER, H.H., BARTHOLINI, G. y PLETSCHER, A. (1974) Enhancement of cerebral noradrenaline turnover by T.R.H. hormone Nature. 248 : 528 - 529.

(26) '00 LAKKE, J.P.W.F., VAN PRAAG, H.M., VANTNISK, R., DOORFNBOS y WITI, F.G.S. ( 1974 ).. H.. Effects of administration of TRH in Parkinsonism. Clin. Neurol Neurosurg 3/4; 1 - 5 .. LI, CH., BARNAFI, L., CHRETIEN, M. y CHUNG, D. ( 1965 ) Citado por Hughes y colaboradores. ( 1975 ). Nature 208 : 1093 - 1094. LINDSTROM, L.H., GUNNE, L.M., OEST, L.G. y PERSON, E. (1977) T.R.H. in chronic schizophrenia Acta Psychiat Neural Scand 55, 74 - 80. LINEE, P. y GOURET, C.. ( 1.972 ). Test des crampes abdominales provoquées chez la souris par la phenyl benzoquinone. J. Pharmacol (Paris) 3, 4,. 513 - 515. LIPTON, M.A., BISSETTE, G., NEMEROFF, C.B., LOOSEN, P.T. y FRANGE, A.J. Jr. (1976) Neurotensin : a possible mediator of thermorégulation in the mouse. En : drugs, Biogenic Aminés And Thermorégulation Edited By P. Lomax and E. Schonbaw M. pp 54-57, Karger, Basel.. LOOSEN, P.T., WILSON, I.C., LARA, P.P., FRANGE, A.J. Jr. y PETTUS, C. (1976 Treatment of depressive state in alcohol withdrawal syndromes by T.R.H. Arzeimittelforschung. 26,. 1164 - 1166.. LUTTINGER, D., WIGGINS, R., KING, R.A., NEMEROFF, C.B. y PRANGE, A.J. Jr. (1.980) Potentiation of ethanol - induced narcosis and hypotermia by neurotensin Trans. Am. Sol. Neurochem. 11 , 355..

(27) 201. MAEDA, K., KATO, Y., y OHGO, S.. (1975). Growth hormone and prolactin release after injection of T.R.H. in patients with depression. J. Clin. Endocrinol. Metab. 25 : 1539 - 1550. MAEDA, K. y FROHMAN, L=A. (l9SO) Release of somatostatin and T.R.H. from rat hypothalamic fragments invitro Endocrinology. 105 :. 1837 - 1842.. MAILMAN, R.B., FRYE, G.D., MUELLER, R.A. y BRÉESE, G.R.. (197S). T.R.H. Reversal of ethanol-induced decrease in cerebellar cGMP Nature, 272 : 832 - 833. MAILMAN, R.B., FRYE, G.D., MUELLER, R.A. y BRÉESE, G.R. (1979J Change in brain guanosine 3' - 5' monophosphate (c GMP) content by T.R.H. J. Pharmacol Exp. Ther. 208 :. 169 - 175. MALICK, J.B. (1976) Antagonism of isolation — induced aggression in mice by T.R.H. Pharmacol Biochem Behavior,. 5 : 665 — 669. MALTHE-SORENSSEN, D., NOOD, PL., CHEWEY, DL. y COSTA, E. ( 1978) Modulation of the turnover rate of acetylcholine in rat brain by intraventricular injections of T.R. H.,Somatostatin,Neurotensin and angiotensin II. J. Neurochem 31 : 685 - 691. MARTIN, B.R,, DEWEY, W.L., CHAU-PHAM, T y PRANGE, A.J., Jr (1977) Interactions of T.R.H. and morphine sulfate in rodents. Life. Sei. 20. : 715 - 722.

(28) 202. MARTINO, E., LERNMARK, A., SEO, H., STEINER, D.F. y REFETOFF, S. (197S) High concentration of T.R.H. in. Pancreatic islets. Proc. Nati. Acad. Sei. USA 75 : 4265 - 4267. MARTINO, E., SGO H., LENMARK, A. y REFETOFF, S.. ( 1980 ). Ontogenic patterns of T.R.H.-Like material in rat hypothalamus, Pancreas, and retina : Selective effect of light deprivation. Proc. Nati. Acad. Sei. USA : 77 : 4345 - 4348. MARUYAMA, I., HAYASHI, G., SMITS, S.E. y TAKEMORI, A.G. (1971) Studies on the relationship between 5-Hydroxytriptamine turnover in brain and tolerance and Physical dependence in mice. J. Pharmacol Exp. Ther. 178 : 20-28. MATSUI, T., PRASAD, C. y PETERKOFSKY, A.. ( 1979 ). Metabolism of T.R.H. in brain extracts J. Biol Chem.: 254 : 2439 - 2445.. Me. CAUL, J.A., CASSELL, K.J. y STERN, G.M. ( 1974 ) Intravenous T.R.H. in Parkinson's disease Lancet, ii,. 735. MC KELVY, S.F., SHERIDAN, M., JOSEPH, S., PHELPS, C.H. y PERRIE,S. (1975) Biosynthesis of T.R.H. in organ cultures of the guinea Pig median eminence Endocronology 97 : 908 - 918. METCALF, G.. ( 1974 ). T.R.H. : a possible mediator of thermorégulation. Nature,. 258. : 310 - 311..

(29) 203. METCALF, G. y DETTMAR, P.W. ( 1981 ) Its T.R.H. an endogenous ergotropic substance in the brain Lancet. 1:. 586 - 589. MORLEY, J.E., GARVÍN, T.J., PEKARY, A.E. y HERSHMAN, J.M. T.R.H. in the gastrointestinal. (197?). tract.. Biochem-Biophys Res. Commun. 79 : 314 - 318. MORLEY, J.E.. (1979). Extra Hipothalamic T.R.H. : ITS distribution and its functions Life Sei.. 25 :. 1539 - 1550. MORLEY, J.E., BASHORE, R.A., REED, A., CARLSON, H.E. y HERSHMAN,Ü.M. (l979a) T.R.H. and thyroid hormones in amniotic fluid AM. J. Obstetgynecol. 134 : 531 - 584. MORLEY, J.E., STEINBACH, J.H., FELDMAN, E.J. y SOLOMON,T.E. ( 1979 b) Effects of T.R.H. on the gastrointestinal tract Life Sciences. 24 :. 1059 - 1066. MORLEY, J.E., LEVINE, A. y SILVIS, S.. ( 1981 ). Endogenous opiates inhibit gastric acid secretion induced by central administration of T.R.H. Life Sciences. 29 : 293 - 297. MYERS, R.D., METCALF, G. y RICE, J.C. (1977) Identification by microinjection on T.R.H.-Sensitive Sites in the cat's brai stem that mediate respiratory, temperature and other autonomie changes. Brain Res. 126. :. 105- 115.

(30) 204 NEARY, J.T., KIEFFER, J.D., NAKAMURA, C., MOVER, H. SOODAK, M. y MALOOF, F. ( 1978 a] The development pattern of T.R.H. degrading of rats. Endocrinology, 103. :. NEARY, J.T., NAKAMURA. activity in the plasma. 1849 - 1854. C., DAVIES, I.J., SOODAK, M. y MALOOF,F. (l978b). Lower levels of T.R.H. degrading activity in human cord and in maternal sera tham in the serum of euthyroid, non pregnant adults. J. Clin. Invest. 62 : 1 - 5. NEMEROFF, C.B., PRANGE, A.J., Jr., BISSETTE, G., BRÉESE, G.R. y LIPTON, M.A. ( 1975] T.R.H. and its beta-alanine analog : Poteniation of the anticonvulsant potency of phénobarbital in mice Psychopharmacol Commun,. 1 : 305 - 317. NEMEROFF, C.B., DIEZ, J.A. BISSETTE, E.G., PRANGE, A.J. Jr., HARRELL.L.E. y LIPTON, M.A. (1977 a) Lack of affect on chronically administered T.R.H. on regional Rat brain tyrosine hydroxylase activity. Pharmacol. Biochem. Benav. 6 : 467 - 469. NEMEROFF, C.B., BISSETTE, G., PRANGE, A.J. Jr., LOOSEN, P.T. BARLOW, T.S. y LIPTON, M.A. ( 1977 b) Neurotensin: Central nervous system effects of a Hypothalamic peptide Brain. Res. 128 : 485 - 496. NEMEROFF, C.B., LOOSEN, P.T., BISSETTE,G., MANBERG, P.A. LIPTON, M.A. y PRANGE, A.J. Jr. (1978) Pharmaco-Behavioral effects of hypothalamic peptides in animals and man. Focus on T.R.H. and neurotensin Psychoneuroendocrinology,. 1 : 279 - 310.

(31) 205 NEMEROFF, C.B., BISSETTE, G., MANBERG, P.A., OSBAHR, A.J. BRÉESE, G.R. y PRANGE, A.J. Jr. (i960) Neurotensin-induced hypothermia : Evidence for an interaction with dopaminergic systems and the hypothalamic-pituitary-thyroid axis. Brain. Res. 195 : 69 -84. OGAWA, N., YAMAWAKI, Y., KURODA.H., OFUJI.T., ITOGA.E. y KITO.S. (1981) Discrete regional distributions of T.R.H. receptor binding in monkey central nervous system. Brain. Res. 205 :. 169-174. OLIVER, C., CHARVET, J.P-., CODACCIONI, J.L., VAGUE, J. y PORTER, J.C. (1974) T.R.H. in human C.S.F. Lancet 1 : 873. OSBAHR, A.J., NEMEROFF, C.B., MANBERG, P.J. y PRANGE, A.J. Jr (1979) Centrally administered neurotensin: Activity in the Julou-Courvoisier muscle relaxation test in mice Eur. J. Pharmacol. 54 : 299 - 302. OSBAHR, A.J., NEMEROFF, C.B., LUTTINGER, D., MASON, G.A. y PRANGE,A.J. Jr. (1.981) Neurotensin-Induced antinociception in mice : Antagonism by T.R.H. J. Pharmacol. Exp. Ther. 217 : 645 - 651. OTSUKI, M., DAKODA, M. y BABA, S.. (1973). Influence of glucocorticoids on T.R.H. induced T.S.H. response in man J. Clin. Endocrinol Metab.. 36. : 95 - 102.. PALOP, D., RIBES, A., ANGLADA, J. y ESCARTIN, P.. (1977). Toxicidad crónica de la T.R.H. Estudios histológicos Comunicación presentada en la III reunión de la Asociación Española de Farmacólogos (Madrid)..

(32) 206 PALOP, D., ANGLADA, J. y ESCARTIN, P.. (1.979). Estudia de la actividad analgésica de la T.R.H. y otros oligopeptidos administrados por vía intracerebroventricular. Comunicación presentada en la IV reunión Nacional de la A.E.F. y 1§ Reunión Hispano—Postuguesa de Farmacologia (Santiago de Compostela). PARKER, C.R. Jr., NEAVES. N.B., BARNEA, A. y PORTER, J.C. (197?) ri. Studies on the uptake of H T.R.H. and its metabolits by synaptosome preparations of the rat brain Endocrinology 101 : 66-75. PASTERNAK, G., GOODMAN, R. y SNYDER, S.H. (1975) Citado. por Hughes y cols. (1975). Life Sei. 16, 1765. PATÓN, W.D.M. y ZAR, M.A.. ( 1968). The origin of acetylcholine released from guinea pig intestine and longitudinal strips J. Physiol 194, 13 - 33. PEARSE, A.G.E. y TAKOR, T.. (1979). Embryology of the diffuse neuroendocrine system and its relationship to the common peptides. Fed. Proc. : 38 : 2288 - 2294. PEKARY, A.E., MEYER, V.N , VAILLANT, C y HERSHMAN, J.M. (1.980) T.R.H. and a homologous peptide in the male rat reproductive system Biochem. Biophys Res. Commun: 95. : 993 - 1000. PERT, C.B. y SNYDER, S.H. (1973) Opiate receptors : Its demonstration in nervous tissue Science 179, 1011 - 1014.

(33) 207. PETERKOFSKY, A. y BATTAINI, F. ( 1980 ) The biological activities of the neuropeptide histidyl-proline diketopiperazine Neuropeptides 1 : 105 - 118. PETERS, W.P., JOHNSON, M.W., FRIEDMAN, P.A. y MITCH, W.E. ( 1981 ) Pressor effect of naloxone in septic shock. Lancet, 1 : 529 - 532. PIVA, F. y STEINER, H. ( 1972 ) Bioassay and toxicology of T.R.H. Front. Horm. Res. 1 : 1 1 - 2 1. PLEUVRY, B.J. y TOBIAS, M.A. ( 1971 ) Comparison of the antinociceptive activities of physostigmine, Oxotremorin and Morphine in the mouse Br. J. Pharmac. 43 : 70S - 714. PLOTNIKOFF, N.P., PRANGE, A.J., Jr., BRÉESE, G.R., ANDERSON, M.A. Y WILSON, I.C. ( 1972 ) T.R.H. : Enhancement of dopa activity by a hypothalamic hormnose Science, 178 : 417 - 418. PLOTNIKOFF, N.P. y KASTIN, A.S. ( 1974 ) Pharmacological studies with a tripeptides, Prolyl - Leucyl glicine amide Archives Internationales de Pharmacodynamie etdc thérapie 211 : 211 - 224. PLOTNIKOFF, N.P., PRANGE, A.J. Jr., BRÉESE, G.R. y WILSON, J.C. ( 1974 ) T.R.H. : Enhancement of dopa activity in thyroidetomized rats Life Sei : 14 : 1271 - 1278.

(34) 208. PLOTNIKOFF, N.P., BRÉESE, G.R. y PRANGE, A.J., Jr. ( 1975 ) T.R.H. : Dopa potentiation and biogenic amine studies. Pharmacol - Biochem Bemav, 3 : 665 - 670. PORTER, C.C. LOTTI, V.J. y DEFELICE, M.J. ( 1977 ) The effect of T.R.H. and a related tripeptide, L.-N. (2-Oxopiperidin - 6 ylcarbonyl) - L-histidyl - L-thiazolidine 4-carboxamide (MK-771, ONT) on the depressant action of barbiturates and alcohol in mice and rats. Life. Sei. 21 : 811 - 820. PRANGE, A.J., WILSON, I.C., LARA, P.P.,ALLTOP, L.B. y BRÉESE, G.R. (1972) Effects of T.R.H. hormone in depresión Lancet II : 999 - 1002. PRANGE, A.J., Jr., y WILSON, I.C. ( 1972 ) T.R.H. for the immediate relief of depression a preliminary report Psychopharmacologia 26, 82. PRANGE, A.J., Jr., BRÉESE, C.R. GOTT, J.M., MARTIN, B.R. WILSON, I. y PLOTNIKOFF, N.P. ( 1974 ) T.R.H. Antagonism of pentobarbital in rodents Life Sei, 14, 447 - 455. PRANGE, A.J., Jr., BRÉESE, G.R., JAHNKE, G.D., MARTIN, B.R. COOPER,B.R., GOTT, J.M. WILSON, I.C., ALLTOP, L.B., LIPTON, M.A., BISSETTE, G., Nemeroff, C.B. y LOOSEN, P.T. ( 1975 a ) Modification of pentobarbital effects by natural and synthetic polypeptides: dissociation of brain and pituitary effects Life Sei, 16 : 1907 -. 1914..

(35) 209. PRANGE, A.J. Jr., BRÉESE, G.R., JAHNKE, G.D., COOPER, B.R. -GOTT, J.M. WILSON, I.C., LIPTON, M.A. y PLOTNIKOFF, N.P. ( 1975 b ) Parameters of alteration of pentobarbital response by hypothalamic polypeptides Neuro Psychobiology 1 : 121 - 131. PRANGE, A.J., Jr., NEMEROFF, C.B. LIPTON, M.A., BRÉESE, G.R. y WILSON, I.C. ( 1978 a ) Peptides and the central nervous system En : Handbook of pharmacology Edited by L.L. Iversen, S.D. Iversen and S.H. Snyder pp 1 - 107 Plenum Press, NEW YORK. PRANGE, A.J., Jr. NEMEROFF, C.B. y LIPTON, M.A. ( 1978 b ) Behavioral effects of peptides: basic and clinical studies En : Psychopharmacology: A Generation of Progress, Edited by M.A. Lipton, A. Dimascio y K.F. Killam, pp 441 - 448 Raven press, NEW YORK. PRANGE, A.J., Jr., NEMEROFF, C.B. y LOOSEN, P.T. ( 1978 c ) Behavioral effects of hypothalamic peptides En : Centrally acting peptides, Hughes, J. (Ed) pp 99 - 118, Ciba Symposium, LONDON. PRANGE, A.J., Jr., NEMEROFF, C.B., LOOSEN, P.T. BISSETTE, G., OSBAHR, A.J., WILSON, I.C. y LIPTON, M.A. ( 1979 ) Behavioral effects of T.R.H. in animals and man : A review En : Central Nervous System Effects of Hypothalamic Hormones and Other Peptides edited by Collu et al, Raven-Press, NEW YORK. PRASAD, C. y PETERKOFSKY, A ( 1976 ) Demostration of pyroglutamylpeptidasa and amidase activities in hamster hypothalamic extracts J. Biol Chem : 251, 3229 - 3234.

(36) 210. PRASAD, C., MATSUI, T. y PETERKOFSKY,A( 1977 ) Antagonism of sthanol narcosis by histidylproline - diketopiperazine Nature 268, 142 - 144. PRASAD, C., MATSUI, T., WILLIAMS, J.T. y PETERKOFSKY, A. ( 1978 ) Thermorégulation in rats : Opposing effects of T.R.H. hormone and its metabolite histidyl—proline—diketo piperazine Biochem Biophys Res. Commun. 85, 1582. REDDING, T.W. y SCHALLY, A.V. ( 1969 ) Studies on the inactivation of T.R.H. Proceedings of the Society for Experimental Biology and Medicine, 131 : 415 - 421. REDDS, J.D., CATRAVAS, G.N. y HUNT, W.A. ( 1976 a ) Ethanol induced depletion of cerebellar guanosine - 3' - 51 Cyclic monophosphate levels Science, 193 : 58 - 59. REDDS, J.D., HUNT, W.A. y CATRAVAS, G.N. ( 1976 b ) Lack of alteration in regional brain adenosine—31 — 5' Cyclic monophosphate levels after acute and chromic treatment with sthanol Life, Sei. 18 : 989 - 992. REICHLIN, S. SAPERSTEIN, R., JACKSON, I.M.D., BDYD, A.E. y PATEL, Y. ( 1976 ) Hypothalamic Hormones Ann. Rev. Physiol. 38 : 389 - 423.

(37) 211. REICHLIN, S., MARTIN, J.B., JAKSON, I.M.D. ( 1978 ) •* Regulation of thyroid-stimulating hormone (l.S.H.) secretion En : The Endocrine Hyphotalamus : Jeffcoate SL, Hutchinson J.M. EDS 229 - 269, Academic Press NEW YORK. REIGLE, T.J., AVNI, J., PLATZ, P.A., SCHILDKRAUT, J.J. y PLOTNIKOFF, N.P. ( 1974 ) Norepinephrine metabolism in the rat brain following acute and chronic administration of T.R.H. Psychopharmacologia, 37 : 1 - 6. RENAUD, L.P. y MARTIN, J.B. ( 1975 ) T.R.H. : Depressant action on central neuronal activity Brain. Res. 86 : 150 -154. RENAUD, L.P. MARTIN, J.B. y BRAZEAU, P. ( 1975 ) Depressant action of T.R.H., LH-RH. and somatostatin on activity of central neurones. Nature, 255 : 233 - 235. RENAUD, L.P. y MARTIN, J.B. ( 1976 ) Microiontophoresis of T.R.H.: Effects on the activity of central neurons En : Anatomical Neuroendocrinology W.E. STUMPF y L.D. Grant (EDS) S. Karger ( BASEL ). RENAUD, L.P., PITTMAN, Q.J., BLUME, H.W., LAMOUR, Y. y ARNAULD, E.(1979) Effects of peptides on central neuronal excitability En : Central Nervous System Effects of hypothalamic hormones and other peptides Collu, R., Barbeau, A., Ducharme, J.R. y Rochefort J.C. eds; 147 - 161 Raven Press. NEW YORK.

(38) RIVIER, J., VALE, W., MONAHAM, M., LING, N. y BURGUS, R. ( 1972 ) Synthetic T.R.H. analogs: Part. 3: Effect of replacement or modification of histidine residue on biologic activity J. Med. Chem. 15 : 479 - 482. RUPNOW, J.H., HINCLE, P.M. y DIXON, J.E. ( 1979 ) A Macromolecule which gives rise to T.R.H. Biochem. Biophys. Res. Commun. 89 : 721 - 728. SAWIN, C.T. y HERSHMAN, J.M. ( 1976 ) Clinical use of T.R.H. Pharmacol Ther. 1 : 351 - 366. SCANLON, M.F., WEIGHTMAN, D.R., SHALE, D.J. ( 1979 ) Dopamine is a Physiological regulator of T.S.H. secretion in normal man. Clin. Endocrinol. 10 : 7 - 15. SCHAEFFER, J.M., AXELROD, J. y BROWNSTEIN, M.J. ( 1977 ) Regional differences in Dopamine-Mediated release of T.R.H. like material from synaptosomas Brain Res. 138 : 571 - 574. SCHALCH, D.J., GONZALEZ - BARCENA, D., KASTIN, A.J..SCHALLY, A.V. y LEE, L.A. ( 1972 ) Abnormalities in the release of T.S.H. in response to T.R.H. in patients with dosorders of the pituitary, Hypothalamus and basal ganglia J. Clin. Endocrinol. Metab. 35 : 609 - 615.

(39) 213. SCHALLY, A.V., ARIMURA, A. y KASTIN, A.J. ( 1973 ) Hypothalamic regulator hormones Science. 179 : 341 - 350. SCHALLY, A.V., y ARIMURA, A. ( 1978 ) Physiology and nature of Hypothalamic regulatory hormones. En : Clinical Neuroendoc. Martini I, and Besser, G.M. (EDS) 2 - 4 Academic Press, NEW YORK. SCHENKEL - HULLIGER, L. KOGLLA, E.P., HARTMANN, A. y MAITRE, L. ( 1974 ) Tremorogenic effects of T.R.H. in rats Experientia, 30 : 1168 - 1170. SCHMIDT, D.E. ( 1977 ) Effects of T.R.H. on Pentobarbital - induced decrease in cholinergic neuronal activity. Psychopharmacol. Comm. 1 : 469 - 473. SHAMBAUGH, G. , KUBEK, M. y WILBER, J.F. ( 1979. ). T.R.H. activity in the human placenta J. Clin. Endocrinol Metab. 48 : 483 - 486. SIMON, E.J., y HILLER, J.M. ( 1978 ) The opiate receptors Annu. Rev. Pharmacol. Toxicol. 18 : 371 - 394. SIMON, P. GOUJET, M.A. y BOISSIER, J.R. ( 1975 ) T.R.H. Données depsychopharmacologie expérimentale Therapie, 30 : 485 - 497.

(40) 214. SCHMIDT, D.E. ( 1977 ) Effects of T.R.H. on pentobarbital induced decrease in cholinergic neuronal activity Communications in Psychopharmacology, I, 469 - 473. SMITH, J.R., LA HANN, T.R., CHESNUT, R.M., CARINO, M.A. y HORITA,A. ( 1976 ) T.R.H.: Stimulation of colonie activity following ventricular administration. intracerebro-. Science. 196 : 660 - 662. SNYDER, P.J. y UTIGER, R.D. ( 1972 } Response to T.R.H. in normal man J. Clin. Endocrinol. Metab. 34 : 380 - 385. SNYDER, S.H. ( 1973 ) Amphétamine phychosis : A "Model" Schizofrenia mediated by ctecholamines. AM. J. Psychiat. 130 : 61-67. SNYDER, S.H., PERT, C.B. y PASTERNAK, G.W. ( 1974 ) The opiate receptor Ann. Intern. Med. 81 : 534 - 590. SNYDER, S.H. ( 1978 ) The opiate receptor and morphine-like peptides in the brain. AM. J. Psychiatry, 135 : 645 - 652. SOWERS, J.R., HERSHMAN, J.M., SKOWSKY, W.R. y CARLSON, H.E. ( 1976 ) Effects of T.R.H. on serum arginine vasopressin in euthyroid and hypothyroid subjects Horn. Res. 7 : 232 - 237.

(41) 215. SPARKES, G.G., y SPENCER, P.S.J. ( 1971. ). Antinociceptive activity of morphine after injection of biogenic amines in the cerebral ventricles of the conscious Rat. Br. J. Pharmacol. 42 : 230 - 241. SPINDEL, E. y WURTMAN, R.J. ( 1.980. ). T.R.H. immunoreactivity in Rat brain regions, spinal cord and pancreas: Validation by high-pressure liquid chromatography and thin-layer chromatography Brain. Res. 201 : 279 - 288. STEINER, F.A. ( 1972. ). Effects of locally applied hormones and neurotransmiters on hypothalamic neurons. Proc. Fourth Int. Cong. Endocrinology, WASHINGTON, June, 202 - 204 Excerpta Medica. Amsterdam.. STEINER, F.A. ( 1975. ). Electrophysiological mapping of brain sites sensitive to coticosteroids, ACTH and hyphotalamic releasing hormones En : Anatomical Neuroendocrinology pp. 270 - 275 S. Karger BASEL. STILLE, G. ( 1953. : W.E. Stumpf y L.D. Grant /EDS). ). Die bedeutung zentrallerregewder krampfes. wurkunen fur die hemming des electro-. Naunyn Schmiedebergs Arch. Pharmacol, 217 : 57. STOLK, J.M. y NISULA, B.C. ( 1975 ) Interaction of the tripeptide pyroglutamylhistidyl-proline amide (T.R.H.) with brain norepinephrine metabolism: Evidence for an extrahypophyseal action of T.R.H. on central nervous system function. En : Hormones, Homeostasis and the Brain. W.H. Gispen, Tj. B. Van Wimersma Greidanus, B. Bolus y D. de Wied (t_DS) pp. 47 - 56 Prog. Brain Res. 42, Elsevier AMSTERDAM.

(42) 216. STUBBE, P., GATZ, J., HEIDEMANN, P., VON ZUR MÜHLEN, A. y HESCH, R.D. ( 1978 ) T.B.G., T3, Î4 and Thyrotrophin in Newborn Infants and children Hormone and Metabolic Research, 10 : 58-61. SUGRUE, M. F. ( 1979 ) On the role of 5-HT in drug induced antinociception BR. J. Pharmac. 65 : 677 - 681. SWINYARD, E.A. ( 1972 ) Electrically induced convulsions En : Experimental Models of Epilepsy, Edited by D.M. Purpura, J.K., Penry, D.B. Tower, D.M. Woodburg and R.D. Walter pp. 434 - 458 Raven-Press. NEW YORK. TABER, R.I. y LATRANYJ M.B.(l.98l) Antagonism of the analgesic effect of opioid and non-opioid agents by p-chorophenylalamine Eur. J. Pharmacol 75, 215 - 222. TACHE, Y., DU RUISSEAU, P., DUCHARME, U.R. y COLLU, R. ( 1977 ) Antagonism of pentobarbital—induced hormonal changes by T.R.H. in rats Eur. J. Pharmacol 45 : 369 - 376. TACHE, Y., VALE, V. y BROWN, M. ( 1980 ) T.R.H.-C.N.S. action to stimulate gastric acid secretion Nature, 287 : 149 - 151. TAGAKI, H., TAKASHIMA, T. y KIMURA, K. ( 1964 ) Antagonism of the analgesic effect of morphine in mice by tetrabenazine and reserpine Arch. Int. Pharmacodyn 149, 3-4, 484 - 492.

(43) 217 •TAKEMORI, A.E., TULUNAY, F.C. y YANO, I. ( 1975 ) Differential effects on morphine analgesia and naloxone antagonism by biogenic aminé modifiers Life Sei, 17 : 21 - 28. TANJASIRI, P., KOZBUR, X., y FLORSHEIM, W.H. ( 1976 ) Somastotatin in the physiologic feedback control of TSH Life Sei, 19 : 657 - 660. TASHJIAN, A.M., Jr., BAROWSKY, N.J. y JENSEN, O.K. ( 1971 ). T.R.H.: Direct evidence for stimulation of prolactin production by pituitary cells in culture. Biochem. Biophys. Research Communs 43 : 516 - 523. TAYLOR, W. L. y DIXON, J.E. ( 1978 ). Characterization of a pyroglutamate aminopeptidase from rat serum that degrades T.R.H. The Journal of Biological Chemistry 253,. 6934 - 6940. TERENIUS, L. y WALHSTROM, A. ( 1975 ) Citado por Hughes y cols 1.975 Acta Physiol Scand 94, 74 - 81. TERENIUS, L. ( 1978 ) Endogenous Peptides and analgesia Ann Rev Pharmacol. Toxicol 18, 189 - 204 TESCHEMACHER, H., OPHEIM, K.E., COX, B.M. y GOLDSTEIN, A. ( 1975 ) A peptide-like substance from pituitary that acts like morphine I Isolation Life Sei. 16, 1771 - 1776.

(44) 218 TIENGO, M. ( 1980 ) Nalaxone in Irreversible shock Lancet 2 : 690. TYERS, N.B. ( 1980 ). A classification of opiate receptors that mediate antinociception in animals Br. J. Pharmac, 69, 503 - 512. TIWÂRY, C.M., ROSEMBLOOM, A.L., ROBERTSON, M.F. y PARKER, U.C. (1975) Effects of T.R.H. in minimal brain dysfunction . Pediatrics, 56, 119 - 121. TSANG, D. y MARTIN, J.B. ( 1976 ) Effect of hypothalamic hormones on the concentration of adenosine 3', 5' - Monophosphate in incubated pineal glands Life Sei, 19, 911 - 918. TULUNAY, F.C., SPARSER, S.B. y TAKEMORI, A.E. ( 1975 ) ,. The effect of dopaminergic stimulation and blockade on the nociceptive and antinociceptive responses of mice. Eur. J. Pharmacol, 33, 65 - 70. .TULUNAY, F.C. YANO, I. y TAKEMORI, A.E. ( 1976 ). The effect of biogenic amine mdifiers on morphine analgesia and its anatagonism by naloxone Eur. J. Pharmacol 35, 285 - 292 TYNDEL, M. ( 1974 ). Psychiatric study of 1000 alcoholis patients Can. Psychiat Ass. J. 19, 21-24.

(45) 219. USHIJIMA, Y., YAMADA, K., MODA, Y. y FURUKAWA, T. ( 1982 ). Jumping tehavior induced by T.R.H. in ôombination iwl apomorphine in mice Psychopharmacology, 76 : 1 - 4. VALE, W., GRANT, G. y GUILLEMIN, R. ( 1973 ) Chemistry of the hypothalamic releasing factors 'studies in structure sunction relationhips En : Frontiers in Neuroendocrinology (Ganong, Wf, y Martini, L, EDS.) pp : 375 - 413., OXFORD UNIVERSITY PRESS, NEW YORK. VALE, W., RIVIER, C. y BROWN, M. ( 1977 ) Regulatory Peptides of the Hypothalamus Ann. Rev. Physiol. 39, 473 - 527. VIJAYAN, E. y MC CANN, S.M. ( 1977 ) Suppression of feeding and 'drinking activity in rats following intraventricular fnyection of T.R.H. Endo, 100 : 1727 - 1730. „... VOGEL, R.A., PAPPAS, B.A., WILSON, J. , FRYE, G.D., MUELLER, R.A. '•I and BRÉESE, G.R. ( 1978 a ) Anti-conflict properties of T.R.H. alone orin combination with ethanol or"chlordiazepoxide Neurosci. A.B.S., 4 : 504. VOGEL, R.A., COOPER, B.R., BARLOW, T.S., PRANGE, A.J., Jr., MUELLER, R.A. and BRÉESE, G.R. ( 1978 b ) Effects of T.R.H. on locomotor activity, operant performance and in— gestive behavior J. Pharmacol. Exp. Ther., 208 : 161 - 168.

(46) 220. WAHREN y FELIG ( 1976 ) Influence of somastotatin oncarbohydrate disposal and absorption in diabetes mellitus Lancet 2 : 1213 - 1216. WARBERG, J., ESKAY, R.L., BARNEA, A., REYNOLDS, R.C. y PORTER, J.C. ( 1977 ). Release of luteinizing hormone releasing hormone and T.R.H. from a synaptosome-enriched fraction of hypothalamic homogenates Endocrinology, 100 : 814 - 825. WEI, E., SIGEL.-S., LOM, H. y WAY, E.L. ( 1975 ) T.R.H. and shaking behavior in rat Nature, 253 : 739 - 740. WEI, E., LOH, H.'y WAY, E.L. (1976 ) Potency of the N3 im- Methyl analog of T.R.H. in the reduction of shaking movements in the rat Eur. J. Pharmacol. 36 : 227 - 229. WEINGOLD, H.P., LACHIN, I.M. y BELL, A.H. ( 1968 ) Depression as a sympton of alcoholism J. Abnorm. Psychol. 72 : 195 - 197 •. WHITE, R.P. y BEALE, U.S. ( 1975 ) Electroenphalographic (EEG) Effects of T.R.H. on rabbits Neurosci. ABST. 1 : 727 WHITE, N., JEFFCOATE, S.L., GRIFFITHS, E.G. y HOOPER, K.C. ( 1976 ) Effect of thyroid status on the T.R.H. degrading activity of rat serum. Journal of Endocrinology, 71 : 13 - 19.

(47) 221. WHITE, N., GRIFFITHS, E.G., JEFFCOATE, S.L., MILNER, R.D.G. y PREECE, M.A. ( 1.980 ) Age related changes in the degradation of T.R.H. by human and rat serum. J. Endocr. 86 : 397 - 402. WILSON, I.C., PRANGE, A.J., Jr., LARA, P.P., ALLTOP, L.B., STIKELEATHER, R.A. y LIPTON, M.A. ( 1973 ) T.R.H. (Lopremone): Psychobiological responses of normal women: (l) subjetive experience Archs. Gen. Psychiat. 29 : 15 - 32. WINOKUR, A. y UTIGER, R.D. ( 1974 ) T.R.H. : Regional distribution in rat brain Science, 185 : 205 - 266. WINOKUR, A., DAVIS, R. y UTIGER, R.D. ( 1977 ) Subcellular distribution of T.R.H. in rat brain and Hypothalamus Brain Res. 120 : 423 - 434. WINOKUR,'A. y BECKMAN, A. ( 1978 ) Effects of T.R.H., Norepinephrine and acetylcholine on the activity of neurons in the hypothalamus, septum and cerebral cortex of the rat Brain - Res : 150 : 205 - 209. WINTERS, A.J., ESKAY, R.L. y PORTER, J.C. ( 1974 ) Concentration and distribution of T.R.H. and LRH in the human fetal brain J. Clin Endocrinol Metab 39 : 960 - 963.

(48) 222. WIRZ-JUSTICE, A. y LICHTSTEINER, M ( 1975 ) Plasma Free Tryptophan, MAO activity and noradrenaline uptake in brain after T.R.H. Experientia, 31, 725. YANAGISAWA, T., PRASAD, C. WILIAMS, S. y PETERKOFSKY, A. ( 1979 ). Antagonism of ethanol-induced decrease in rat brain GGMP concentration by histidyl-proline-diketopiperazine, a T.R.H. metabolite Biochem Biophys Research Communs, 86 : 1146 - 1153. YANAGISAWA, T., PRASAD, C y PETERKOFSKY, A. ( 1980 ). The subcellular and organ distribution and natural form of histidylproline-diketopiperazine in rat brain determined by a specific radioimmunossay J. Biol. Chetn : 255 : 10.290. YARBROUGH, G.G. ( 1978. ). Studies on the neuropharmacology of T.R.H. hormone and a new T.R.H. analog. EUR. J. Pharmacol 48 : 19 - 27. YARBROUGH, G.G. y LOTTI ( 1978. }. Interactions of T.R.H. and MK-771 With Central Noradrenergic mechanisms. Pharmacologist 20 : 207. YARBROUGH, G.G., y SINGH, O.K. ( 1978. ). Intravenous T.R.H. enhances the excitatory actions of acethylcholine on rat cortical neurons Experientia, 34 , 390.

(49) 223. YARBROUGH, G.G. ( 1979 ) On the neuropharmacology of T.R.H. hormone Prog. Neuro Biol. 12 : 291 - 312. YASHON, D. ( 1978 ) Spinal Injury New York : Appleton - Century - Crofts : 248 - 254. YOUNGBLOOD, W.W., LIPTON, M.A. y KIZER, U.S. ( 1978 ). T.R.H. - like immunoreactive in urine, serum and extrahypothalamic brain: non identity with synthetic pyr-glu-his~pro-NH2 (T.R.H.) Brain-Res. 151 : 99 - 115.

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