Thyrotropin releasing hormone: antagonism of pentobarbital narcosis in the monkey

doi:10.1016/0091-3057(76)90224-0

Pharmacology Biochemistry and Behavior

Volume 4, Issue 6, June 1976, Pages 709-712

https://doi.org/10.1016/0091-3057(76)90224-0 Get rights and content

Abstract

The effect of TRH on pentobarbital narcosis in 12 rhesus monkeys was examined. Vital signs monitored included respiration rate, heart rate, temperature, sleeping time, and time of reappearance of certain reflexes. Blood samples were obtained for pentobarbital assay. Two dose schedules for TRH administration were used. One group of 6 animals received a single dose of 20 mg/kg 30 min after barbiturate administration, while the other group received 3 injections of 20 mg/kg spaced at 30, 40 and 50 min after injection of pentobarbital. Both groups were sex balanced. TRH administration resulted in dramatically increased respiration and heart rates and arrested the progress of barbiturate induced hypothermia. The extended dose schedule prolonged increased respiration rate and a differential effect of TRH on pentobarbital induced hypothermia across sexes was observed. All animals regained reflexes sooner and sleeping time was reduced by 22%. No differences in pentobarbital blood levels with TRH were observed. These results extend earlier work in rodents to primates and suggest a possible use of TRH in cases of acute barbiturate intoxication.

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Cited by (44)

Neuropharmacodynamic evaluation of the centrally active thyrotropin-releasing hormone analogue [Leu<sup>2</sup>]TRH and its chemical brain-targeting system
2002, Brain Research
Citation Excerpt :
TRH also has been shown to exert a variety of extrahypothalamic effects in animals. The best-documented effect of this neuropeptide is its analeptic action [3,11,12,16,22] mediated by a cholinergic mechanism [14], and a robust effect of TRH on the stimulation of acetylcholine (ACh) synthesis [23] and, therefore, the subsequent increase of the ACh level [9] has also been shown. Cholinergic dysfunction is intimately associated with numerous CNS maladies such as Alzheimer’s disease (AD) [6,33].
The centrally active thyrotropin-releasing hormone (TRH) analogue pGlu–Leu–Pro–NH₂ ([Leu²]TRH) showed a significant increase in the extracellular acetylcholine concentration during its perfusion to the hippocampus in rats, and this effect was manifested upon the delivery of the analogue in much smaller quantities compared to TRH when measured by in vivo intracranial microdialysis. The neuropharmacodynamic efficacy of [Leu²]TRH upon intravenous administration was augmented by the use of a brain-targeting derivative in which the progenitor sequence of the mature peptide was embedded in a molecular architecture that promoted enhanced brain delivery, retention and in situ generation of the pharmacologically active molecule. Compared to the unmodified peptide, the targeting system significantly improved the cumulative effect of the treatment on extracellular acetylcholine levels in rats.
Chemosensitivity of serotonergic neurons in the rostral ventral medulla
2001, Respiration Physiology
The medullary raphé contains two subtypes of chemosensitive neuron: one that is stimulated by acidosis and another that is inhibited. Both types of neuron are putative chemoreceptors, proposed to act in opposite ways to modulate respiratory output and other pH sensitive brain functions. In this review, we will discuss the cellular properties of these chemosensitive raphé neurons when studied in vitro using brain slices and primary dissociated cell culture. Quantification of chemosensitivity of raphé neurons indicates that they are highly sensitive to small changes in extracellular pH (pH_o) between 7.2 and 7.6. Stimulation by acidosis occurs only in the specific phenotypic subset of neurons within the raphé that are serotonergic. These serotonergic neurons also have other properties consistent with a specialized role in chemoreception. Homologous serotonergic neurons are present within the ventrolateral medulla (VLM), and may have contributed to localization of respiratory chemoreception to that region. Chemosensitivity of raphé neurons increases in the postnatal period in rats, in parallel with development of respiratory chemoreception in vivo. An abnormality of serotonergic neurons of the ventral medulla has been identified in victims of sudden infant death syndrome (SIDS). The cellular properties of serotonergic raphé neurons suggest that they play a role in the CNS response to hypercapnia, and that they may contribute to interactions between the sleep/wake cycle and respiratory control.
Synthesis and behavioral evaluation of a chemical brain-targeting system for a thyrotropin-releasing hormone analogue
1998, European Journal of Medicinal Chemistry
A chemical brain-targeting system, in which a redox 1,4-dihydropyridine < = > pyridinium function serves as a targeting moiety and a cholesteryl ester contributes to the improved penetration across the blood-brain barrier, was synthesized for a centrally active TRH analogue, pGlu-Leu-Pro-NH₂. Our retrometabolic design was also based on the progenitor sequence, Glu-Leu-Pro-Gly, where the C-terminal glycine (Gly) functions as an amide precursor via peptidyl glycine α-amidating monooxygenase (PAM) and glutamine (Gln) is the precursor of the N-terminal pyroglutamyl (pGlu) by glutaminyl cyclase. The molecular design included an endopeptidase (post-proline cleaving enzyme) cleavable spacer function. Treatment with the chemical targeting system significantly improved memory-related behavior, without altering thyroid function, in a passive avoidance paradigm in rats bearing bilateral fimbrial lesions.
An update on the CNS actions of TRH and its analogs
1998, Life Sciences
This brief review will discuss the recent literature on several of the central actions of TRH and its analogs. The most prominent of these actions include: (1) the arousal or analeptic effect in drug narcotized animals or in concussion models; (2) the reversal of cognitive deficits produced by various drugs or procedures, and (3) the improvement of several neurological deficits produced in animal models of spinal and/or cerebellar injury. The mediation of these TRH effects by neurotransmitters is discussed. While little has been published on the human neuropsychopharmacology of TRH, and especially of its analogs, the future holds considerable therapeutic promise for these interesting drugs.
The effect of TRH on ethanol-induced sedation in alcohol-preferring and -nonpreferring rats
1993, Neuropeptides
TRH antagonism of ethanol sedation was evaluated in selectively-bred alcohol-preferring (P) and -nonpreferring (NP) rats. Intracerebroventricular (i.c.v.) infusions of TRH significantly reduced sleep time in the NP rats. In the P rats, TRH tended to reduce sleep, but this reduction was not significant. TRH had no significant effect on peripheral blood alcohol concentrations. The present results show that NP rats are more sensitive to the analeptic effect of TRH compared to P rats. These data support and extend those of others who have demonstrated a TRH antagonism on drug-induced sedation. Differential sensitivity to TRH may reflect differences in TRH receptor activity and/or TRH metabolism. Sensitivity to TRH analepsis may be associated with sensitivity to ethanol.
Distribution of thyrotropin-releasing hormone binding sites: autoradiographic study in infant and adult human hippocampal formation
1993, Brain Research
The rostrocaudal distribution of thyrotropin-releasing hormone (TRH) binding sites was studied in the human hippocampus. Cryostat sections of the right and left hippocampi from 6 infants (2 h to 5 months age) and 11 adults (24 to 92 years) were subjected to in vitro quantitative autoradiography using [³H]MeTRH as a ligand. A single class of high affinity [³H]MeTRH binding sites with an apparent dissociation constant in the nanomolar range has been shown both in the infant and the adult. The maximal number of these sites was higher in the infant. No significant difference was observed between the general patterns of the right and the left hippocampi when taking postmortem delay and age as parameters. The highest concentrations of [³H]MeTRH binding sites were localized in the uncinate gyrus, the uncal subiculum and in the whole length of the molecular layer of the dentate gyrus. The lowest densities were present in the ventral subiculum. The major difference observed between the infant and the adult appeared in the molecular layer of the dentate gyrus where the densities were two-fold higher in infants (189±6versus88±2fmol/mg of tissue). The only marked difference in the distribution was localized in the caudal part of the body where no specific labeling was found in the presubiculum of the infant.

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Thyrotropin releasing hormone: antagonism of pentobarbital narcosis in the monkey

Abstract

Life Sci.

Clin. Chim. Acta

Life Sci.

Interactions of thyrotropin releasing hormone with centrally acting drugs

Effects of thyrotropin releasing hormone (TRH) on the actions of pentobarbital and other centrally acting drugs

J. Pharmac. exp. Ther.