Intravenous and intratracheal thyrotropin releasing hormone and its analog taltirelin reverse opioid-induced respiratory depression

[helvella]

All too often we ignore TRH ( thyrotropin releasing hormone) - despite its fundamental role in telling the pituitary to produce TSH. It is left out of so many discussions.

This paper is now suggesting that TRH could have a role as a medicine in its own right!

If the concepts make sense, perhaps these other effects of TRH are rather more important than has been considered so far. Could elevated TRH be one of the factors which cause raised blood pressure in some with hypothyroidism?

Of course, until measuring TRH is a serious option, and at low cost, we are unlikely to see any progress.

One of the obvious questions is whether TRH used in the way described then affects TSH production and, in turn, thyroid hormone levels?

J Pharmacol Exp Ther. 2018 Apr 19. pii: jpet.118.248377. doi: 10.1124/jpet.118.248377. [Epub ahead of print]

Intravenous and intratracheal thyrotropin releasing hormone and its analog taltirelin reverse opioid-induced respiratory depression in isoflurane anesthetized rats.

Boghosian JD1, Luethy A1, Cotten JF2.

Author information

1 Massachusetts General Hospital.

2 Massachusetts General Hospital [e-mail].

Abstract

Thyrotropin releasing hormone (TRH) is a tripeptide hormone and a neurotransmitter widely-expressed in the CNS that regulates thyroid function and that maintains physiologic homeostasis. Following injection in rodents, TRH has multiple effects including increased blood pressure and breathing. We tested the hypothesis that TRH and its long-acting analog, taltirelin, will reverse morphine-induced respiratory depression in anesthetized rats following intravenous(IV) or intratracheal(IT) administration. TRH (1 mg/kg plus 5 mg/kg/hour IV) and talitrelin (1 mg/kg IV), when administered to rats pretreated with morphine (5 mg/kg IV), increased ventilation from 50±6 to 131±7% and 45±6 to 168±13% (percent baseline; n=4±SEM), primarily through increased breathing rates (from 76+/-9 to 260±14% and 66±8 to 318±37%). By arterial blood gas analysis, morphine caused a hypoxemic respiratory acidosis with decreased oxygen and increased carbon dioxide pressures. TRH decreased morphine effects on arterial carbon dioxide pressure, but failed to impact oxygenation; taltirelin reversed morphine effects on both arterial carbon dioxide and oxygen. Both TRH and talirelin increased mean arterial blood pressure in morphine-treated rats (from 68±5 to 126±12% and 64±7 to 116±8%, respectively; n=3 to 4). TRH, when initiated prior to morphine (15 mg/kg IV), prevented morphine-induced changes in ventilation; and TRH (2 mg/kg IV) rescued all four rats treated with a lethal dose of morphine (5 mg/kg/min until apnea). Similar to IV administration, both TRH (5 mg/kg IT) and taltirelin (2 mg/kg IT) reversed morphine effects on ventilation. TRH or taltirelin may have clinical utility as IV or inhaled agents to antagonize opioid-induced cardiorespiratory depression.

KEYWORDS:

anesthesia; anesthetics; drug development; g protein-coupled receptors (GPCRS); neuroendocrine system; neuropeptides; opioids; peptide hormones; respiratory pharmacology; thyrotropin/TRH

PMID: 29674333

DOI: 10.1124/jpet.118.248377

ncbi.nlm.nih.gov/pubmed/296...

[silverfox7]

My late husband got his PhD in 1972 on TRH. Apart from drawing many of the graphs I haven't a clue about what it was about but the fact he was able to get his quantification shows it was probably an area of little knowledge and seemingly it still is. Things scientifically move very slowly and buzz words moved onto neuropeptides and neurotransmitters but I wish I could undrrstand it. He did want us to go to Hull through to buy our next car as the reg at the time was TRH!

If he was still with us I'm sure he would have had a lot to comment on and I wish I had made the effort to understand it more.

[helvella Administrator in reply to silverfox7]

Thank you - it does look like there is movement on the TRH front. Quite few recent papers at least mention TRH!

Did you get your car from Hull?

[silverfox7 in reply to helvella]

No told him not to be silly. But feel a bit guilty now as I do have a personal plate but money was tight then plus I didn't think the TRH would be guaranteed.

[TSH110 in reply to silverfox7]

My brothers maths teacher bagged LCM1 as his number plate he knew the guy who has something to do with numberplate issue in Liverpool and was able to get it!

[crimple]

Interesting paper Helvella. Pity it's not easy to measure TRH. As you say it coul lea to so much more being learned about TSH.