Stimulant effect of thyrotropin-releasing hormone and its analog, RGH 2202, on the diaphragm respiratory activity, and their antagonism with morphine: possible involvement of the N-methyl-D-aspartate receptors

Харкевич, Д. А.; Chizh, Boris A.; Kasparov, Sergey

doi:10.1016/0006-8993(91)90920-q

Cited by 19 publications

(9 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…85,86 Although in the rabbit single bolus infusions of thyrotropin-releasing hormone were unable to reverse morphine-induced respiratory depression, 85 studies in the vagotomized artificially ventilated rat showed that thyrotropin-releasing hormone and its analog RGH 22012 effectively antagonized morphine-induced respiratory depression as measured by diaphragmatic activity, possibly through an action at N-methyl-D-aspartate acid receptors. 87 Additionally, a more recent study showed that thyrotropin-releasing hormone antagonized morphine respiratory depression in an in vitro brainstem-spinal cord preparation from 1-to 4-day-old rats. 88…”

Section: Thyrotropin-releasing Hormonementioning

confidence: 99%

Averting Opioid-induced Respiratory Depression without Affecting Analgesia

et al. 2018

View full text Add to dashboard Cite

The ventilatory control system is highly vulnerable to exogenous administered opioid analgesics. Particularly respiratory depression is a potentially lethal complication that may occur when opioids are overdosed or consumed in combination with other depressants such as sleep medication or alcohol. Fatalities occur in acute and chronic pain patients on opioid therapy and individuals that abuse prescription or illicit opioids for their hedonistic pleasure. One important strategy to mitigate opioid-induced respiratory depression is cotreatment with nonopioid respiratory stimulants. Effective stimulants prevent respiratory depression without affecting the analgesic opioid response. Several pharmaceutical classes of nonopioid respiratory stimulants are currently under investigation. The majority acts at sites within the brainstem respiratory network including drugs that act at α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (ampakines), 5-hydroxytryptamine receptor agonists, phospodiesterase-4 inhibitors, D1-dopamine receptor agonists, the endogenous peptide glycyl-glutamine, and thyrotropin-releasing hormone. Others act peripherally at potassium channels expressed on oxygen-sensing cells of the carotid bodies, such as doxapram and GAL021 (Galleon Pharmaceuticals Corp., USA). In this review we critically appraise the efficacy of these agents. We conclude that none of the experimental drugs are adequate for therapeutic use in opioid-induced respiratory depression and all need further study of efficacy and toxicity. All discussed drugs, however, do highlight potential mechanisms of action and possible templates for further study and development.

show abstract

Section: Thyrotropin-releasing Hormonementioning

confidence: 99%

Averting Opioid-induced Respiratory Depression without Affecting Analgesia

et al. 2018

View full text Add to dashboard Cite

show abstract

“…In particular, TRH has been shown to improve the recovery following spinal cord injury (19). Importantly, TRH has also been involved in the modulation of spinal cord pain transmission (12,33) and has been shown to act as an antinociceptive agent more potent than morphine when injected centrally (11). The regional distribution of the rTRHR2 message in the spinal cord and in the thalamus points to a potential role for rTRHR2 in the modulation of pain perception.…”

Section: Rtrhr2: a Novel Trh Receptor Not Expressed In The Pituitarymentioning

confidence: 99%

Cloning and Characterization of a cDNA Encoding a Novel Subtype of Rat Thyrotropin-releasing Hormone Receptor

Cao

O’Donnell

et al. 1998

Journal of Biological Chemistry

130

View full text Add to dashboard Cite

The thyrotropin-releasing hormone (TRH) 1 is a tripeptide (pyroglutamic acid-histidine-proline-amide) synthesized from a precursor polypeptide whose sequence contains 5 copies of the TRH sequence (5-7).Originally isolated from the hypothalamus, TRH is present in the central nervous system (thalamus, cerebral cortex, and spinal cord,) as well as in the periphery (pancreas, gastrointestinal tracts, and placenta). In the hypothalamus, TRH is synthesized by peptidergic neurons of supraoptic and paraventricular nuclei. It is then axonally transported to be stored in the median eminence. When secreted in the bloodstream, it reaches the pituitary where it stimulates the production of thyroid stimulating hormone which in turn stimulates the production of thyroxin (T 4 ) in the thyroid gland (8).In addition to this pivotal role in controlling the synthesis and secretion of thyroid stimulating hormone and other hormones from the anterior pituitary, TRH has been implicated as a neurotransmitter (9). TRH abundantly exists in the central nervous system and exogenous administration of TRH elicits a variety of behavioral changes (see Ref. 10 for a review).The distribution of TRH containing cells, fibers, or receptors suggests a potential role of TRH in the perception of noxious stimuli. TRH is present in the periaqueductal gray, the nuclei raphe magnus and pallidus, and the dorsal horn of the spinal cord. TRH-binding sites have been described in the brain, the pituitary, in both the dorsal and ventral horns of the spinal cord as well as in peripheral tissues. When injected centrally, TRH induces a short lasting supraspinal antinociception. The analgesia induced by intracerebroventricular TRH injection is powerful since it is twice as great, on a molar basis, as that of morphine (11). This TRH-induced antinociception is detected in models of chemically and mechanically, but not thermally induced pain. On the other hand, intrathecal TRH injections do not affect basal antinociceptive thresholds (11). However, it is known that TRH enhances spinal reflexes (both in vivo and in vitro) and modulates pain transmission (4,12,13). Although the mode of action of TRH at the level of the spinal cord is unclear, there is evidence suggesting that the TRH-induced facilitation of spinal transmission involves the activation of the N-methyl-D-asparatate receptor (14).TRH actions are mediated by the stimulation of specific cell surface receptors. Studies of pituitary TRH receptors have suggested that the TRHR1 receptor triggers the phospholipase C-protein kinase C transduction pathway (3,15). A cDNA sequence encoding a G-protein-coupled TRHR was originally isolated from mouse pituitary using an expression cloning strategy (15). Subsequently, several groups have described the cloning of rat TRH receptor cDNAs expressed in a pituitary tumor cell line (GH 3 ) or in the pituitary gland (1, 3). In addition, two isoforms of the rat TRHR have been shown to be generated from a single gene by alternative splicing (2). These isoforms are 387 and 412 amin...

show abstract

“…An agent that prevents or reverses OIRD while preserving analgesia would have significant clinical utility. Interestingly, the breathing effects of TRH and its stable analog posatirelin (RGH 2202), after central or peripheral administration, abolish morphine-induced respiratory depression as quantified by integrated diaphragmatic electromyographic activity in mechanically ventilated rats (Kharkevich et al, 1991). Similarly, TRH reversed morphine-induced respiratory depression in an in vitro rat pup brainstem/spinal cord model (Takita et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Intravenous and Intratracheal Thyrotropin Releasing Hormone and Its Analog Taltirelin Reverse Opioid-Induced Respiratory Depression in Isoflurane Anesthetized Rats

Boghosian

Luethy

Cotten

2018

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Thyrotropin releasing hormone (TRH) is a tripeptide hormone and a neurotransmitter widely expressed in the central nervous system that regulates thyroid function and 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 or intratracheal (IT) administration. TRH (1 mg/kg plus 5 mg/kg/h, i.v.) and talitrelin (1 mg/kg, i.v.), when administered to rats pretreated with morphine (5 mg/kg, i.v.), increased ventilation from 50% ± 6% to 131% ± 7% and 45% ± 6% to 168% ± 13%, respectively (percent baseline; = 4 ± S.E.M.), primarily through increased breathing rates (from 76% ± 9% to 260% ± 14% and 66% ± 8% to 318% ± 37%, respectively). 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; = 3 to 4). TRH, when initiated prior to morphine (15 mg/kg, i.v.), prevented morphine-induced changes in ventilation; and TRH (2 mg/kg, i.v.) rescued all four rats treated with a lethal dose of morphine (5 mg/kg/min, until apnea). Similar to intravenous 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 an intravenous or inhaled agent to antagonize opioid-induced cardiorespiratory depression.

show abstract

Stimulant effect of thyrotropin-releasing hormone and its analog, RGH 2202, on the diaphragm respiratory activity, and their antagonism with morphine: possible involvement of the N-methyl-D-aspartate receptors

Cited by 19 publications

References 17 publications

Averting Opioid-induced Respiratory Depression without Affecting Analgesia

Averting Opioid-induced Respiratory Depression without Affecting Analgesia

Cloning and Characterization of a cDNA Encoding a Novel Subtype of Rat Thyrotropin-releasing Hormone Receptor

Intravenous and Intratracheal Thyrotropin Releasing Hormone and Its Analog Taltirelin Reverse Opioid-Induced Respiratory Depression in Isoflurane Anesthetized Rats

Contact Info

Product

Resources

About