Abstract
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; n = 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; n = 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.
Introduction
Thyrotropin releasing hormone [(TRH); Protirelin] is a processed, carboxyamidated tripeptide (L-pyro-glutamyl-L-histidyl-L-prolinamide) originally isolated from the hypothalamus, where it regulates pituitary release of thyroid-stimulating hormone and prolactin. However, TRH is expressed widely in the central nervous system and may provide neurostimulatory, regulatory, and trophic effects. In rodents, TRH mediates physiologic effects through two homologous G-protein-coupled receptors, TRH1 and TRH2; however, only a single human TRH receptor has been identified (Straub et al., 1990; Matre et al., 1993). Other additional receptors may exist that remain to be identified (Hinkle et al., 2002; Hogan et al., 2008; Kelly et al., 2015).
TRH is also a Food and Drug Administration–approved drug with numerous nonendocrine effects upon exogenous administration (e.g., increases in locomotor activity, body temperature/oxygen consumption, heart rate/blood pressure, breathing, anorexia, and neural regeneration). TRH has been studied as a therapy for multiple human conditions including neurodegenerative diseases such amyotrophic lateral sclerosis and spinal cord injury as well as epilepsy, depressed mood, fatigue, and shock (Khomane et al., 2011). However, TRH development as a therapeutic is limited by its poor and inconsistent bioavailability, and for most applications its neuroendocrine effects are undesired. TRH is unstable in blood with a half-life of 5 minutes or less. Due to its instability and high aqueous solubility (cLogP −2.8), only a small fraction of TRH administered intravenously/systemically crosses the blood-brain barrier, and its oral bioavailabilty is poor (Khomane et al., 2011). Although most studies administer TRH by direct injection (e.g., by intracerebroventricular, intravenous, subcutaneous, or intraperitoneal routes), interestingly, TRH may have bioavailability when administered by nasal or intratracheal routes as well (Morimoto et al., 1994, 2000; Kubek et al., 2009; Lehrer, 2014).
To address the therapeutic limitations of TRH, many analogs have been developed with improved bioavailability/stability and diminished neuroendocrine effects (e.g., azetirelin, montirelin, posatirelin, and taltirelin), and analogs that inhibit endogenous TRH degradation have also been identified (Khomane et al., 2011). Taltirelin, which is the only TRH analog approved as a human therapeutic, is administered orally to treat spinal cerebellar degeneration patients in Japan. Taltirelin, relative to TRH, has 5- to 10-fold less neuroendocrine effects (i.e., TSH and prolactin release), and as a neurostimulant is 10- to 100-fold more potent with a duration of action 8-fold longer (Kinoshita et al., 1998).
TRH and its analogs activate breathing in a number of species including humans and nonhuman primates (Kraemer et al., 1976; Nink et al., 1991). Breathing effects are likely central in origin, since small TRH doses injected into cerebral ventricles or near the respiratory rhythm-generating pre-Bötzinger complex provoke tachypnea (Hedner et al., 1983; Inyushkin et al., 1999). Additionally, TRH directly activates medullary chemosensing, nucleus tractus solitarius, and hypoglossal motor neurons, and taltirelin restores central carbon dioxide chemosensing in Brown Norway rats (Dekin et al., 1985; Bayliss et al., 1992; Mulkey et al., 2007; Puissant et al., 2015).
Opioids are an important class of drugs for treating acute pain. However, they are highly addictive and notorious in causing sometimes lethal opioid-induced respiratory depression (OIRD). 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). Of note, TRH does not impair opioid analgesia and does not modify the opioid interaction with its receptor (Bhargava et al., 1983). In fact, TRH and taltirelin may both possess antinociceptive properties (Kawamura et al., 1985; Reny-Palasse et al., 1989; Tanabe et al., 2007).
In this study, we tested the hypothesis that intravenously administered TRH or its analog talitrelin would stimulate breathing in intact, anesthetized, spontaneously breathing rats and reverse or prevent OIRD, even at otherwise lethal doses. Moreover, we also tested the hypothesis that TRH and taltirelin administered intratracheally would be effective as breathing stimulants.
Materials and Methods
Animal Studies.
Studies were approved by the Massachusetts General Hospital Institutional Animal Care and Use Committee. Male Sprague-Dawley rats with weights ranging from 324 to 604 g were used. The rats were obtained from Charles River Laboratories (Wilmington, MA) and were housed in the Massachusetts General Hospital Center for Comparative Medicine Animal Facility.
All studies were performed on rats orotracheally intubated with a 14G Braun angiocatheter and spontaneously breathing 1.5% isoflurane in air. Following anesthesia induction in a Plexiglas chamber with 3%–5% isoflurane, rats were quickly intubated by direct visualization using an illuminated, fiber-optic wire, and correct placement was confirmed by exhaled carbon dioxide (Capstar-100 CO2 analyzer; CWE Inc., Ardmore, PA). A variable bypass vaporizer was used for isoflurane administration and airflow (1 l/min) through the vaporizer, and as provided to the rat, was regulated using a mass flow controller valve (Model GE50A; MKS Instruments Inc., Andover, MA). Inspired and expired gas compositions were monitored using a Capnomac Ultima medical gas analyzer (GE Healthcare, Buckinghamshire, United Kingdom) and the Capstar-100 CO2 analyzer (CWE Inc.) via side stream sampling ports. A custom-built, automated heat lamp and rectal thermistor were used to maintain anesthetized rats at a body temperature of 37°C in all studies.
Intravenous TRH, taltirelin, and morphine (each diluted into a 0.5-ml volume of saline) were administered through a 24G lateral tail vein catheter and flushed in with 0.5 ml saline. Intratracheal TRH (5 mg/kg) and taltirelin (2 mg/kg) were diluted in a 100-μl final volume of sterile normal saline, drawn into a 10-cm length of PE50 tubing connected to a 1 ml syringe via 23G hypodermic needle. After insertion into the trachea through the bore of the 14G orotracheal angiocatheter, the entire contents of the PE50 tubing and syringe were briskly expelled into the trachea during inhalation. TRH (diluted to 10 mg/ml in saline) or high-dose morphine (15 mg/ml in normal saline) was administered by continuous infusion with a saline vehicle carrier using a syringe pump (Model 200; KD Scientific, Holliston, MA).
LabView 2013 software (National Instruments, Austin, TX) run on an Apple computer interfaced with three USB-6009 data acquisition boards (National Instruments) was used for all data acquisition (128 Hz sampling rate), signal analysis (in 4-second time epochs), and gas flow control.
Breathing Studies.
Rodent breathing (rate, tidal volume, and minute ventilation) was quantified using a heated pneumotachometer (Model 8420; Hans Rudolph Inc., Shawnee, KS) in combination with a differential pressure transducer and a demodulator (Models CD15 and MP45-14-871; Validyne Engineering, Northridge, CA) and a Capstar-100 CO2 analyzer (CWE Inc.). The stable airflow from the mass flow controller was directed through the vaporizer and via tubing into the pneumotachometer. The intubated rat breathed air/gas from a side port created by a Luer T-shaped coupling piece of the main gas flow tubing (Supplemental Fig. 1). Oscillations in the primary air/gas flow stream and in the exhaled CO2 signal imparted by rat inhalation and exhalation were used to quantify breathing frequency and minute ventilation. Minute ventilation was quantified by numerically integrating the flow signal after digital subtraction of the baseline 1 l/min gas flow (Supplemental Fig. 1). The system was calibrated before each rat study with a rodent ventilator (Model 683; Harvard Apparatus, Holliston, MA) providing a known minute ventilation (150 ml/min). Tidal volume within each 4-second time epoch was calculated by dividing the measured minute ventilation by the frequency.
Blood Pressure and Blood Gas Analysis.
After endotracheal intubation and prior to study, rats were instrumented with a femoral artery catheter while spontaneously breathing ∼2% isoflurane in air. The rat femoral artery was cannulated with a 24G Braun angiocatheter under direct visualization through a stereo microscope and following surgical exposure. Arterial blood pressure was quantified using a pressure transducer (TruWave; Edwards Life Sciences, Irvine, CA) interfaced with a custom-built amplifier (AD620 Operational Amplifier; Jameco Electronics, Belmont, CA). An arterial blood sample (approximately 0.3 ml, heparinized at ∼3 U/ml after withdrawal) was drawn after at least 15 minutes of stable breathing and equilibration with inhaled isoflurane 1.5%, and 15 and 30 minutes after first administration of TRH, taltirelin, or morphine. A Vetscan iStat 1 (Abaxis, Union City, CA) blood gas analyzer was used for blood gas analysis with CG4+ cartridges (Abbott Laboratories, Princeton, NJ). Rats instrumented with a femoral artery catheter were euthanized upon completion of the study.
Drugs.
TRH was purchased from Sigma-Aldrich (St. Louis, MO) and taltirelin was purchased from Tocris Bioscience (Minneapolis, MN). Both were solubilized in sterile, normal saline prior to administration. Isoflurane was purchased from Patterson Veterinary (Greeley, CO) and morphine was purchased from McKesson Medical-Surgical (San Francisco, CA).
Statistical Analysis.
Data are reported as mean ± S.E.M. Statistical analysis was done using Prism 7.0c for Mac OS X software (GraphPad Software, Inc., La Jolla, CA). Unless indicated, comparisons were performed using Student’s t test or one-way analysis of variance followed by Dunnett’s or Sidak’s multiple comparisons post-test; a P-value of less than 0.05 indicates statistical significance.
Results
To determine a relevant TRH dose needed to impact breathing in our rat model, we conducted a TRH dose-breathing response study in orotracheally intubated, anesthetized, spontaneously breathing rats. Intravenous bolus TRH (from 0.5 to 2 mg/kg) caused transient stimulation in minute ventilation (Fig. 1) through effects on both tidal volume and breathing rate (Supplemental Fig. 2).
TRH’s effect on morphine-induced respiratory depression was next tested by administering TRH to rats pretreated with morphine (5 mg/kg, i.v., over 5 minutes; Fig. 2). Rats in these studies were instrumented with a femoral artery catheter for hemodynamic and arterial blood gas monitoring. The dose of morphine that was chosen, as known from prior experience, is nonlethal in anesthetized rats spontaneously breathing air and provides an approximately 50% decrease in ventilation. Minute ventilation was 46% ± 3% of baseline in morphine-treated rats due to decreases in both breathing rate and tidal volume, 68% ± 4% and 69% ± 4% of baseline, respectively (Fig. 2A; n = 5 ± S.E.M.), with effects lasting over 40 minutes. Due to its transient effects (Fig. 1), TRH was administered to morphine-treated rats by intravenous bolus (1 mg/kg) followed by continuous intravenous infusion (5 mg/kg/h), which by itself in the absence of morphine (Fig. 2B) caused a sustained increase in minute ventilation and respiratory rate for at least 40 minutes. Marked changes in respiratory rate were observed in morphine-treated rats upon TRH administration (Fig. 2C), which reversed and even overcorrected minute ventilation. The combination of morphine and TRH caused a rapid, shallow breathing pattern with a rapid breathing rate and small tidal volumes.
Arterial blood gas results were consistent with the breathing data (Fig. 3). TRH by itself caused mild respiratory alkalosis. However, morphine by itself caused respiratory acidosis and hypoxia by increasing PaCO2 and decreasing PaO2 levels, respectively. TRH treatment lessened the respiratory acidosis of morphine at 15 minutes only, but had no effect on oxygenation. Results similar to those of breathing were also observed in rat hemodynamics (Supplemental Fig. 3; Fig. 3). By itself, TRH caused an increase in mean arterial blood pressure (23 ± 3 mm Hg maximal change; Supplemental Fig. 3A), but TRH induced a greater change in the presence of morphine (+53 ± 7 mm Hg; Supplemental Fig. 3C; P < 0.01 by Student’s t test).
We next examined the effects of taltirelin, a long-acting TRH analog, on rat breathing and observed results similar to those of TRH. By itself (Fig. 4A), taltirelin (1 mg/kg, i.v. bolus) caused a modest increase in minute ventilation and breathing rate. However, in morphine-treated animals taltirelin caused a marked increase in breathing rate and minute ventilation (Fig. 4B), with an onset slower than TRH. In arterial blood gas results, taltirelin prevented morphine-induced hypercarbia and hypoxia but induced mild metabolic, lactate acidosis that increased with time (Fig. 3, A and D). Like TRH, taltirelin increased mean arterial blood pressure (Supplemental Fig. 3D; +54 ± 7 mm Hg); we did not study hemodynamics in rats treated with taltirelin only.
We also studied the efficacy of TRH in preventing, rather than reversing, morphine-induced depression of breathing. Initiating TRH administration just prior to morphine prevented morphine-induced (15 mg/kg, i.v., over 15 minutes; note, the dose 3-fold higher than used in earlier studies) inhibitory effects on minute ventilation [Supplemental Fig. 4; P = 0.7 for the baseline breathing data point just prior to morphine (108% ± 7%) relative to that upon completion of morphine dose (102% ± 12%)]. Tachypnea and diminished tidal volume were induced by morphine administered to TRH pretreated rats (Supplemental Fig. 4). Upon discontinuation of the TRH infusion, its breathing effects faded and morphine-induced respiratory depression emerged (Supplemental Fig. 4).
To test the limits of TRH efficacy as a reversal agent for OIRD, we next employed a clearly lethal dose of morphine. Four rats were administered morphine at a high dose and a rapid rate (5 mg/kg/min until 16 seconds of apnea were observed; on average 21 ± 5 mg/kg in less than 5 minutes) followed by TRH (2 mg/kg, i.v. bolus). After 30 minutes, intravenous naloxone, a morphine antagonist (Fig. 5) was given. TRH restored ventilation in all four rats. The three control animals that received intravenous saline in lieu of TRH all died following high-dose morphine administration (data not shown). Since we did not use hemodynamic monitoring in these studies, and since we did not wish to disturb the animals by palpation, the exact time of death (i.e., cardiac arrest) for control animals following induction of apnea was not determined.
Finally, we tested the hypothesis that intratracheal TRH will have bioavailability sufficient to reverse morphine-induced respiratory depression. To test this hypothesis, TRH was administered by bolus into the trachea (5 mg/kg dissolved in 100 μl of saline; also, see Materials and Methods) of morphine-treated rats and was determined effective and similar to intravenous TRH in reversing morphine-induced respiratory depression for at least 40 minutes (Fig. 6). Similar results were observed with taltirelin (2 mg/kg, intracheally; n = 4; data not shown). Intratracheal saline (100 μl bolus) by itself did not stimulate breathing in morphine-treated (5 mg/kg, i.v.), anesthetized rats (n = 3; data not shown); one of the saline-treated rats died approximately 15 minutes after saline administration.
Discussion
In this paper, we report studies that address the breathing and hemodynamic effects of intravenous and intratracheal TRH and its analog, taltirelin, in intubated, spontaneously breathing rats before and after intravenous morphine administration. Both TRH and taltirelin reversed morphine-induced respiratory and hemodynamic depression. Importantly, TRH was also effective in reversing otherwise lethal levels of OIRD and preventing OIRD, and both TRH and taltirelin were effective when administered intratracheally.
There are limitations to our study that should be considered when interpreting our results. All studies were done in anesthetized rats, which itself enhances the breathings effects of TRH and increases the respiratory depressant effects of morphine (Schaefer et al., 1989). We also used only single doses of TRH or taltirelin with morphine. Additionally, rats are intolerant of hypoxia while under anesthesia, which causes hypotension and would affect the lethality of morphine (Hou et al., 2005). Future studies will be required to sort out the effects of anesthetics and to optimize dosing for both TRH and taltirelin. Taltirelin did cause an increase in plasma lactate levels in arterial blood gas analysis, which is also concerning. However, taltirelin and TRH both cause an increase in oxygen consumption and prevent the hypothermia associated with anesthesia and opioids (Bhargava et al., 1983; Sharp et al., 1984; Schuhler et al., 2007; Puissant et al., 2015). We speculate that an increase in oxygen demand (from metabolic effects and/or the increased work of breathing), combined with the hypotension and the hypoxia present upon taltirelin administration, may have yielded inadequate blood perfusion and oxygen delivery to tissues. Administration of taltirelin at a lower dose prior to morphine administration, and/or in the absence of anesthetic, may minimize lactate production.
The combination of TRH and morphine (Figs. 2 and 5; Supplemental Fig. 4) or taltirelin and morphine (Fig. 4) caused a rapid, shallow breathing pattern. One reason for this pattern may be the restrictive effects of opioid-induced skeletal muscle rigidity on pulmonary compliance with increased work of breathing (Weinger et al., 1989). Regardless, this mode of ventilation is undesired for at least two reasons. First, it is inefficient in carbon dioxide elimination due to an increase in the ratio of dead space to alveolar ventilation compared with a slow and deep ventilation pattern (Kreit, 2015). Second, smaller tidal volumes promote atelectasis with hypoxia from intrapulmonary shunting. Arterial blood gas results bear this out (Fig. 3). TRH, despite overcorrection of morphine-induced decreases in minute ventilation, failed to normalize arterial carbon dioxide and oxygen levels. Similarly, marked overcorrection by talitrelin merely normalized these levels. However, that said, any ventilation is better than none as evidenced by TRH rescue of rats treated with a lethal, apnea-inducing dose of morphine (Fig. 5). Future studies will need to address the impact of TRH and taltirelin dosing on arterial blood gas results. For example, would lower doses support a more sober, slower, and deeper ventilatory pattern better suited for reversing hypercarbia and hypoxia? Additionally, an agent such as dexmeditomidine, an α2 agonist known to eliminate opioid-induced muscle rigidity, might be coadministered with TRH or taltirelin to determine if tidal volumes increase (Weinger et al., 1989).
In our studies, the breathing and hemodynamic response to TRH is exaggerated in the presence of opioids, which implies these drugs are influencing each other’s mechanism of action. This interaction, of course, could be occurring at one or more levels (e.g., receptor, neuron/cell signaling, neural circuit, and/or organ levels). For example, cell signaling events downstream from the TRH receptor may perhaps bias that downstream from the mu opioid receptor, an active area of investigation in novel opioid drug development (Schmid et al., 2017). Other investigators have also observed an interaction between opioids and TRH (Bhargava et al., 1983). TRH decreases both tolerance to opioid antinociception and symptoms of acute withdrawal in rodents. Again, it should be noted that TRH does not alter opioid-induced antinociception and does not impact opioid binding to its receptor.
The respiratory tract is a viable route for needle-free, systemic drug delivery. For example, nasal naloxone provides rapid reversal of opioids in the setting of overdose (Barton et al., 2002), and inhaled insulin protein provides normalization of blood sugar levels (Mastrandrea, 2010). We determined that intratracheally delivered TRH reversed OIRD, which suggests inhaled TRH may be a feasible method of rapid, needle-free TRH administration. Additionally, because TRH metabolism on the tracheal and alveolar surfaces is minimal and since transepithelial TRH transport is limited, TRH’s short plasma half-life may be overcome by depositing a large TRH dose in the lung for stable, prolonged systemic uptake (Morimoto et al., 1994, 2000; Lehrer, 2014). Future work, of course, is needed to optimize TRH delivery through the respiratory tract of the rat, an obligate nose breather with a long and complex nasopharyngeal anatomy (e.g., dosing and nebulized particle-size optimization), and to determine if pharmacokinetics are in fact improved relative to intravenous delivery. We also need to address the possibility that TRH effects on breathing are mediated in part through receptors on the lung epithelium, which might be tested by studies in vagotomized rats.
TRH is an endogenous neuropeptide, and the results of this study imply that varying TRH or TRH receptor signaling levels due to effects of genetics, disease, pharmacology, and/or other reasons may modify an animal’s or a patient’s physiologic response to an opioid and risk for OIRD. Of course, endogenous TRH may have a markedly different pattern of distribution and concentration levels relative to that of TRH supplied by exogenous administration. There are several animal models in which these ideas could be tested. For example, TRH and TRH receptor knockout mice have been developed and are viable and may be prone to OIRD (Yamada et al., 1997; Rabeler et al., 2004; Sun et al., 2009). Notably, the TRH1 knockout mouse has a prolonged sleep time with pentobarbital (Thirunarayanan et al., 2013). Similarly, the obese leptin knockout mouse (ob/ob) and the Brown Norway rat are TRH deficient in certain neuronal populations (Burgueno et al., 2007; Puissant et al., 2015). Of note, the ob/ob mouse has disordered ventilation at baseline and the Brown Norway rat lacks a hypercarbic ventilatory response (O’Donnell et al., 1999; Puissant et al., 2015). Alternatively, a transgenic animal overexpressing the TRH precursor protein gene, prepro-TRH, using its native promoter might be prepared for study (Schuman et al., 2014). Additionally, it will be interesting to determine if there are differences in the breathing effects of intravenous TRH relative to agents that increase endogenous TRH levels through blockade of TRH proteolysis (Scalabrino et al., 2007), or following leptin administration, which induces endogenous TRH expression (Burgueno et al., 2007) and gates TRH responsivity (Rogers et al., 2009). Finally, benzodiazepines (e.g., chlordiazepoxide and midazolam) are antagonists/inverse agonists of the TRH receptor and antagonize some physiologic responses to TRH administration (e.g., TSH and prolactin secretion) (Roussel et al., 1986; Lu et al., 2004). By themselves, benzodiazepines cause minimal respiratory depression. However, benzodiazepines augment OIRD when coadministered with an opioid and are a contributing factor in many opioid-related deaths (McCormick et al., 1984). We speculate this may be mediated in part through effects at the TRH receptor.
A number of central nervous system stimulants have varying levels of efficacy in reversing OIRD while preserving opioid-induced analgesia (i.e., as physiologic antagonists). For example, doxapram and Gal-021 are breathing stimulants that act peripherally through potassium channel inhibition to cause carotid body activation (Mitchell and Herbert, 1975; Cotten et al., 2006; Golder et al., 2015). In human studies, however, Gal-021 may have a ceiling in its efficacy, reversing only modest levels of OIRD, which will limit utility (Roozekrans et al., 2015). Similarly, doxapram has limited efficacy and may act in part through increased opioid clearance via augmented cardiac output (Roozekrans et al., 2017). In our study, however, TRH distinguished itself in reversing very deep/lethal levels of OIRD, suggesting excellent efficacy in this use. In this way, TRH resembles ampakines (e.g., CX-717), which act through effects on the brainstem respiratory rhythm generating the pre-Bötzinger complex and also cause a rapid, shallow breathing pattern (Ren et al., 2009). Phase II clinical trials have demonstrated ampakine efficacy in reversing OIRD (www.respirerx.com). Interestingly, and also like ampakines, TRH has limited breathing effects in the absence of opioids. However, ampakines are allosteric modulators of excitatory, glutamate receptors, a molecular target very different from the TRH receptor.
In conclusion, TRH is a Food and Drug Administration–approved drug and an endogenous neuropeptide with myriad physiologic effects, which has been studied as a potential therapeutic agent for a wide range of human afflictions. Our current studies suggest TRH, or one of its over 20 analogs such as taltirelin, may also have clinical utility as an opioid drug therapy adjunct to prevent and/or reverse OIRD without analgesia compromise. Further preclinical and clinical studies are warranted to better define TRH dosing, efficacy, safety, route of administration, and tolerability in this clinical use.
Acknowledgments
We thank our colleagues, Dr. Hua-Jun Feng, Dr. Stuart Forman, Dr. Youssef Jounaidi, Dr. Keith Miller, and Dr. Douglas Raines, at Massachusetts General Hospital for helpful discussions.
Authorship Contributions
Participated in research design: Boghosian, Luethy, Cotten.
Conducted experiments: Boghosian, Luethy, Cotten.
Performed data analysis: Boghosian, Luethy, Cotten.
Wrote or contributed to the writing of the manuscript: Luethy, Boghosian, Cotten.
Footnotes
- Received February 8, 2018.
- Accepted April 18, 2018.
This research was supported by the Massachusetts General Hospital Department of Anesthesia, Critical Care, and Pain Medicine; the National Institutes of Health National Heart Lung and Blood Institute [Grant R01HL117871]; and Kantonsspital Aarau, Aarau, Switzerland [Grant 1410.000.062].
↵This article has supplemental material available at jpet.aspetjournals.org.
Abbreviations
- OIRD
- opioid-induced respiratory depression
- TRH
- thyrotropin releasing hormone
- Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics