RT Journal Article SR Electronic T1 Intravenous and intratracheal thyrotropin releasing hormone and its analog taltirelin reverse opioid-induced respiratory depression in isoflurane anesthetized rats JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP jpet.118.248377 DO 10.1124/jpet.118.248377 A1 James D. Boghosian A1 Anita Luethy A1 Joseph F. Cotten YR 2018 UL http://jpet.aspetjournals.org/content/early/2018/04/19/jpet.118.248377.abstract AB 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.