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.

Thyrotropin-releasing hormone (TRH) was reported to stimulate respiration and abolish the respiratory depressant effect of morphine-like analgesics. Some TRH analogs which have a diminished hormonal activity may be of interest as potential non-specific opioid antagonists. The mechanism of this effect of TRH and its analogs is still unclear. Thus, in the present work the respiratory stimulant effect of TRH and its analog RGH 2202 was studied in the urethane-anesthetized vagotomized artificially-ventilated rats. The integrated diaphragmatic electromyogram was used to evaluate the effects of the drugs. TRH and RGH 2202 administered either i.v. or directly onto the dorsal medullary surface significantly increased the respiratory activity of the diaphragm. TRH and RGH 2202 also effectively antagonized the diaphragm activity depression caused by morphine. The latency, time course and activity of RGH 2202 turned out to be close to those of TRH. The possible involvement of N-methyl-D-aspartate (NMDA) receptors in the mechanism of action of TRH and RGH 2202 was also investigated. It was shown that the non-competitive NMDA antagonists ketamine and MK-801 and the competitive antagonist D-amino-5-phosphonovalerate after local or i.v. administration prevented or discontinued the diaphragm activity stimulation by TRH and RGH 2202. Moreover, they blocked the antagonistic action of TRH and RGH 2202 on the morphine-induced diaphragm activity depression. Thus, we conclude, that TRH and RGH 2202 cause similar stimulant effects on the respiratory activity of the diaphragm and effectively antagonize its depression by morphine. These effects are likely to be mediated by the NMDA receptors located in the central respiratory structures.