Effects of YM-14673, a new TRH analogue, on responses to morphine in rodents

The influence of YM-14673 (N alpha-[[(S)-4-oxo-2-azetidinyl]-carbonyl]-L-histidyl-L-prolinamide dihydrate), a new thyrotropin releasing hormone (TRH) analogue, on morphine-induced hypothermia, development of cerebral ischemia and analgesia was investigated in rodents. YM-14673, in doses not affecting the normal rectal temperature, antagonized morphine-induced hypothermia in mice. Morphine-induced hypothermia was also antagonized by administration of TRH, in doses increasing normal rectal temperature. Morphine increased the appearance rate of convulsions in rats subjected to bilateral occlusion of the carotid artery. YM-14673, unlike TRH, reduced the appearance rate of convulsions increased by morphine in the ischemic rats. Morphine-induced analgesia measured by the hot plate method was not affected by both YM-14673 and TRH. Naloxone antagonized the effect of morphine in the 3 models. These results suggest that YM-14673 possesses physiological opioid antagonistic properties.