Tolerance and cross-tolerance to stress-induced increases in plasma Met-enkephalin in rats with adaptively increased resting secretion.

Plasma concentrations of both native (pentapeptide plus its sulfoxide) and peptidase-derivable (trypsin followed by carboxypeptidase-B) Met-enkephalin showed brisk increases in response to the stresses of immobilization, hemorrhage, and electric footshock in conscious, freely moving, adult male rats. Daily exposure to 150-min periods of immobilization resulted in a maintained increase in baseline plasma concentrations of native Met-enkephalin 21.5 h after the sixth day and a further increase after 39 days. The plasma native Met-enkephalin response to acute immobilization was attenuated on day 7 and completely absent on day 40. Unstressed rats showed a plasma native Met-enkephalin response to hemorrhage of 15% blood volume and a further increase in response to 25% hemorrhage. Immediately after initial acute immobilization or 6 days of daily immobilization when plasma native Met-enkephalin was elevated but the response to acute immobilization was attenuated, plasma native Met-enkephalin responses to hemorrhage were also attenuated. Rats that had been immobilized daily for 40 days and showed no plasma native Met-enkephalin response to acute immobilization also showed no responses to hemorrhage. After 39 days of immobilization when there was no plasma native Met-enkephalin response to acute immobilization, there was also no response to footshock. Thus, development of tolerance or adaptive loss of plasma native Met-enkephalin response to immobilization with repeated exposure to this stressor is associated with cross-tolerance or adaptive loss of the responses to the stresses of hemorrhage or electric footshock. Development of tolerance and cross-tolerance of plasma responses of peptidase-derivable Met-enkephalin paralleled that of native Met-enkephalin. Thus, adaptation of plasma Met-enkephalin responses to repeated exposure to a stressor included both increased resting secretion and decreased acute responses to homotypic or novel stressors.