VARIATION IN TOLERANCE TO THE ANTINOCICEPTIVE, HORMONAL AND THERMAL EFFECTS OF MORPHINE AFTER A 5-DAY PRETREATMENT OF MALE-RATS WITH INCREASING DOSES OF MORPHINE

The manifestation of tolerance to the effects of morphine on nocicepti on and the secretion of anterior pituitary hormones, and the correlati on of hormonal effects to changes in body temperature and to hypothala mic monoamines were studied in male rats. Morphine (three times a day in increasing doses) or saline (control) were administered intraperito neally during a 5-day treatment and either saline or morphine was admi nistered as an acute challenge 92 h later. The influence of the therma l environment on the effect of morphine on the body temperature was al so studied. The 5-day morphine regimen was sufficient for the developm ent of tolerance to the antinociceptive effect of morphine. After a 92 -h lag-time, the tolerance was still complete. Tolerance to the depres sant effect of morphine (10-25 mg/kg) on cold-stimulated TSH secretion was seen at 2 h, but was only barely detectable at 1 h, after the inj ection of a challenge dose. On the other hand, a tolerance to the stim ulatory effect of morphine on prolactin secretion was already seen 1 h after the acute dose of morphine. Tolerance to the hypothermic effect of morphine (25 mg/kg) was evident in rats kept at +4 degrees C after the challenge dose. On the contrary, no tolerance to the hyperthermic effect of morphine (15 or 25 mg/kg) was observed in rats kept at +30 degrees C. However, the hyperthermia was reversed when these rats were moved to +4 degrees C for 30 min, irrespective of whether they were m orphine pretreated or not. Thus the removal of the hyperthermic stimul us decreased the core temperature of all rats.We conclude, that with a 5-day morphine regimen and a 4-day lag time, tolerance developed to t he antinociceptive, hypothermic and some hormonal effects of morphine but not to its hyperthermic effect or to its effects on hypothalamic 5 -HIAA concentrations. Neither the changes in the rectal temperature no r the minor alterations in the concentrations of the hypothalamic amin e neurotransmitters correlated with the manifestation of tolerance to the cold-stimulated TSH secretion.