Behavioral sensitization to intermittent morphine in mice is accompanied by reduced adrenocorticotropine but not corticosterone responses

The present study was aimed to test the hypothesis that behavioral sensitization to intermittent administration of morphine is accompanied by sensitization of adrenocorticotropine (ACTH) and corticosterone responses and with signs of hyperactivity of the hypothalamic–pituitary–adrenocortical function in mice. Male mice were injected subcutaneously with 40 mg/kg morphine or saline every 72 h for 16 days (in total, six injections were performed) and the effects were compared to those after single drug injection. Hormones were investigated 60 min after the last (6th) morphine or saline injection, i.e. 3 days after the 5th injection of intermittent treatments. Locomotor sensitization was confirmed in a separate series. ACTH levels in response to the last morphine injection of the repeated dosage regimen were found to be lower compared to those in acutely morphine-treated mice. Morphine administration was followed by increases in plasma corticosterone, but no significant differences between the acutely and repeatedly treated groups were observed. The body weight of morphine-treated mice showed a characteristic pattern with decreases measured the day after morphine administration. No statistically significant differences in adrenal and thymus weights were found. In conclusion, behavioral sensitization to morphine in mice is accompanied by a blunted rather than an enhanced ACTH response to drug injection. Unchanged levels of plasma corticosterone demonstrate an absence of tolerance and possible involvement of ACTH unrelated mechanisms needs further verification. Intermittent administration of morphine for 2 weeks failed to induce marked signs of glucocorticoid overexposure.