The role of corticosterone in the blockade of tolerance to morphine analgesia by formalin-induced pain in the rat.

We previously reported that morphine fails to produce analgesic tolerance when administered in the presence of formalin-induced pain, which may be related to activity of the hypothalamic-pituitary-adrenal axis. In the present study, we examined whether suppression of corticosterone secretion during pain prevents the blockade of tolerance to morphine analgesia. Male Long-Evans rats were injected with morphine (20 mg/kg) or saline for 4 consecutive days in the presence or absence of formalin-induced pain. To suppress corticosterone activity, some animals were injected daily with the corticosterone synthesis inhibitor, metyrapone (100 mg/kg), 24 h and 30 min before formalin injections. The analgesic effect of a test dose of morphine (10 mg/kg) was then measured in the tail-flick test 24 h after tolerance induction (i.e. day 5). The presence of pain during tolerance induction prevented the development of analgesic tolerance. Furthermore, inhibition of corticosterone synthesis by metyrapone prevented the blockade of tolerance by pain. These results suggest that the blockade of tolerance to morphine analgesia by formalin-induced pain depends on stress-induced corticosterone increases.