Relationship between hypothalamic-pituitary-adrenal activity and blockade of tolerance to morphine analgesia by pain: A strain comparison

We previously reported that morphine fails to produce analgesic tolerance when administered in the presence of formalin-induced pain. The hypothalamic-pituitary-adrenal (HPA) axis is known to respond to stressful stimuli, including pain. To examine whether the blockade of tolerance by pain is related to HPA activity, we assessed the development of tolerance to morphine analgesia in an inbred strain of rats that lack typical stress-induced HPA responses (Lewis strain). Lewis rats lack typical stress-induced activation of corticotropin-releasing hormone, adrenocorticotropin hormone and glucocorticoids. Female Lewis rats were injected with morphine (20 mg/kg, i.p.) or saline for 4 consecutive days in the presence or absence of pain induced by injection of formalin into the hind-paw. The analgesic effect of morphine (5, 10 or 20 mg/kg, i.p.) was then measured in the tail-flick test 24 h after tolerance induction. Inbred female Fischer rats, which show significant stress-induced HPA activity, were used for comparison. Analgesic tolerance was produced in both strains when morphine was delivered in the absence of pain. However, the presence of pain during morphine administration prevented the development of analgesic tolerance in Fischer, but not in Lewis, rats. The differential effects of pain on the development of tolerance to morphine analgesia are suggested to be related to genetically determined differences in stress-induced HPA activity.