The potentiating effects of restraint stress and continuous naloxone infusion on the analgesic potency or morphine are additive.

The analgesic potency of morphine in the rat can be increased by either continuous administration of an opiate antagonist, which also increases the number of mu-opioid receptors in the brain, or by immobilization stress. To examine further the plasticity of brain opioid mechanisms, this study assessed the combined effects of continuous naloxone treatment and physical restraint on the analgesic potency of morphine. Osmotic pumps releasing 0.3 mg/kg/h of naloxone were implanted subcutaneous (SC) in two groups of rats for 7 days and empty (SHAM) pumps were implanted in two other groups. Twenty-four hours after the pumps were removed, all animals were injected with morphine in cumulative doses and tested in the tail-flick procedure. One group of naloxone-treated rats and one group of SHAM-treated rats were tested while restrained; the other two groups were tested while unrestrained. Naloxone infusion alone and restraint alone each increased significantly the analgesic potency of morphine by 1.4-fold whereas the combination of these two treatments increased analgesic potency by almost 2-fold, significantly more than either treatment alone. All animals were retested with morphine 6 days later; the analgesic potency of morphine in the SHAM groups was still potentiated by stress but the potentiating effect of the earlier naloxone infusion was no longer evident. It appears that the opioid receptors mediating stress-induced potentiation of morphine-induced analgesia can be upregulated transiently by 7-day infusion of naloxone.