Two experiments were conducted to explore the effects of chronic antidepressant treatment on endogenous opioid systems. In the first study, mice received desipramine for 21 days, a regimen which down-regulates beta-adrenergic receptors [13]. Subsequently, hotplate jump latencies were measured after acute saline, morphine or naloxone, to test for dynamic changes in endogenous opioid systems. Chronic desipramine treatment resulted in a significant attenuation of morphine analgesia, but had no effect on latencies of saline and naloxone treated mice. In the second experiment, naltrexone or propranolol were given with desipramine for 21 days, in an attempt to block the development of subsensitivity to morphine. Naltrexone had no effect on desipramine attenuation of morphine analgesia. Propranolol given with desipramine slightly lowered jump latencies of acute saline controls, resulting in a significant analgetic effect of morphine. These data suggest that attenuation of morphine analgesia by chronic desipramine treatment may be mediated by actions on noradrenergic systems, rather than direct effects on opioid receptors.