The spinal effects of two opiate compounds with nonequilibrium properties, chloroxymorphamine (COA) and chlornaltrexamine (CNA), were studied in the rat. Permanent indwelling cannulas to the spinal subarachnoid space allowed repeated injections of drugs to be made into a circumscribed receptor population. At various times after injection of the alkylating agents, the analgesic efficacy of morphine was measured. A single intrathecal injection of the antagonist, CNA, was found to dramatically inhibit the analgesic effect of intrathecally administered morphine challenges from 2 to 13 days. Pretreatment with CNA also reduced the analgesic effect of subcutaneously administered morphine, but only mildly compared to the potent inhibition of intrathecally administered morphine. In contrast to CNA, pretreatment with naltrexone intrathecally did not significantly inhibit the analgesic effect of intrathecal morphine challenges. Unlike the pure antagonistic effect of CNA, a single intrathecal injection of COA produced an immediate dose-related analgesia. Subsequently, the analgesic effect was absent, and replaced by a potent and long-term antagonism of morphine analgesia, which was still present as long as 21 days after COA. As was found with CNA, the inhibition by COA of the analgesic effect of morphine administered intrathecally was much more potent than that of subcutaneously administered morphine. The intrathecal injection of chlorambucil, a non-specific alkylating agent, produced no analgesia and did not affect the analgesic efficacy of subsequent treatment with morphine. The non-opioid analgesic effect of serotonin injected intrathecally was not affected by pretreatment with COA, and only slightly inhibited by the previous spinal injection of CNA. Using this test system, our results indicate that COA and CNA possess a much greater potency and longer duration of inhibition of narcotic receptors than previously demonstrated.