Recent studies have shown that different regimens of footshock elicit either "opiate" (naloxone-sensitive) or "histaminergic" (cimetidine-sensitive but naloxone-insensitive) analgesic responses. Presently, the nature of these responses was further investigated by characterizing the development of tolerance to these stress paradigms and by assessing the degree of cross-tolerance between these treatments and morphine (MOR) in rats. Daily exposure to the "opiate" stress paradigm for 7 days resulted in a significant loss of this form of footshock-induced analgesia (FSIA), but the same exposure to the "histaminergic" regimen resulted in no such tolerance. One day later, animals from the "opiate"-stressed group exhibited MOR analgesia that was comparable to that in unstressed animals, whereas animals chronically exposed to the "histaminergic" paradigm showed highly potentiated responses to MOR. However, when naive animals were made tolerant to MOR, acute "opiate" FSIA was significantly attenuated, whereas the "histaminergic" analgesia was unaffected. These results, showing one-way cross-tolerance between MOR and "opiate" FSIA, are consistent with the hypothesis that opiate FSIA uses a subset of opiate receptors activated by systemic MOR. The one-way cross-sensitization between MOR and "histaminergic" analgesia observed presently, taken with previous findings, suggests that opiate-containing and histamine-containing neurons comprise separate endogenous analgesic systems that mutually inhibit each other. The absence of tolerance and opiate cross-tolerance exhibited by the cimetidine-sensitive analgesia suggests that drugs designed to activate this analgesic system should be devoid of such liabilities.