The role of neural histamine in morphine-analgesia and in morphine-induced potentiation of stress analgesia was studied. Pretreatment of rats with alpha-fluoromethylhistidine (alpha-FMH) (200 micrograms i.c.v./rat; daily for five days) increased the analgesic potency of morphine, centrally or peripherally injected, in the tail-flick assay. This increase was significantly blocked by i.c.v. or i.p. beta-funaltrexamine (beta-FNA) a mu selective irreversible opioid receptor antagonist, whereas i.c.v. injected naltrexone did not block the increased analgesic potency of the i.c.v. morphine. Rats subjected to cold-restrained stress (60 min at 4 degrees C) showed increased tail-flick latency, compared to the unstressed group. The analgesic potency of morphine was significantly greater in rats subjected to restraint with respect to unstressed rats. However, the inhibition of histamine biosynthesis by alpha-FMH significantly reduced cold-restraint analgesia in controls, and also inhibited the analgesic efficacy of the opiate. These results indicate that neural histamine may be responsible for pain response modifications observed in rats subjected to cold-restraint conditions, and of morphine-potentiation of stress analgesia. The data also suggest a close association between increased analgesic potency of morphine and inhibition of histaminergic effects, possibly implying a functional supersensitivity and an increase in opioid receptors.