Role of brain Ca2+ in electro-acupuncture analgesia and the development of analgesic tolerance to electro-acupuncture and morphine were studied. At the same time, the inhibition by protein synthesis inhibitors of the development of analgesic tolerance to electro-acupuncture was observed. The results showed that like morphine tolerance, the brain Ca2+ and cAMP levels in mice were enhanced with the development of analgesic tolerance to electro-acupuncture. After treatment with protein synthesis inhibitors anisomycin, actinomycin or cycloheximide the development of analgesic tolerance to electro-acupuncture was inhibited, and concurrently, the brain Ca2+ and cAMP levels in the animals greatly reduced. From the changes of brain Ca2+ and cAMP levels, the analgesic effects by electro-acupuncture, morphine and lanthanides seem to be very similar and share a mutual ion basis and the mechanism of action. So does the development of analgesic tolerance to electro-acupuncture and morphine. These findings also suggest that the inhibition induced by the inhibitors of the analgesic tolerance to electro-acupuncture and morphine may be related to synthesis of new peptides or RNA in brain.