The possible role of brain histamine in the mechanisms of morphine tolerance and physical dependence is under investigation in mice. L-histidine and histamine, given during the 'withdrawal' phase, significantly increase tolerance to the analgesic effects of morphine but reduce the degree of physical dependence. Metiamide significantly inhibits tolerance but has no consistent effect on physical dependence. These results suggest that H2 receptors may be involved in the development of morphine tolerance. Mepyramine does not significantly affect tolerance, and with regard to dependence there is an effect only on body weight loss, which is increased. However, combined treatment with metiamide and mepyramine inhibits tolerance significantly more than metiamide alone; and withdrawal jumping is also reduced more significantly by combined treatment than by the separate administration of these drugs. It is suggested that brain histamine is definitely implicated in the mechanisms of the 'withdrawal' phase of morphine tolerance and physical dependence in mice, with H2 receptors probably playing the more important part.