One class of drugs in which tolerance is a very potent phenomenon, and for which there is a long history of research, is the opiates, including morphine. Bernard there has been a long history of both description of the phenomenon of tolerance and theorizing about the mechanisms involved. In general, prior research has used two main approaches. The first uses pharmacological methods to identify possible physiological substrates for tolerance. Mechanisms which have been studied include: the operation of immune mechanisms; changes in protein synthesis; changes in adrenal activity; and changes in neurotransmitters. The second is a 'molar' approach to the behavioral phenomena of tolerance, with little attention to possible physiological substrates. Schmidt and Livingston demonstrated less tolerance in dogs treated with lower doses of morphine. The effect of interdose interval (IDI) for repeated doses of morphine on tolerance development has been the subject of even less study.