Opiate receptor down-regulation and tolerance

The aim of the study was to investigate in the mouse the relationship between opiate-receptor down-regulation and opiate tolerance. Animals were treated for variable periods of time either by daily i.p. administration of different doses of morphine for as long as 30 days or by pellet implantation with 75-mg morphine pellet for as long as 3 day. Changes in morphine pharmacodynamics were assessed in two tests: tailflick analgesia and hypothermia. Receptor binding in specific brain structures was measured by the use of tritiated dihydromorphine and standard autoradiographic techniques. The results from the daily dose experiments indicate that in the anterior hypothalamus the periaqueductal grey and the paraventricular nucleus of the thalamus tolerance was invariably accompanied by down-regulation; however, there were treatment condition for which down-regulation occurred in the absence of tolerance, most notably, down-regulation was present without detectable tolerance after 2 days of treatment. There were other instances in which the degree of down-regulation was not directly proportional to the degree of tolerance. In addition, the maximum degree of down-regulation appeared limited to about 50 percent. In the pellet experiments, receptor binding was measured in the dorsal raphe of spinal cord, as well as those areas in the daily dose experiments. The results also illustrate that down-regulation occurs in certain instances, but the association between down-regulation and tolerance, and vice versa, is not as frequent as it is in the daily dose experiments. Here again the maximum degree of down-regulation is limited to about 50 percent. The data from both dosage regimes clearly demonstrate that exposure to morphine can cause opiate-receptor down-regulation; however, there appears to be no simple temporal or quantitative relationship between the down-regulation and tolerance to analgesia and hypothermia.