Development of antinociceptive tolerance and changes of opioid receptor ligand binding in central nervous system of the mouse forced to single and repeated swimming in the cold water.

The present study was designed to characterize underlying mechanism involved in the development of tolerance in the production of antinociceptive effect induced by repeated cold water swimming stress (CWSS) using the tail-flick test. Mice were forced to swim at 4 degrees C for 3min and the tail-flick test was performed 5, 10, 20, and 30min after the swimming. The profound antinociception was induced by a single CWSS. However, when the mice were exposed to CWSS repeatedly seven times, they showed a tolerance in the production of antinociception. In the opioid receptor binding study, Bmax of delta opioid receptor (DOR) was decreased in the brainstem, midbrain and the spinal cord areas by both a single and repeated CWSS, without altering Kd value. However, Bmax values of mu opioid receptor (MOR) and kappa opioid receptor (KOR) were increased in the brainstem, midbrain and spinal cord regions by repeated CWSS, without changing Kd values. Our results suggest that the development of tolerance in the production of antinociception in mice forced to the repeated CWSS may be, at least, due to the reduction of DOR number in the brainstem, midbrain and the spinal cord regions.