Sites of action of morphine involved in the development of physical dependence in rats

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Abstract
Morphine withdrawal was precipitated by injection of 3H-naloxone into restricted parts of the ventricular system of rats made tolerant to and dependent on morphine by repeated pellet implantation. The spread of the drug was evaluated by autoradiography and compared with the withdrawal signs precipitated in the same experiment. When the antagonist could spread into the tissue surrounding the 4th ventricle and the caudal parts of the aqueduct (penetration depth about 1.5 mm), a strong withdrawal syndrome was displayed. In contrast, only weak or no withdrawal signs were observed when the spread of naloxone was restricted to the surroundings of the lateral ventricles, the 3rd ventricle, and the rostromedial parts of the aqueduct. The same was true when the spread of the antagonist was limited to the ventral surface of the brain stem. It is concluded that structures located in the anterior part of the fossa Rhomboidea, and possibly also in the caudal part of the periaqueductal grey matter, are sites for the development of physical dependence on morphine giving rise to the withdrawal signs studied in these experiments.