Autoradiographic studies concerning the supraspinal site of the antinociceptive action of morphine when inhibiting the hindleg flexor reflex in rabbits

Abstract

Previous investigations in unrestrained, conscious rabbits showed that the site of action of morphine when it inhibits the hindleg flexor reflex is located in structures easily reached from the 4th ventricle. In the present investigation using 14C-morphine, the site of action of the drug was localized more precisely. The distribution pattern of morphine around the 4th ventricle after intraventricular and intracisternal injection was visualized by autoradiography and correlated with the pharmacological effect in the individual experiments. Thus, structures bordering the caudal parts of the 4th ventricle and the extraventricular cerebrospinal fluid space within this region could be excluded as sites of action. On the other hand, structures in the floor of the rostral part of the fossa rhomboidea are highly putative as sites of morphine action. The concentration of morphine along the permeation route from the ventricle to nearby structures was determined by combining the results of radioassay, autoradiography and optical scanning. The concentrations calculated for structures at different distances from the ventricular wall were compared with those concentrations obtained after systemic application of equieffective morphine dosages. It was concluded that the relevant receptors are located somewhat more than 1000 μm away from the ventricular wall. When a weak antinociceptive effect is observed, this region corresponds to the border zone of the autoradiographically-blackened area. The results are discussed with reference to the technical problems of this procedure as well as the anatomical structures and physiological mechanisms involved in supraspinal control of spinal nociceptive reflex activity.