MU-OPIOID RECEPTOR REGULATION DURING OPIOID TOLERANCE AND SUPERSENSITIVITY IN RAT CENTRAL-NERVOUS-SYSTEM

We have analyzed by radiometric procedures in rat central nervous syst em the changes in the properties of mu-opioid receptors associated wit h tolerance and supersensitivity to the opioid agonist sufentanil. Thi s study has used [H-3]-[D-Ala(2),MePhe4,Gly-(ol)5(2)]-enkephalin, a hi ghly selective ligand, to label mu-opioid receptors in both membranes and tissue sections. The induction of opioid tolerance by chronic infu sion for 7 days of high doses of sufentanil, a high efficacy agonist, produced mu-opioid receptor down-regulation, with a significant decrea se in their density in both cortical (-67%) and spinal cord membranes (-55%) and no changes in the affinity constant. Autoradiographic studi es showed an overall decrease of[H-3]-Ala(2),MePhe4,Gly-(ol)5(2)]-enke phalin binding in the somatosensory cortex (around -30%). When the dih ydropyridine-Ca++ channel antagonist nimodipine was administered alone for 7 days, no significant changes in the density or affinity constan t of mu-opioid receptors were observed. However, the chronic and simul taneous administration of nimodipine and sufentanil (7 days), induced a pronounced modification on the density of mu-opioid receptors of the rat central nervous system and blocked the down-regulation observed i n sufentanil-treated (tolerant) rats. These neurochemical findings may account for the functional interaction we have observed previously in the analgesic studies between nimodipine and sufentanil. Our data str ongly suggest a functional role of L-type Ca++ channels in the mediati on of opioid tolerance and supersensitivity.