Mu-opioid receptor regulation during opioid tolerance and supersensitivity in rat central nervous system.

We have analyzed by radiometric procedures in rat central nervous system the changes in the properties of mu-opioid receptors associated with tolerance and supersensitivity to the opioid agonist sufentanil. This study has used [3H]-[D-Ala2,MePhe4,Gly- (ol)5(2)]-enkephalin, a highly selective ligand, to label mu-opioid receptors in both membranes and tissue sections. The induction of opioid tolerance by chronic infusion for 7 days of high doses of sufentanil, a high efficacy agonist, produced mu-opioid receptor down-regulation, with a significant decrease in their density in both cortical (-67%) and spinal cord membranes (-55%) and no changes in the affinity constant. Autoradiographic studies showed an overall decrease of[3H]-Ala2,MePhe4,Gly-(ol)5(2)]-enkephalin binding in the somatosensory cortex (around -30%). When the dihydropyridine-Ca++ channel antagonist nimodipine was administered alone for 7 days, no significant changes in the density or affinity constant of mu-opioid receptors were observed. However, the chronic and simultaneous 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 in 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 strongly suggest a functional role of L-type Ca++ channels in the mediation of opioid tolerance and super-sensitivity.