@article {Diaz1545, author = {A Diaz and F Ruiz and J Fl{\'o}rez and M A Hurl{\'e} and A Pazos}, title = {Mu-opioid receptor regulation during opioid tolerance and supersensitivity in rat central nervous system.}, volume = {274}, number = {3}, pages = {1545--1551}, year = {1995}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/274/3/1545}, eprint = {https://jpet.aspetjournals.org/content/274/3/1545.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }