Pretreatment of rats with the irreversible mu-receptor antagonist, beta-FNA, fails to prevent naltrexone-induced upregulation of mu-opioid receptors.
This study examined the effect of beta-funaltrexamine (beta-FNA), an irreversible mu-receptor antagonist, on naltrexone-induced upregulation of mu-(mu cx + mu nex) and delta nex-opioid receptors. [The subscripts 'cx' and 'nex' denote binding sites 'in' (cx) and 'not in' (nex) the opioid receptor complex.] Rats were treated according to the following protocol. Two naltrexone or two placebo pellets were implanted subcutaneously in a nylon mesh on day 1. and were removed intact on day 8. Rats were given either saline or 20 nmol of beta-FNA in 10 microliters of saline (i.c.v.) on days 1, 3, 5 and 6, 60 min prior to implantation of the pellet. On day 9 frozen lysed-P2 membranes were prepared for assay of mu binding sites. In other experiments, membranes were depleted of mu-receptors by pretreatment with the site-directed acylating agent 2-(4-ethoxybenzyl)-l-diethylaminoethyl-5-isothiocyanatobenzimid azole.HCl (BIT) for assay of delta nex binding sites, using [3H] [D-ala2, D-leu5]enkephalin. The results demonstrated that beta-FNA did not upregulate the mu binding sites and also did not prevent naltrexone-induced upregulation of mu binding sites. Both beta-FNA and naltrexone increased the Bmax of delta nex binding sites and their effects were additive. These data suggest that the mechanism(s) responsible for antagonist-induced upregulation of opioid receptors are more complex than previously appreciated.
Rothman
R B
RB
Laboratory of Clinical Science, NIMH, Bethesda, MD 20892.
Long
J B
JB
Bykov
V
V
Jacobson
A E
AE
Rice
K C
KC
Holaday
J W
JW
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016308:Enkephalin, Leucine-2-Alanine / Q000494:pharmacology; D004745:Enkephalins / Q000494:pharmacology; D066298:In Vitro Techniques; D017879:Isothiocyanates; D007700:Kinetics; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D010111:Oxymorphone / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000378:metabolism*; D017450:Receptors, Opioid, mu; D013861:Thiocyanates; D015854:Up-Regulation / Q000187:drug effects*
D004745:Enkephalins; D017879:Isothiocyanates; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D013861:Thiocyanates; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009271:Naltrexone; D016308:Enkephalin, Leucine-2-Alanine; C024524:beta-funaltrexamine; C042097:2-(4-ethoxybenzyl)-1-diethylaminoethyl-5-isothiocyanatobenzimidazole; C042285:6-fluoro-6-desoxyoxymorphone; D010111:Oxymorphone