beta-FNA binds irreversibly to the opiate receptor complex: in vivo and in vitro evidence.
beta-Funaltrexamine (beta-FNA) is an alkylating derivative of naltrexone. Considerable data support its use as an irreversible mu receptor antagonist. However, pretreatment of rats with beta-FNA attenuates the ability of delta antagonists and naloxone to reverse delta receptor-mediated physiological effects, suggesting that physically adjacent mu and delta receptors interact in vivo. The purpose of this study was to determine which opiate receptor subtype is altered by i.c.v. injections of beta-FNA, as well as by in vitro incubations with beta-FNA, and then to examine the hypothesis that pretreatment of rats with beta-FNA increases the IC50 for naloxone at the altered binding site. The results demonstrate that beta-FNA alters the conformation of the opiate receptor complex, as evidenced by a decrease in the Bmax of the lower affinity [3H]D-Ala2-D-Leu5-enkephalin binding site and a doubling of the naloxone IC50 for displacing [3H]D-Ala3-D-Leu5-enkephalin from this site. [3H]D-Ala2-MePhe4,Gly-ol5-enkephalin binding sites were not detectably altered by i.c.v. injections of beta-FNA. These data collectively support the concept of coupling among opioid receptor subtypes.
Rothman
R B
RB
Laboratory of Preclinical Pharmacology, St. Elizabeths Hospital, Washington, District of Columbia.
Long
J B
JB
Bykov
V
V
Jacobson
A E
AE
Rice
K C
KC
Holaday
J W
JW
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000378:metabolism; D016308:Enkephalin, Leucine-2-Alanine; D004745:Enkephalins / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D009270:Naloxone / Q000378:metabolism; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000378:metabolism*; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu
D004745:Enkephalins; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C055635:LY 164929; D009270:Naloxone; D004743:Enkephalin, Leucine; D009271:Naltrexone; D016308:Enkephalin, Leucine-2-Alanine; C024524:beta-funaltrexamine