Effects of beta-funaltrexamine on dose-effect curves for heroin self-administration in rats: comparison with alteration of [3H]DAMGO binding to rat brain sections.
These studies were undertaken to determine the effects of mu-opioid receptor depletion through irreversible alkylation on the dose-effect curve for heroin self-administration. Heroin maintained responding in rats with an inverted U-shaped dose-effect curve and administration of 10 nmol of beta-funaltrexamine i.c.v. (beta-FNA) significantly increased the ED50 on the ascending limb from 1.9 to 5.3 micrograms/infusion, and from 24.3 to 211.8 micrograms/infusion on the descending limb. Administration of saline i.c.v. produced no effect on heroin self-administration. Administration of 40 nmol of beta-FNA increased the ED50S from 5.1 to 33.9 and from 14.4 to 502.8 micrograms/infusion on the ascending and descending portions of heroin's dose-effect curve, respectively. beta-FNA (40 nmol, i.c.v.) had no effect on cocaine self-administration. [3H]DAMGO binding density was decreased in the caudate and nucleus accumbens by 29 or 54% 24 h after administration of 10 or 40 nmol of beta-FNA i.c.v., respectively. The effects of beta-FNA on heroin self-administration were completely overcome by increasing the dose of heroin however, as the shape and slope of the self-administration dose-effect curve was not different when higher doses of heroin were made available for self-administration compared to control data or saline administration. Therefore, there appear to be spare mu-opioid receptors for heroin for the production of its reinforcing effects in rats. Furthermore, the self-administration dose-effect curves returned to control values prior to the return of [3H]DAMGO binding, further suggesting that the full complement of mu-opioid receptors is not necessary for heroin to produce its reinforcing effects. These findings support the existence of spare mu-opioid receptors for heroin in maintaining self-administration in rats.
Martin
T J
TJ
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1083, USA. tjmartin@bgsm.edu
DeMontis
M G
MG
Kim
S A
SA
Sizemore
G M
GM
Dworkin
S I
SI
Smith
J E
JE
D000701:Analgesics, Opioid / Q000493:pharmacokinetics*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D002421:Caudate Nucleus / Q000187:drug effects / Q000503:physiopathology; D003042:Cocaine / Q000008:administration & dosage; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000493:pharmacokinetics*; D003932:Heroin / Q000008:administration & dosage*; D006556:Heroin Dependence / Q000503:physiopathology*; D009042:Motivation; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000503:physiopathology; D011869:Radioligand Assay; D051381:Rats; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000502:physiology; D012646:Self Administration
D000701:Analgesics, Opioid; D004745:Enkephalins; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009271:Naltrexone; D003932:Heroin; C024524:beta-funaltrexamine; D003042:Cocaine