Chronic intracerebroventricular infusion of the antiopioid peptide, Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2 (NPFF), downregulates mu opioid binding sites in rat brain.
Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2 (NPFF), an endogenous mammalian antiopioid peptide, has been shown by other laboratories to attenuate the acute antinociceptive effects of morphine, the development of morphine tolerance, and naloxone-induced withdrawal in morphine-dependent rats. The present study determined the effect of chronic NPFF on mu opioid receptors and mRNA for the endogenous opioids dynorphin and enkephalin. Rats received ICV infusions of either saline or NPFF (5 micrograms/h) for 13 days via Alzet 2002 osmotic minipumps. Homogenate binding studies, which used whole brain membranes, demonstrated that NPFF decreased the Bmax of mu binding sites (labeled by [3H][D-Ala2-MePhe4,Gly-ol5]enkephalin) from 262 +/- 12 to 192 +/- 12 fmolmg protein, and increased the Kd from 1.1 to 2.3 nM. Quantitative receptor autoradiography and in situ hybridization experiments were conducted with sections collected at the level of the striatum. The density of mu opioid binding sites labeled by [3H][D-Ala2-MePhe4,Gly-ol5]enkephalin was decreased in all brain areas measured except the corpus callosum, and there was no change in dynorphin mRNA or enkephalin mRNA in the caudate, the nucleus accumbens, or the ventral pallidum. Rats chronically administered ICV morphine sulfate (20 micrograms/h) for 14 days developed tolerance to morphine and a low degree of dependence, as measured by naloxone-precipitated withdrawal. Chronic administration of NPFF concurrently with morphine sulfate did not significantly alter naloxone-induced withdrawal signs or the development of morphine tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)
Rothman
R B
RB
Clinical Psychopharmacology Section, NIDA Addiction Research Center, NIH, Baltimore, MD 21224.
Brady
L S
LS
Xu
H
H
Long
J B
JB
D000595:Amino Acid Sequence; D000818:Animals; D002552:Cerebral Ventricles; D015536:Down-Regulation; D004361:Drug Tolerance; D004723:Endorphins / Q000235:genetics; D007263:Infusions, Parenteral; D008297:Male; D008969:Molecular Sequence Data; D009020:Morphine / Q000494:pharmacology; D009021:Morphine Dependence / Q000503:physiopathology; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000187:drug effects*; D013997:Time Factors
D004723:Endorphins; D009842:Oligopeptides; D012333:RNA, Messenger; D017450:Receptors, Opioid, mu; D009020:Morphine; C053651:phenylalanyl-leucyl-phenylalanyl-glutaminyl-prolyl-glutaminyl-arginyl-phenylalaninamide