Intracerebroventricular administration of anti-endothelin-1 IgG selectively upregulates endothelin-A and kappa opioid receptors.
Endothelin (ET) type A receptor antagonists enhance morphine-induced antinociception and restore morphine analgesia in morphine tolerant rats [Peptides 23 (2002) 1837; Peptides 24 (2003) 553]. These studies suggest that the central ET and opioid systems functionally interact. To explore this idea further, we determined the effect of i.c.v. administration of anti-ET-1 IgG (rabbit) on brain opioid receptor and ET receptor expression. Three days after implanting cannula into the lateral ventricle, male Sprague-Dawley rats were administered 10 microl (i.c.v.) of either control rabbit IgG (2.5 microg/microl) or anti-ET IgG (2.5 microg/microl) on day 1, day 3, and day 5. On day 6, animals were killed and the caudate and hippocampus collected. Anti-ET IgG had no significant effect on expression, measured by Western blots, of mu, delta or ET-B receptors, but increased kappa opioid (59%) and ET-A (33%) receptor protein expression in the caudate. [35S]-GTP-gamma-S binding assays demonstrated that anti-ET IgG decreased [D-Ala2-MePhe4, Gly-ol5]enkephalin efficacy, but not potency in the caudate. Control experiments showed that there was no detectable rabbit IgG in caudate and hippocampal samples. These results suggest that ET in the CSF negatively regulates kappa opioid and ET-A receptors in certain brain regions. These findings support the hypothesis that CSF neuropeptides have regulatory effects and further demonstrate a link between ET and the opioid receptor system.
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Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, PO Box 5180, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.
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Rothman
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D000818:Animals; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004399:Dynorphins / Q000378:metabolism; D019332:Endothelin-1 / Q000276:immunology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D007074:Immunoglobulin G / Q000008:administration & dosage*; D007276:Injections, Intraventricular; D008297:Male; D011863:Radioimmunoassay / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000145:classification / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D013460:Sulfur Isotopes / Q000493:pharmacokinetics; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
D019332:Endothelin-1; D007074:Immunoglobulin G; D017466:Receptors, Endothelin; D017473:Receptors, Opioid, kappa; D013460:Sulfur Isotopes; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D004399:Dynorphins