Antinociceptive effects of morphine-6-glucuronide in homozygous MDR1a P-glycoprotin knockout and in wildtype mice in the hotplate test

Citation
J. Lotsch et al., Antinociceptive effects of morphine-6-glucuronide in homozygous MDR1a P-glycoprotin knockout and in wildtype mice in the hotplate test, LIFE SCI, 66(24), 2000, pp. 2393-2403
Citations number
41
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
LIFE SCIENCES
ISSN journal
0024-3205 → ACNP
Volume
66
Issue
24
Year of publication
2000
Pages
2393 - 2403
Database
ISI
SICI code
0024-3205(20000505)66:24<2393:AEOMIH>2.0.ZU;2-9
Abstract
Morphine-6-glucuronide (M6G), a major metabolite of morphine with agonist o pioid-receptor activity, was reported to be a substrate of P-glycoprotein ( P-gp). Inhibition of P-gp may thus result in higher brain uptake of M6G. Th e goal of this observer-blinded, placebo controlled study, was to compare t he antinociceptive effects of M6G in homozygous P-gp knockout (mdr1a(-/-)) and wildtype (mdr1a(+/+)) mice. M6G was injected intraperitoneally as a sin gle dose of 0, 0.5, 1, 2.5, 5, and 10 mg/kg. Eight P-gp knockout and eight wildtype mice were studied per dose. A hot plate test was performed before and 5, 15, 30, 60, 90, 120, and 150 min after M6G administration. Plasma-co ncentrations of M6G, morphine, and morphine-3-glucuronide (M3G) were measur ed after intraperitoneal injection of 5 mg/kg M6G in another 14 P-gp knocko ut and 14 wildtype mice. No difference neither in the dose response relatio nship, nor in the time course of response latency times were observed betwe en P-gp knockout and wildtype mice. However, latency times increased with h igher doses of M6G, with antinociception significantly different from place bo at a M6G dose of 5 and 10 mg/kg. P-gp knockout mice tended to have highe r plasma concentrations than the wildtype. However, plasma concentrations w idely overlapped between groups and therefore no statistical significant gr oup difference could be detected. We conclude that despite reported doublin g of M6G brain uptake, absence of mdr1a coded P-gp does not enhance antinoc iceptive effects of M6G in the hotplate test after acute single-dose admini stration in mdr1a(-/-) knockout mice.