Effect of Subchronic Intravenous Morphine Infusion and Naloxone-Precipitated Morphine Withdrawal on P-gp and Bcrp at the Rat Blood-Brain Barrier

• Type: Article in International Scientific Journal
• Date: 2016

Authors

Chaves, C (Author) Other; Gomez Zepeda, D (Author) Other; Auvity, S (Author) Other; Menet, MC (Author) Other; Crete, D (Author) Other; Labat, L (Author) Other; Fernando Remiao (Author) FFUP; Cisternino, S (Author) Other; Decleves, X (Author) Other

Journal

Title: Journal of Pharmaceutical Sciences

Vol. 105

Pages: 350-358

ISSN: 0022-3549

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 5 Citations

Scopus - 9 Citations

Other information

Authenticus ID: P-00K-EGR

DOI: 10.1002/jps.24697

Abstract (EN): Chronic morphine regimen increases P-glycoprotein (P-gp) and breast cancer-resistance protein (Bcrp) expressions at the rat blood-brain barrier (BBB) but what drives this effect is poorly understood. The objective of this study is to assess subchronic continuous morphine infusion and naloxone-precipitated morphine withdrawal effects on P-gp/Bcrp contents and activities at the rat BBB. Rats were treated either with (i) a continuous i.v. morphine for 120 h, (ii) escalating morphine dosing (10-40 mg/kg, i.p., 5 days), (iii) a chronic morphine regimen (10 mg/kg s.c., 5 days) followed by a withdrawal period (2 days) and treatment for 3 additional days. Animal behavior was assessed after naloxone-precipitated withdrawal (1 mg/kg, s.c.). P-gp/Bcrp expressions and activities were determined in brain microvessels by qRT-PCR, Western blot, UHPLC-MS/MS, and in situ brain perfusion of P-gp or Bcrp substrates. Results show continuous i.v. morphine did not change P-gp/Bcrp protein levels in rat brain microvessels, whereas naloxone-precipitated withdrawal after escalating or chronic morphine dose regimen increased Mdr1a and Bcrp mRNA levels by 1.4-fold and 2.4-fold, respectively. Conversely, P-gp/Bcrp protein expressions remained unchanged after naloxone administration, and brain uptake of [H-3]-verapamil (P-gp) and [H-3]mitoxantrone (Bcrp) was not altered. The study concludes subchronic morphine infusion and naloxone-precipitated morphine withdrawal have poor effect on P-gp/Bcrp levels at the rat BBB.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 9