title: Effect of Subchronic Intravenous Morphine Infusion and Naloxone-Precipitated Morphine Withdrawal on P-gp and Bcrp at the Rat Blood-Brain Barrier.
abstract: 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 [3H]-verapamil (P-gp) and [3H]-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.
authors.forename: Catarina
authors.initials: C
authors.lastname: Chaves
authors.forename: David
authors.initials: D
authors.lastname: Gómez-Zepeda
authors.forename: Sylvain
authors.initials: S
authors.lastname: Auvity
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Menet
authors.forename: Dominique
authors.initials: D
authors.lastname: Crété
authors.forename: Laurence
authors.initials: L
authors.lastname: Labat
authors.forename: Fernando
authors.initials: F
authors.lastname: Remião
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cisternino
authors.forename: Xavier
authors.initials: X
authors.lastname: Declèves
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D007262:Infusions, Intravenous; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D040901:Proteomics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009270:Naloxone; D009020:Morphine