Peripheral inflammatory hyperalgesia modulates morphine delivery to the brain: a role for P-glycoprotein.
P-glycoprotein (Pgp, ABCB1) is a critical efflux transporter at the blood-brain barrier (BBB) where its luminal location and substrate promiscuity limit the brain distribution of numerous therapeutics. Moreover, Pgp is known to confer multi-drug resistance in cancer chemotherapy and brain diseases, such as epilepsy, and is highly regulated by inflammatory mediators. The involvement of inflammatory processes in neuropathological states has led us to investigate the effects of peripheral inflammatory hyperalgesia on transport properties at the BBB. In the present study, we examined the effects of lambda-carrageenan-induced inflammatory pain (CIP) on brain endothelium regulation of Pgp. Western blot analysis of enriched brain microvessel fractions showed increased Pgp expression 3 h post-CIP. In situ brain perfusion studies paralleled these findings with decreased brain uptake of the Pgp substrate and opiate analgesic, [(3)H] morphine. Cyclosporin A-mediated inhibition of Pgp enhanced the uptake of morphine in lambda-carrageenan and control animals. This indicates that the CIP induced decrease in morphine transport was the result of an increase in Pgp activity at the BBB. Furthermore, antinociception studies showed decreased morphine analgesia following CIP. The observation that CIP modulates Pgp at the BBB in vivo is critical to understanding BBB regulation during inflammatory disease states.
Seelbach
Melissa J
MJ
Department of Medical Pharmacology College of Medicine, The University of Arizona, Tucson, Arizona, USA.
Brooks
Tracy A
TA
Department of Medical Pharmacology College of Medicine, The University of Arizona, Tucson, Arizona, USA.
Egleton
Richard D
RD
Department of Medical Pharmacology College of Medicine, The University of Arizona, Tucson, Arizona, USA.
Davis
Thomas P
TP
Department of Medical Pharmacology College of Medicine, The University of Arizona, Tucson, Arizona, USA.
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000818:Animals; D001522:Behavior, Animal; D001692:Biological Transport; D001921:Brain / Q000473:pathology*; D002351:Carrageenan; D016572:Cyclosporine / Q000494:pharmacology; D004727:Endothelium / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007839:Functional Laterality; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology*; D008833:Microcirculation / Q000378:metabolism; D009020:Morphine / Q000008:administration & dosage*; D009294:Narcotics / Q000008:administration & dosage*; D020556:Neutrophil Infiltration; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004791:Enzyme Inhibitors; D009294:Narcotics; D009020:Morphine; D016572:Cyclosporine; D002351:Carrageenan