P-glycoprotein trafficking at the blood-brain barrier altered by peripheral inflammatory hyperalgesia.

Abstract

P-glycoprotein (ABCB1/MDR1, EC 3.6.3.44), the major efflux transporter at the blood-brain barrier (BBB), is a formidable obstacle to CNS pharmacotherapy. Understanding the mechanism(s) for increased P-glycoprotein activity at the BBB during peripheral inflammatory pain is critical in the development of novel strategies to overcome the significant decreases in CNS analgesic drug delivery. In this study, we employed the λ-carrageenan pain model (using female Sprague-Dawley rats), combined with confocal microscopy and subcellular fractionation of cerebral microvessels, to determine if increased P-glycoprotein function, following the onset of peripheral inflammatory pain, is associated with a change in P-glycoprotein trafficking which leads to pain-induced effects on analgesic drug delivery. Injection of λ-carrageenan into the rat hind paw induced a localized, inflammatory pain (hyperalgesia) and simultaneously, at the BBB, a rapid change in colocalization of P-glycoprotein with caveolin-1, a key scaffolding/trafficking protein. Subcellular fractionation of isolated cerebral microvessels revealed that the bulk of P-glycoprotein constitutively traffics to membrane domains containing high molecular weight, disulfide-bonded P-glycoprotein-containing structures that cofractionate with membrane domains enriched with monomeric and high molecular weight, disulfide-bonded, caveolin-1-containing structures. Peripheral inflammatory pain promoted a dynamic redistribution between membrane domains of P-glycoprotein and caveolin-1. Disassembly of high molecular weight P-glycoprotein-containing structures within microvascular endothelial luminal membrane domains was accompanied by an increase in ATPase activity, suggesting a potential for functionally active P-glycoprotein. These results are the first observation that peripheral inflammatory pain leads to specific structural changes in P-glycoprotein responsible for controlling analgesic drug delivery to the CNS.

• Authors: Gwen McCaffrey, William D Staatz, Lucy Sanchez-Covarrubias, Jessica D Finch, Kristen Demarco, Mei-Li Laracuente, Patrick T Ronaldson, Thomas P Davis
• Journal: Journal of neurochemistry (J Neurochem) Vol. 122 Issue 5 Pg. 962-75 (Sep 2012) ISSN: 1471-4159 [Electronic] England
• PMID: 22716933 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Caveolin 1
• Carrageenan
• Adenosine Triphosphatases

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Adenosine Triphosphatases (metabolism)
• Animals
• Blood-Brain Barrier (drug effects, physiopathology)
• Carrageenan (toxicity)
• Caveolin 1 (metabolism)
• Disease Models, Animal
• Female
• Hyperalgesia (drug therapy, etiology, pathology)
• Microvessels (drug effects, metabolism, pathology)
• Molecular Weight
• Neurogenic Inflammation (chemically induced, complications)
• Protein Transport (drug effects)
• Rats
• Rats, Sprague-Dawley