Abstract
Pain is a dominant symptom associated with inflammatory conditions. Pharmacotherapy with opioids may be limited by poor blood-brain barrier (BBB) permeability. One approach that may improve central nervous system (CNS) delivery is to target endogenous BBB transporters such as organic anion-transporting polypeptide 1a4 (Oatp1a4). It is critical to identify and characterize biological mechanisms that enable peripheral pain/inflammation to “transmit” upstream signals and alter CNS drug transport processes. Our goal was to investigate, in vivo, BBB functional expression of Oatp1a4 in animals subjected to peripheral inflammatory pain. Inflammatory pain was induced in female Sprague-Dawley rats (200–250 g) by subcutaneous injection of 3% λ-carrageenan into the right hind paw; control animals were injected with 0.9% saline. In rat brain microvessels, Oatp1a4 expression was increased during acute pain/inflammation. Uptake of taurocholate and [d-penicillamine2,5]-enkephalin, two established Oatp substrates, was increased in animals subjected to peripheral pain, suggesting increased Oatp1a4-mediated transport. Inhibition of inflammatory pain with the anti-inflammatory drug diclofenac attenuated these changes in Oatp1a4 functional expression, suggesting that inflammation in the periphery can modulate BBB transporters. In addition, diclofenac prevented changes in the peripheral signaling cytokine transforming growth factor-β1 (TGF-β1) levels and brain microvascular TGF-β receptor expression induced by inflammatory pain. Pretreatment with the pharmacological TGF-β receptor inhibitor 4-[4-(1,3-benzodioxol-5-yl)-5-(2-pyridinyl)-1H-imidazol-2-yl]benzamide (SB431542) increased Oatp1a4 functional expression in λ-carrageenan-treated animals and saline controls, suggesting that TGF-β signaling is involved in Oatp1a4 regulation at the BBB. Our findings indicate that BBB transporters (i.e., Oatp1a4) can be targeted during drug development to improve CNS delivery of highly promising therapeutics.
Footnotes
This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant R01-DA11271] (to T.P.D.); and the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant R01-NS42652] (to T.P.D.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.174151.
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ABBREVIATIONS:
- CNS
- central nervous system
- ALK
- activin receptor-like kinase
- BBB
- blood-brain barrier
- BSP
- bromosulfophthalein
- DPDPE
- [d-penicillamine2,5]-enkephalin
- ELISA
- enzyme-linked immunosorbent assay
- E13S
- estrone-3-sulfate
- Oatp
- organic anion transporting polypeptide
- PI
- protease inhibitor
- PVDF
- polyvinylidene difluoride
- TGF
- transforming growth factor
- SB431542
- 4-[4-(1,3-benzodioxol-5-yl)-5-(2-pyridinyl)-1H-imidazol-2-yl]benzamide
- HPLC
- high-performance liquid chromatography
- P-gp
- P-glycoprotein.
- Received August 17, 2010.
- Accepted November 30, 2010.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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