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-penicillamine(2,5)]-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.