Opioids are widely indicated in the treatment of various clinical pain states. Morphine is the most commonly prescribed narcotic analgesic used in the treatment of chronic pain. Under normal physiological conditions morphine transport across the blood-brain barrier (BBB) to its site of action in the CMS is impeded by the presence of P-glycoprotein (Pgp), an efflux transport pump located on the luminal membrane of BBB endothelial cells. The major hypothesis of this study is that peripheral inflammation alters the expression, localization, and functional activity of Pgp at the BBB resulting in altered opioid (morphine) uptake across the BBB in vivo. Briefly, the specific aims of this application will be addressed as follows: 1) Examine time course dependent alterations in BBB Pgp expression and localization during lambda-carrageenan induced peripheral inflammation, using techniques of Western blot and confocal microscopy. 2) Investigate time course alterations in BBB Pgp functional activity under lambda-carrageenan peripheral inflammation, using techniques of in-situ brain perfusion. Results gained from this study will provide a better understanding of BBB function and regulation leading to altered drug transport following pathological insult. ? ? ?
| Seelbach, Melissa J; Brooks, Tracy A; Egleton, Richard D et al. (2007) Peripheral inflammatory hyperalgesia modulates morphine delivery to the brain: a role for P-glycoprotein. J Neurochem 102:1677-90 |
