In this study, we examine the mechanisms underlying this effect, in particular the roles of cholecystokinin (CCK) and nerve growth factor (NGF), in an animal model of central nervous system (CNS) inflammation induced by spinal administration of lipopolysaccharide (LPS).

Although spinal administration of LY-225910 (25 ng), a CCK-B antagonist, enhanced morphine analgesia in naive rats, it was unable to do so in LPS-treated animals. Conversely, spinal CCK-8S administration (1 ng) decreased morphine analgesia in LPS-treated rats, but not in naive animals. Further, spinal anti-NGF (3 mu g) was able to reduce morphine analgesia in LPS-treated rats, but not in naive animals, an effect that was reversed by spinal administration of LY225910. While CCK-8S concentration was increased EPZ-6438 solubility dmso in spinal cord extracts of LPS animals as compared to controls, morphine-induced spinal CCK release in the extracellular space, as selleck compound measured by in-vivo spinal cord microdialysis was inhibited in LIPS animals as compared to controls, and this was reversed by anti-NGF pretreatment. Finally, chronic spinal administration

of beta-NGF (7 mu g/day) for 7 days enhanced spinal morphine analgesia, possibly by mimicking a CNS inflammatory state. We suggest that in intrathecally LPS-treated rats, spinal CCK release is altered resulting in enhanced morphine analgesia, and that this mechanism may be regulated to an important extent by NGF. (C) 2008 Elsevier Ltd. All GPX6 rights reserved.”
“Purpose:

Congenital ureteropelvic junction obstruction has been associated with aberrant ureteral smooth muscle organization. Recent evidence has shown that BMP4 may be involved in ureteral morphogenesis. We determined whether the disruption of BMP4 signaling results in abnormal smooth muscle investment of the ureter and ureteropelvic junction.

Materials and Methods: We used a Cre mediated Bmp4 knockout system to conditionally excise the Bmp4 gene in developing mouse embryos. Kidney rudiments were isolated from embryos at varying gestational ages from WT and conditional knockout mice. Metanephric kidney explants were cultured in the presence or absence of the BMP antagonist Noggin. Agarose beads pre-incubated with Gremlin, another BMP antagonist, were used for localized disruption of BMP signaling. Frozen sections and whole metanephric explants were then analyzed by immunofluorescence.

Results: Bmp4 gene excision resulted in a dose dependent loss of ureteral smooth muscle. Antagonism of BMP signaling inhibited ureteral smooth muscle investment in a dose dependent manner and was paralleled by a dose dependent decrease in the immediate downstream targets of BMP signaling, phosphorylated Smad1, 5 and 8. Localized antagonism of BMP resulted in the focal disruption of ureteral smooth muscle investment.