Bradykinin (BK) is an inflammatory mediator that plays a pivotal role in pain and hyperalgesia to heat in inflamed tissues by exciting nociceptors and sensitizing them to heat through activation of protein kinase C (PKC). It has been suggested that the capsaicin receptor (VR1), a nociceptor-specific cation channel sensitive to noxious heat, protons, and capsaicin, is a channel that is modified by BK in these effects. In this study, we examined how BK modulates the activity of VR1. We measured VR1 currents using the patch-clamp technique in human embryonic kidney-derived (HEK293) cells expressing VR1 and B2 BK receptor. We found that BK lowered the threshold temperature for activation of VR1 currents in HEK cells down to well below the physiological body temperature in a concentration-dependent manner through PKC activation. We also demonstrated that in capsaicin-sensitive dorsal root ganglion (DRG) neurons the activation threshold of heat-induced current, which is considered to be VR-1 mediated, was lowered by BK and that this effect was also mediated by PKC. These data further support the supposition that modulation of VR1 is a mechanism for the BK-induced excitation of nociceptors and their sensitization to heat.

No abstract

No abstract

The membrane pore proteins, aquaporins (AQPs), facilitate the osmotically driven passage of water and, in some instances, small solutes. Under hyperosmotic conditions, the expression of some AQPs changes, and some studies have shown that the expression of AQP1 and AQP5 is regulated by MAPKs. However, the mechanisms regulating the expression of AQP4 and AQP9 induced by hyperosmotic stress are poorly understood. In this study, we observed that hyperosmotic stress induced by mannitol increased the expression of AQP4 and AQP9 in cultured rat astrocytes, and intraperitoneal infusion of mannitol increased AQP4 and AQP9 in the rat brain cortex. In addition, a p38 MAPK inhibitor, but not ERK and JNK inhibitors, suppressed their expression in cultured astrocytes. AQPs play important roles in maintaining brain homeostasis. The expression of AQP4 and AQP9 in astrocytes changes after brain ischemia or traumatic injury, and some studies have shown that p38 MAPK in astrocytes is activated under similar conditions. Since mannitol is commonly used to reduce brain edema, understanding the regulation of AQPs and p38 MAPK in astrocytes under hyperosmotic conditions induced with mannitol may lead to a control of water movements and a new treatment for brain edema.

Interleukin (IL)-1b is known to play a role in the formation of brain edema after various types of injury. Aquaporin (AQP)4 is also reported to be involved in the progression of brain edema. We tested the hypothesis that AQP4 is induced in response to IL-1b. We found that expression of AQP4 mRNA and protein was significantly up-regulated by IL-1b in cultured rat astrocytes, and that intracerebroventricular administration of IL-1b increased the expression of AQP4 protein in rat brain. The effects of IL-1b on induction of AQP4 were concentration and time dependent. The effects of IL-1b on AQP4 were mediated through IL-1b receptors because they were abolished by co-incubation with IL-1 receptor antagonist. It appeared that IL-1b increased the level of AQP4 mRNA without involvement of de novo protein synthesis because cycloheximide, a protein synthesis inhibitor, did not inhibit the effects of IL-1b. Inhibition of the nuclear factor-jB (NF-jB) pathway blocked the induction of AQP4 by IL-1b in a concentration-dependent manner. These findings show that IL-1b induces expression of AQP4 through a NF-jB pathway without involvement of de novo protein synthesis in rat astrocytes.