Role of Spinal Microglia in Visceral Hyperalgesia and NK1R Up-Regulation in a Rat Model of Chronic Stress

Abstract

Background & Aims Chronic psychological stress is associated with visceral hyperalgesia and increased expression of spinal NK1 receptors (NK1R). We aimed to identify the role of spinal microglia in this process. Methods Male Wistar rats were exposed to water avoidance (WA) or sham stress 1 hour each day for 10 days and given daily injections of minocycline, the p38 inhibitor SB203580, or saline. Phosphorylation levels of the kinase p38 (P-p38), the microglia marker OX42, NK1R, and IκBα were assessed by immunoblotting and/or immunostaining of spinal samples collected at Day 11. The visceromotor response (VMR) to colorectal distension at baseline and following WA were also assayed in rats given injections of minocycline, SB203580 or vehicle. The effects of fractalkine were assessed on the VMR in rats exposed to minocycline or vehicle. Results P-p38 protein levels and immunoreactivity were increased in stressed rats and co-localized with OX42-positive cells and neurons in the dorsal horn. This increase was reversed by minocycline or SB203580 exposure. Stress-induced increased NK1R expression was blocked by minocycline but not SB203580. WA-induced decreased IκBα expression was blocked by minocycline and SB203580. WA-induced hyperalgesia was blocked by minocycline and SB203580 IT. Fractalkine-induced hyperalgesia was blocked by minocycline. Conclusions This is the first demonstration that stress-induced activation of spinal microglia has a key role in visceral hyperalgesia and associated spinal NK1R upregulation.

Neuroprotection by Minocycline Caused by Direct and Specific Scavenging of Peroxynitrite

“…Its beneficial in vivo activities have been suggested to be mainly based on its capacity to dampen glia activation and to reduce the tissue concentration of inflammatory mediators contributing to the degeneration process (11,(15)(16)(17)(18)(19). Accordingly, alterations of cell function by the antibiotic are best described for brain macrophages and microglial cells (20,21). The majority of studies describe a reduced up-regulation of inflammatory components, such as surface markers, cytokines, or pro-inflammatory enzymes (22,23).…”

Alteration of antral and proximal colonic motility induced by chronic psychological stress involves central urocortin 3 and vasopressin in rats

“…This model elicits a greater deal of psychological stress than physical stress, and the consequent effects on gastrointestinal (GI) motility and visceral hyperalgesia have been examined (4,6,22,23). In the WA model, animals are placed on a floating board, which is an environment that induces psychological stress (29).…”

Difference in expression of two neurokinin-1 receptors in adenoma and carcinoma from patients that underwent radical surgery for colorectal carcinoma

“…Neurokinin receptor signaling has been well studied using rodent animal cells (41)(42)(43)(44)(45). Activation of the NK-1R at the membrane triggers G protein-mediated signaling events: Activation of phospholipase C, leading to inositol triphosphate formation, which stabilizes intracellular Ca 2+ and eventually activates protein kinase C; activation of adenylate cyclase, leading to stimulation of protein kinase A; and activation of phospholipase A2 and production of arachidonic acid.…”