Modulation of Tau Expression in the Colonic Muscle Layer of a Rat Model with Opioid-Induced Constipation
Modulation of Tau Expression in the Colonic Muscle Layer of a Rat Model with Opioid-Induced Constipation
Jinzhao Li1, Yawen Zhang2, Binghan Jia1, Yuqiong Zhao1, Huijuan Luo1, Xiaojie Ren1, Yuan Li3, Xiaoyan Bai1, Jing Ye3 and Junping Li1*
ABSTRACT
The main objective of this study was observe the distribution and expression of tau in the distal colonic muscle layers using opioid-induced constipation (OIC) rat model and to explore the mechanistic correlation between the tau phosphorylation and occurrence of OIC. The rat model of OIC was generated by intraperitoneal (i.p) injection of loperamide hydrochloride (Lop; 5mg/kg), and was evaluated by examining the fecal properties, intestinal propulsion mobility, immunohistochemistry (IHC), western blot (WB) and ELISA for detecting levels of Tau, P-Ser396-tau, P-Ser404-tau, protein kinase C (PKC), p38 MAPK (p38), p-p38 MAPK (p-p38) and µ-opioid receptors (MORs) in the colonic samples. The gene sequencing approach was used to detect alternatively spliced tau isoforms in the distal colonic muscle layer. Sequencing analysis revealed that 3 isoforms of tau, namely 2N4R, 1N4R and 0N4R were expressed in the distal colonic myocardium tissue. OIC rats had small, dry and hard feces, and intestinal propulsion velocity was significantly slower, especially in the distal colon. P-Ser396-Tau, P-Ser404-Tau, PKC, p-p38, p38, and Tau positive cells were distributed in the intestinal muscle plexus of the distal colon, and all of them were colocalized with MORs; though the expressions levels of tau and p38 remained unchanged, others indexes above significantly increased in the distal colonic muscle layer of OIC rats. However, after the administration of p38 blocker SB203580, OIC rats had salami-like feces, with an increase in colonic propulsion velocities; although the expressions levels of Tau and p38 didn’t change significantly in distal colonic muscle layers, the expressions levels of P-Ser396-Tau, P-Ser404-Tau, and p-p38 significantly reduced. To conclude there is a unique distribution pattern of tau within the distal colonic musculature of OIC rats. The abnormal activation of MORs contributes to the hyperphosphorylation of tau protein, which in turn induces the development of OIC.
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