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Upregulation of the high-affinity choline transporter in colon relieves stress-induced hyperalgesia.
J Pain Res. 2018; 11:1971-1982.JP

Abstract

Background

Irritable bowel syndrome (IBS) is a common disease with hyperalgesia, the mechanisms of which remain elusive. The cholinergic system is known to be involved in pain inhibitory pathways in multiple diseases, and its involvement in IBS is unknown.

Objective

We aimed to determine whether high-affinity choline transporter CHT1, a major determinant of the cholinergic signaling capacity, is involved in regulating intestinal sensations associated with stress-induced visceral pain.

Materials and methods

An IBS rat model was established by chronic water avoidance stress (WAS). Colonic pathologic alterations were detected by H&E staining. Visceral sensations were determined by scoring the abdominal withdrawal reflex (AWR) and visceromotor response (VMR) magnitude of the electromyogram in response to colorectal distension (CRD). Abdominal mechanical hyperalgesia was assessed by counting the number of withdrawal events evoked by applying von Frey filaments. Real-time PCR, Western blot, and immunostaining were performed to identify CHT1 expression in the colon. Acetylcholine (ACh) secretion was determined by ELISA. Effects of MKC-231, a choline uptake enhancer, on visceral pain were examined.

Results

After 10 days of WAS exposure, AWR score and VMR magnitude in response to CRD were significantly enhanced and the number of withdrawal events was elevated. Protein and mRNA levels of CHT1 were considerably increased in the colon after WAS. CHT1 upregulation in the WAS-exposed group was largely abolished by ammonium pyrrolidinedithiocarbamate. The density of CHT1-positive intramuscular cells and enteric neurons in the myenteric plexus was enhanced in WAS-exposed rats. Pharmacologic enhancement of CHT1 activity by MKC-231 gavage could relieve the visceral pain of WAS rats by upregulating CHT1 protein expression and enhancing ACh production.

Conclusion

CHT1 may exert an antinociceptive effect in stress-induced visceral pain by modulating ACh synthesis through nuclear factor kappa B signaling. MKC-231 could be used as a potential drug to treat disorders with hyperalgesia.

Authors+Show Affiliations

Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China, yubp62@163.com. Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei, China, yubp62@163.com.Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China, yubp62@163.com. Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei, China, yubp62@163.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30288092

Citation

Lin, Meng-Juan, and Bao-Ping Yu. "Upregulation of the High-affinity Choline Transporter in Colon Relieves Stress-induced Hyperalgesia." Journal of Pain Research, vol. 11, 2018, pp. 1971-1982.
Lin MJ, Yu BP. Upregulation of the high-affinity choline transporter in colon relieves stress-induced hyperalgesia. J Pain Res. 2018;11:1971-1982.
Lin, M. J., & Yu, B. P. (2018). Upregulation of the high-affinity choline transporter in colon relieves stress-induced hyperalgesia. Journal of Pain Research, 11, 1971-1982. https://doi.org/10.2147/JPR.S164186
Lin MJ, Yu BP. Upregulation of the High-affinity Choline Transporter in Colon Relieves Stress-induced Hyperalgesia. J Pain Res. 2018;11:1971-1982. PubMed PMID: 30288092.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Upregulation of the high-affinity choline transporter in colon relieves stress-induced hyperalgesia. AU - Lin,Meng-Juan, AU - Yu,Bao-Ping, Y1 - 2018/09/21/ PY - 2018/10/6/entrez PY - 2018/10/6/pubmed PY - 2018/10/6/medline KW - high-affinity choline transporter KW - irritable bowel syndrome KW - myenteric plexus KW - visceral hyperalgesia SP - 1971 EP - 1982 JF - Journal of pain research JO - J Pain Res VL - 11 N2 - Background: Irritable bowel syndrome (IBS) is a common disease with hyperalgesia, the mechanisms of which remain elusive. The cholinergic system is known to be involved in pain inhibitory pathways in multiple diseases, and its involvement in IBS is unknown. Objective: We aimed to determine whether high-affinity choline transporter CHT1, a major determinant of the cholinergic signaling capacity, is involved in regulating intestinal sensations associated with stress-induced visceral pain. Materials and methods: An IBS rat model was established by chronic water avoidance stress (WAS). Colonic pathologic alterations were detected by H&E staining. Visceral sensations were determined by scoring the abdominal withdrawal reflex (AWR) and visceromotor response (VMR) magnitude of the electromyogram in response to colorectal distension (CRD). Abdominal mechanical hyperalgesia was assessed by counting the number of withdrawal events evoked by applying von Frey filaments. Real-time PCR, Western blot, and immunostaining were performed to identify CHT1 expression in the colon. Acetylcholine (ACh) secretion was determined by ELISA. Effects of MKC-231, a choline uptake enhancer, on visceral pain were examined. Results: After 10 days of WAS exposure, AWR score and VMR magnitude in response to CRD were significantly enhanced and the number of withdrawal events was elevated. Protein and mRNA levels of CHT1 were considerably increased in the colon after WAS. CHT1 upregulation in the WAS-exposed group was largely abolished by ammonium pyrrolidinedithiocarbamate. The density of CHT1-positive intramuscular cells and enteric neurons in the myenteric plexus was enhanced in WAS-exposed rats. Pharmacologic enhancement of CHT1 activity by MKC-231 gavage could relieve the visceral pain of WAS rats by upregulating CHT1 protein expression and enhancing ACh production. Conclusion: CHT1 may exert an antinociceptive effect in stress-induced visceral pain by modulating ACh synthesis through nuclear factor kappa B signaling. MKC-231 could be used as a potential drug to treat disorders with hyperalgesia. SN - 1178-7090 UR - https://www.unboundmedicine.com/medline/citation/30288092/Upregulation_of_the_high_affinity_choline_transporter_in_colon_relieves_stress_induced_hyperalgesia_ L2 - https://dx.doi.org/10.2147/JPR.S164186 DB - PRIME DP - Unbound Medicine ER -
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