Inhibition of the high affinity choline transporter enhances hyperalgesia in a rat model of chronic pancreatitis

Luo, Dan; Chen, Lei; Yu, Baoping

doi:10.1016/j.bbrc.2017.05.036

Cited by 6 publications

(6 citation statements)

References 37 publications

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“…Acetylcholine level was dramatically higher in WAS group than the sham control, which is consistent with the previous study [ 12 ] and indicates that acetylcholine may be released in the inflammatory or noninflammatory algesia models and mediate the antinociceptive effect. The content of acetylcholine was significantly reduced in a dose-dependent manner after the injection of HC-3 in both sham and WAS groups.…”

Section: Discussionsupporting

confidence: 92%

“…High-affinity choline transporter of choline uptake system, which is designated as CHT1, has been verified to be specifically expressed on the presynaptic terminals and involves in the choline uptake [ 10 , 11 ]. Our previous study has showed that CHT1 is increased in the model of pancreatitis-induced pain, and CHT1 inhibitor can enhance the behavioral response to abdominal mechanical stimulation in rats [ 12 ]. However, the involvement of CHT1 in the noninflammatory visceral hypersensitivity induced by chronic stress remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Blockage of High-Affinity Choline Transporter Increases Visceral Hypersensitivity in Rats with Chronic Stress

Zhao

Lin

Pan

et al. 2018

Gastroenterology Research and Practice

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Background Visceral hypersensitivity is a common feature of irritable bowel syndrome. Cholinergic system involves in the development of visceral hypersensitivity, and high-affinity choline transporter (CHT1) is of crucial importance in choline uptake system. However, involvement of CHT1 in visceral hypersensitivity remains unknown. The research aimed to study the CHT1 expression in dorsal root ganglions (DRGs) and the role of CHT1 in visceral hypersensitivity. Methods Repetitive water avoidance stress (WAS) was used to induce visceral hypersensitivity in rats. Colorectal distension (CRD) was determined, and the abdominal withdrawal reflex (AWR) and threshold intensity data were recorded to measure the visceral sensitivity. After intraperitoneal injection of hemicholinium-3 (HC-3), the specific inhibitor of CHT1, CRD data were also recorded. The CHT1 expression of DRGs was investigated by Western blotting, immunohistochemistry, and quantitative RT-PCR. Acetylcholine levels in the DRGs were detected by the assay kit. Results Repetitive WAS increased the AWR score of CRD at high distension pressure and decreased the mean threshold of rats. The CHT1 expression and acetylcholine concentration of DRG were significantly increased in WAS rats. After the administration of HC-3, the AWR score in WAS group was significantly increased at higher distension pressure while the threshold intensity was significantly reduced compared to the normal saline group. Acetylcholine concentration was significantly lower than the normal saline rats. Conclusion Our research firstly reports that CHT1 is overexpressed in noninflammatory visceral hypersensitivity, and blockage of CHT1 can enhance the visceral hypersensitivity. CHT1 may play an inhibitory role in visceral hypersensitivity.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Blockage of High-Affinity Choline Transporter Increases Visceral Hypersensitivity in Rats with Chronic Stress

Zhao

Lin

Pan

et al. 2018

Gastroenterology Research and Practice

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“… 11 Recently, our team demonstrated for the first time that CHT1 in the dorsal root ganglion may be involved in regulating chronic pain in chronic pancreatitis. 14 The current work further demonstrates that CHT1 may play an important inhibitory role in stress-induced visceral hyperalgesia. Upregulation of CHT1 was observed after establishment of stress-induced visceral pain, possibly as a response to the noxious stimulus.…”

Section: Discussionsupporting

confidence: 62%

“… 13 Our recent study suggested for the first time that CHT1 may exert an important inhibitory function in the visceral hyperalgesia induced by chronic pancreatitis. 14 However, there are as yet no reports on the involvement of CHT1 in pain modulation of irritable bowel syndrome (IBS).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of the high-affinity choline transporter in colon relieves stress-induced hyperalgesia

Lin¹,

Yu²

2018

JPR

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BackgroundIrritable 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.ObjectiveWe 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 methodsAn 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.ResultsAfter 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.ConclusionCHT1 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.

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“…Our recent study reported for the first time that CHT1 might exert an important inhibitory effect in the visceral hyperalgesia induced by chronic pancreatitis. 14 No reports regarding the involvement of CHT1 in the modulation of GI motility have been published to date. Herein, the present study aims to explore the alterations in the expression and distribution of CHT1 in the colon and to determine the role of CHT1 in intestinal dysmotility in a rat model of IBS induced by chronic stress.…”

Section: Introductionmentioning

confidence: 99%

Role of High-affinity Choline Transporter 1 in Colonic Hypermotility in a Rat Model of Irritable Bowel Syndrome

Lin

2018

J Neurogastroenterol Motil

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Background/AimsIrritable bowel syndrome (IBS) is a common disease characterized by intestinal dysmotility, the mechanism of which remains elusive. We aim to determine whether the high-affinity choline transporter 1 (CHT1), a determinant of cholinergic signaling capacity, modulates intestinal motility associated with stress-induced IBS.MethodsA rat IBS model was established using chronic water avoidance stress (WAS). Colonic pathological alterations were evaluated histologically and intestinal motility was assessed by intestinal transit time and fecal water content (FWC). Visceral sensitivity was determined by visceromotor response to colorectal distension. RT-PCR, western blotting, and immunostaining were performed to identify colonic CHT1 expression. Contractility of colonic muscle strips was measured using isometric transducers. enzyme-linked immunosorbent assay was used to measure acetylcholine (ACh). We examined the effects of MKC-231, a choline uptake enhancer, on colonic motility.ResultsAfter 10 days of WAS, intestinal transit time was decreased and fecal water content increased. Visceromotor response magnitude in WAS rats in response to colorectal distension was significantly enhanced. Protein and mRNA CHT1 levels in the colon were markedly elevated after WAS. The density of CHT1-positive intramuscular interstitial cells of Cajal and myenteric plexus neurons in WAS rats was higher than in controls. Ammonium pyrrolidine dithiocarbamate partly reversed CHT1 upregulation and alleviated colonic hypermotility in WAS rats. Pharmacological enhancement of CHT1 activity by MKC-231 enhanced colonic motility in control rats via upregulation of CHT1 and elevation of ACh production.ConclusionUpregulation of CHT1 in intramuscular interstitial cells of Cajal and myenteric plexus neurons is implicated in chronic stress-induced colonic hypermotility by modulation of ACh synthesis via nuclear factor-kappa B signaling.

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Inhibition of the high affinity choline transporter enhances hyperalgesia in a rat model of chronic pancreatitis

Cited by 6 publications

References 37 publications

Blockage of High-Affinity Choline Transporter Increases Visceral Hypersensitivity in Rats with Chronic Stress

Blockage of High-Affinity Choline Transporter Increases Visceral Hypersensitivity in Rats with Chronic Stress

Upregulation of the high-affinity choline transporter in colon relieves stress-induced hyperalgesia

Role of High-affinity Choline Transporter 1 in Colonic Hypermotility in a Rat Model of Irritable Bowel Syndrome

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