Voltage-Gated Potassium Channels in IB4-Positive Colonic Sensory Neurons Mediate Visceral Hypersensitivity in the Rat

Qian, Aihua; Liu, Xinqiu; Yao, Weiyan; Wang, Hongyu; Sun, Jing; Zhou, Lin; Yuan, Yaozong

doi:10.1038/ajg.2009.227

Cited by 30 publications

(38 citation statements)

References 30 publications

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“…Our previous study strongly implicated a role for decreased I A in the excitability of pancreatic nociceptive neurons in TNBS-induced model of CP (22). This was in keeping with other studies in various models of visceral inflammation including cystitis (24), TNBS-induced ileitis (18), gastric ulcers (4), and neonatal colonic sensitization (17).…”

Section: Discussionsupporting

confidence: 68%

“…Thus Kv 4.3 is the most likely channel responsible for I A currents in nociceptive neurons. Its contribution was supported by a study of functional colonic pain in rats, showing downregulation of Kv4.3, but not 1.4 or 3.4, in lumbar DRGs (17). However, despite using a dose that resulted in clear changes in excitability of neurons and I A currents, we were unable to demonstrate a significant increase in the expression of Kv4.3 at the mRNA or protein level.…”

Section: G179 Ngf and Neuronal Excitability In Chronic Pancreatitismentioning

confidence: 53%

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Systemic administration of anti-NGF increases A-type potassium currents and decreases pancreatic nociceptor excitability in a rat model of chronic pancreatitis

Zhu

Mehta

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Colak T, Shenoy M, Pasricha PJ. Systemic administration of anti-NGF increases A-type potassium currents and decreases pancreatic nociceptor excitability in a rat model of chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol 302: G176 -G181, 2012. First published October 28, 2011 doi:10.1152/ajpgi.00053.2011We have previously shown that pancreatic sensory neurons in rats with chronic pancreatitis (CP) display increased excitability associated with a decrease in transient inactivating potassium currents (I A), thus accounting in part for the hyperalgesia associated with this condition. Because of its well known role in somatic hyperalgesia, we hypothesized a role for the nerve growth factor (NGF) in driving these changes. CP was induced by intraductal injection of trinitrobenzene sulfonic acid (TNBS) in rats. After 3 wk, anti-NGF antibody or control serum was injected intra-peritoneally daily for 1 wk. This protocol was repeated in another set of experiments in control rats (receiving intraductal PBS instead of TNBS). Pancreatic nociceptors labeled with the dye Dil were identified, and patch-clamp recordings were made from acutely dissociated DRG neurons. Sensory neurons from anti-NGF-treated rats displayed a lower resting membrane potential, increased rheobase, decreased burst discharges in response to stimulatory current, and decreased input resistance compared with those treated with control serum. Under voltage-clamp condition, neuronal I A density was increased in anti-NGF-treated rats compared with rats treated with control serum. However, anti-NGF treatment had no effect on electrophysiological parameters in neurons from control rats. The expression of Kvassociated channel or ancillary genes Kv1.4, 4.1, 4.2, 4.3, and DPP6, DPP10, and KCHIPs 1-4 in pancreas-specific nociceptors was examined by laser-capture microdissection and real-time PCR quantification of mRNA levels. No significant differences were seen among those. These findings emphasize a key role for NGF in maintaining neuronal excitability in CP specifically via downregulation of I A by as yet unknown mechanisms. dorsal root ganglion; trinitrobenzene sulfonic acid; chronic pancreatitis; excitability; transient A-type potassium current A CARDINAL SYMPTOM OF chronic pancreatitis (CP) is pain, which is also one of the most difficult to treat, a fact that reflects our inadequate understanding of its pathogenesis (1). In recent years, however, some progress has been made in this area, aided by the development of a robust and reproducible rat model of painful CP with construct, face, and predictive validity (19). Using this model, we have demonstrated that CP results in the sensitization of pancreatic nociceptors, with increased spontaneous firings and excitability (22). We therefore postulated that, as with other painful inflammatory conditions, CP caused an increased "afferent barrage" from sensitized primary neurons with amplification and persistence of pain (2). Our studies also suggested an ionic basis for these changes as we found a signi...

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Section: Discussionsupporting

confidence: 68%

Section: G179 Ngf and Neuronal Excitability In Chronic Pancreatitismentioning

confidence: 53%

Systemic administration of anti-NGF increases A-type potassium currents and decreases pancreatic nociceptor excitability in a rat model of chronic pancreatitis

Zhu

Mehta

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Although mechanisms of visceral hypersensitivity are not fully understood, accumulating evidence indicates that sensitization of visceral sensory transmission, which includes both peripheral and central sensitization, represents a candidate mechanism responsible for visceral hypersensitivity in IBS (24). The important role of peripheral sensitization mediated by colonic dorsal root ganglion (DRG) neurons has been widely explored in many studies (22,31,40). However, less is known about central sensitization mechanisms at the spinal level in the pathogenesis of visceral hypersensitivity.…”

mentioning

confidence: 99%

“…peripheral sensitization mediated by colonic dorsal root ganglion (DRG) neurons has been widely explored in many studies (22,31,40). However, less is known about central sensitization mechanisms at the spinal level in the pathogenesis of visceral hypersensitivity.…”

mentioning

confidence: 99%

Role of the potassium chloride cotransporter isoform 2-mediated spinal chloride homeostasis in a rat model of visceral hypersensitivity

Tang

Qian

Song

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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Visceral hypersensitivity represents an important hallmark in the pathophysiology of irritable bowel syndrome (IBS), of which the mechanisms remain elusive. The present study was designed to examine whether cation-chloride cotransporter (CCC)-mediated chloride (Cl(-)) homeostasis of the spinal cord is involved in chronic stress-induced visceral hypersensitivity. Chronic visceral hypersensitivity was induced by exposing male Wistar rats to water avoidance stress (WAS). RT-PCR, Western blotting, and immunohistochemistry were used to assess the expression of CCCs in the spinal cord. Patch-clamp recordings were performed on adult spinal cord slices to evaluate Cl(-) homeostasis and Cl(-) extrusion capacity of lamina I neurons. Visceral sensitivity was estimated by measuring the abdominal withdrawal reflex in response to colorectal distension (CRD). After 10 days of WAS exposure, levels of both total protein and the oligomeric form of the K(+)-Cl(-) cotransporter isoform 2 (KCC2), but not Na(+)-K(+)-2Cl(-) transporter isoform 1 (NKCC1), were significantly decreased in the dorsal horn of the lumbosacral spinal cord. The downregulation of KCC2 resulted in a depolarizing shifted equilibrium potential of GABAergic inhibitory postsynaptic current and impaired Cl(-) extrusion capacity in lamina I neurons of the lumbosacral spinal cord from WAS rats. Acute noxious CRD disrupted spinal KCC2 expression and function 2 h after the final distention in sham rats, but not in WAS rats. Pharmacological blockade of KCC2 activity by intrathecal injection of a KCC2 inhibitor [(dihydroindenyl)oxy] alkanoic acid enhanced visceral nociceptive sensitivity in sham rats, but not in WAS rats. These results suggest that KCC2 downregulation-mediated impairment of spinal cord Cl(-) homeostasis may play an important role in chronic stress-induced visceral hypersensitivity.

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“…Thus, activation of mast cells by a topical agent, such as an irritative allergen [22] could initiate interactions between mast cells and sensory neurons which result in cutaneous hypersensitivity, dysesthesia and pain. In this context, it is noteworthy that mast cell hyperplasia appears to be associated with increased excitability of IB4-binding visceral sensory neurons in an experimental model of irritable colon [37].…”

Section: Discussionmentioning

confidence: 99%

Bandeiraea Simplicifolia Isolectin B4 Binds Mast Cells in Human Skin and this Latter Binding is Up-Regulated in Patients with Atopic Dermatitis and Stinging

Lonne-Rahm

El-Nour²,

Aldskogius³

2012

J Clin Exp Dermatol

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The causes of sensitive skin, a common problem in patients with acne rosacea or atopic dermatitis, and even in individuals without obvious skin disease, remain unclear. The density of nerve fibers, levels of neuropeptides as well as the nature and number of mast cells may play a role in this connection. Unmyelinated nociceptive neurons mediate most of the sensation from the skin, and a large part of these neurons are characterized by their ability to bind the lectin Banderiaea simlicifolia isolectin IB4 (IB4). We therefore, examined whether the distribution and extent of IB4-labeling is modified in patients with enhanced skin sensitivity compared to controls. We used immunohistochemistry to label IB4-binding elements in skin biopsies from patients with atopic dermatitis. Of the 20 patients with atopic dermatitis subjected to the stinger test, 11 were stinger-positive and 9 stinger-negative. Stinger-positive papillary dermis contained a significantly larger number of IB4 binding cells, which were shown by double staining for tryptase as well to be mast cells. Binding of IB4 was also detected on dermal nerves associated with adnexa structures in the stratium corneum and on keratinocytes.Since IB4 binds to specific carbohydrate moieties, the increased binding of IB4 by mast cells indicates that alterations in their glycoprotein composition may play a pathophysiological role in connection with stinging.

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Voltage-Gated Potassium Channels in IB4-Positive Colonic Sensory Neurons Mediate Visceral Hypersensitivity in the Rat

Cited by 30 publications

References 30 publications

Systemic administration of anti-NGF increases A-type potassium currents and decreases pancreatic nociceptor excitability in a rat model of chronic pancreatitis

Systemic administration of anti-NGF increases A-type potassium currents and decreases pancreatic nociceptor excitability in a rat model of chronic pancreatitis

Role of the potassium chloride cotransporter isoform 2-mediated spinal chloride homeostasis in a rat model of visceral hypersensitivity

Bandeiraea Simplicifolia Isolectin B4 Binds Mast Cells in Human Skin and this Latter Binding is Up-Regulated in Patients with Atopic Dermatitis and Stinging

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