Increased prokineticin 2 expression in gut inflammation: role in visceral pain and intestinal ion transport

Watson, Robert P.; Lilley, Elliot; Panesar, Moh; Bhalay, Gurdip; Langridge, S.; Tian, Shin-Shay; McClenaghan, Conor; Ropenga, Anna; Zeng, Fanning; Nash, Mark S.

doi:10.1111/j.1365-2982.2011.01804.x

Cited by 38 publications

(29 citation statements)

References 41 publications

(106 reference statements)

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“…Watson et al . found that elevated Bv8 expression in gut inflammation might contribute to visceral pain and ileal ion transport, which indicated that inhibitors of Bv8 signalling likely have clinical utility in inflammatory gastrointestinal disorders. Using the classical complete Freund's adjuvant‐induced inflammatory pain model, a previous study had demonstrated that Bv8 was involved in inflammatory pain .…”

Section: Discussionmentioning

confidence: 99%

Involvement of Spinal Bv8/Prokineticin 2 in a Rat Model of Cancer‐Induced Bone Pain

Hang

Luo

et al. 2015

Basic Clin Pharma Tox

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Cancer-induced bone pain (CIBP) is seriously disruptive to the quality of life in cancer patients, and present therapies are limited. The Bv8/prokineticin 2, a new family of chemokines, has been demonstrated to be involved in inflammatory and neuropathic pain. However, whether it is involved in CIBP remains unclear. This study was designed to examine whether spinal Bv8 was involved in the development of CIBP in rats. A rat CIBP model was constructed by injecting Walker 256 carcinoma cells into the medullary cavity of rat tibia. Tibia inoculation with Walker 256 tumour cells resulted in the development of mechanical hyperalgesia. Compared with sham rats, spinal Bv8 mRNA and protein levels were markedly and time-dependently increased in CIBP rats. Intrathecal administration of Bv8 neutralizing antibody (5 ng) could markedly attenuate pain behaviour as well as up-regulation of spinal TNF-a expression at day 18 after inoculation. Intrathecal pre-treatment with synthetic Bv8 (50 pg) almost completely abolished these effects. These data suggested that spinal Bv8/prokineticin 2 participated in the development of CIBP. Targeting of spinal Bv8 might be a promising strategy for the management of cancer-induced bone pain. Many common types of cancer, such as prostate, breast and lung, have a tendency to metastasize to bone. Tumour metas-tasis to bone can subsequently cause cancer-induced bone pain (CIBP) [1,2]. CIBP is a complicated pain state including a combination of spontaneous pain, background pain and incident pain. CIBP is one of the most feared and enfeebling symptoms and is seriously disruptive to the patients' quality of life. Although numerous methods including chemotherapy, radiotherapy, nerve blocks and analgesic agents are used to control CIBP, researches have reported that at least 20-40% of CIBP is not adequately controlled because current therapies are both insufficient and associated with undesirable adverse effects [3]. Currently, few analgesic treatments have emerged because the molecular and cellular mechanisms underlying the development of CIBP still remain unclear [4]. Bv8 (also named prokineticin 2), a new family of chemo-kines, has attracted growing interest since its identification in 1999 [5]. It acts on two G protein-coupled receptors called prokineticin receptor 1 (PKR1) and prokineticin receptor 2 (PKR2) [6]. Bv8 is highly expressed by neutrophils and other inflammatory cells, and it is considered as a new pronocicep-tive mediator in the site of inflammation [7]. Recently, Bv8 and its receptors were found broadly distributed in spinal dor-sal horn and dorsal root ganglia (DRG), indicating that Bv8/ PKRs may play an important role in the transmission of noci-ceptive perception [8,9]. Intraplantar injection of Bv8 induces a localized hyperalgesia by reducing the nociceptive thresholds to thermal, chemical and mechanical stimuli [5,10]. Recent studies have indicated that Bv8 is involved in inflammatory and neuropathic pain [7,11]. However, CIBP is a mixed-mechanism pain state that is not totally ...

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Section: Discussionmentioning

confidence: 99%

Involvement of Spinal Bv8/Prokineticin 2 in a Rat Model of Cancer‐Induced Bone Pain

Hang

Luo

et al. 2015

Basic Clin Pharma Tox

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“…These results indicated that visceral pain sensitivity intensified and pain threshold decreased in rats after the establishment of the model. A study by Watson et al [37] showed that PK2 gene expression in the gastrointestinal tract was significantly upregulated in ulcerative colitis patients and rodent models of colitis visceral pain induced by mustard oil, trinitrobenzene sulfonate, water-avoidance stress, and Citrobacter rodentium infection. Therefore, it was believed that enhanced PK2 expression induced visceral pain through the PKR2 pathway.…”

Section: Discussionmentioning

confidence: 99%

Mild Moxibustion Decreases the Expression of Prokineticin 2 and Prokineticin Receptor 2 in the Colon and Spinal Cord of Rats with Irritable Bowel Syndrome

Zhou

Zhao

et al. 2014

Evidence-Based Complementary and Alternative Medicine

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It has been proven that prokineticin 2 (PK2) and its receptor PKR2 play an important role in hyperalgesia, while mild moxibustion can relieve visceral hypersensitivity in a rat model of irritable bowel syndrome (IBS). The goal of the present study was to determine the effects of mild moxibustion on the expression of PK2 and PKR2 in colon and spinal cord in IBS rat model, which was induced by colorectal distension using inflatable balloons. After mild moxibustion treatment, abdominal withdrawal reflex (AWR) scores were assessed by colorectal distension; protein and mRNA expression of PK2 and PKR2 in rat colon and spinal cord was determined by immunohistochemistry and fluorescence quantitative PCR. Compared with normal rats, the AWR scores of rats and the expressions of PK2/PKR2 proteins and mRNAs in colon and spinal cord tissue were significantly increased in the model group; compared with the model group, the AWR scores of rats and the expressions of PK2/PKR2 proteins and mRNAs in colon and spinal cord tissue were significantly decreased in the mild moxibustion group. These findings suggest that the analgesia effect of mild moxibustion may be associated with the reduction of the abnormally increased expression of the PK2/PKR2 proteins and mRNAs in the colon and spinal cord.

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“…Mice lacking either PK2 or PKR1 genes displayed a significant reduction in nociception induced by noxious heat and various chemical stimuli such as capsaicin, protons and formalin [15,19]. Recently, Watson et al found that increased PK2 expression in gut inflammation likely contributes to visceral pain [20]. It has been shown that PKR1 and PKR2 are present in nociceptive primary sensory neurons [15,17].…”

Section: Introductionmentioning

confidence: 99%

Prokineticin 2 potentiates acid-sensing ion channel activity in rat dorsal root ganglion neurons

Qiu

Liu

Qiu

et al. 2012

J Neuroinflammation

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BackgroundProkineticin 2 (PK2) is a secreted protein and causes potent hyperalgesia in vivo, and is therefore considered to be a new pronociceptive mediator. However, the molecular targets responsible for the pronociceptive effects of PK2 are still poorly understood. Here, we have found that PK2 potentiates the activity of acid-sensing ion channels in the primary sensory neurons.MethodsIn the present study, experiments were performed on neurons freshly isolated from rat dorsal root ganglion by using whole-cell patch clamp and voltage-clamp recording techniques.ResultsPK2 dose-dependently enhanced proton-gated currents with an EC50 of 0.22 ± 0.06 nM. PK2 shifted the proton concentration-response curve upwards, with a 1.81 ± 0.11 fold increase of the maximal current response. PK2 enhancing effect on proton-gated currents was completely blocked by PK2 receptor antagonist. The potentiation was also abolished by intracellular dialysis of GF109203X, a protein kinase C inhibitor, or FSC-231, a protein interacting with C-kinase 1 inhibitor. Moreover, PK2 enhanced the acid-evoked membrane excitability of rat dorsal root ganglion neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acid stimuli. Finally, PK2 exacerbated nociceptive responses to the injection of acetic acid in rats.ConclusionThese results suggest that PK2 increases the activity of acid-sensing ion channels via the PK2 receptor and protein kinase C-dependent signal pathways in rat primary sensory neurons. Our findings support that PK2 is a proalgesic factor and its signaling likely contributes to acidosis-evoked pain by sensitizing acid-sensing ion channels.

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Increased prokineticin 2 expression in gut inflammation: role in visceral pain and intestinal ion transport

Cited by 38 publications

References 41 publications

Involvement of Spinal Bv8/Prokineticin 2 in a Rat Model of Cancer‐Induced Bone Pain

Involvement of Spinal Bv8/Prokineticin 2 in a Rat Model of Cancer‐Induced Bone Pain

Mild Moxibustion Decreases the Expression of Prokineticin 2 and Prokineticin Receptor 2 in the Colon and Spinal Cord of Rats with Irritable Bowel Syndrome

Prokineticin 2 potentiates acid-sensing ion channel activity in rat dorsal root ganglion neurons

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