Purinergic Signalling: Pathophysiology and Therapeutic Potential

Burnstock, Geoffrey

doi:10.2302/kjm.2013-0003-re

Cited by 82 publications

(56 citation statements)

References 107 publications

(95 reference statements)

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“…This assertion has been confirmed in many diseases, such as IBS and interstitial cystitis [6]. Clinical and fundamental research had found that a variety of analgesic drugs have good efficacy during the treatment of visceral pain, thus showing a broad therapeutic potential [7,8]. The application of purinergic receptor antagonists has also expanded the treatment of visceral pain.…”

Section: Introductionmentioning

confidence: 93%

Effect of electroacupuncture on P2X3 receptor regulation in the peripheral and central nervous systems of rats with visceral pain caused by irritable bowel syndrome

Weng

Wu²,

Zhou

et al. 2015

Purinergic Signalling

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The aim of this study is to investigate the role of the purinergic receptor P2X 3 in the peripheral and central nervous systems during acupuncture treatment for the visceral pain of irritable bowel syndrome (IBS). A total of 24 8-day-old Sprague-Dawley (SD) neonatal male rats (SPF grade) were stimulated using colorectal distention (CRD) when the rats were awake. The modeling lasted for 2 weeks with one stimulation per day. After 6 weeks, the rats were randomly divided into three groups of eight each: (1) the normal group (NG, n= 8); (2) the model group (MG, n=8); and (3) the model+ electroacupuncture group (EA, n = 8) that received electroacupuncture at a needling depth of 5 mm at the Shangjuxu (ST37, bilateral) and Tianshu (ST25, bilateral) acupoints. The parameters of the Han's acupoint nerve stimulator (HANS) were as follows: sparse-dense wave with a frequency of 2/100 Hz, current of 2 mA, 20 min/stimulation, and one stimulation per day; the treatment was provided for seven consecutive days. At the sixth week after the treatment, the abdominal withdrawal reflex (AWR) score was determined; immunofluorescence and immunohistochemistry were used to measure the expression of the P2X 3 receptor in myenteric plexus neurons, prefrontal cortex, and anterior cingulate cortex; and, a real-time PCR assay was performed to measure the expression of P2X 3 messenger RNA (mRNA) in the dorsal root ganglion (DRG) and spinal cord. After stimulation with CRD, the expression levels of the P2X 3 receptor in the intercolonic myenteric plexus, DRG, spinal cord, prefrontal cortex, and anterior cingulate cortex were upregulated, and the sensitivity of the rats to IBS visceral pain was increased. Electroacupuncture (EA) could downregulate the expression of the P2X 3 receptor and ease the sensitivity to visceral pain. The P2X 3 receptor plays an important role in IBS visceral pain. The different levels of P2X 3 in the peripheral enteric nervous system and central nervous system mediate the effects of the EA treatment of the visceral hyperalgesia of IBS.

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Section: Introductionmentioning

confidence: 93%

Effect of electroacupuncture on P2X3 receptor regulation in the peripheral and central nervous systems of rats with visceral pain caused by irritable bowel syndrome

Weng

Wu²,

Zhou

et al. 2015

Purinergic Signalling

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“…Similar to growth factors, ATP exerts mitogenic effects on numerous cell types [315]. And similar to nucleotides, the growth factors epidermal growth factor (EGF) and vascular endothelial growth factors (VEGF) stimulated a variety of cellular responses, including cell proliferation and migration [316,317]. ATP and UTP were found to drive, in the identical cell type, intracellular signal cascades and cellular responses corresponding to those of EGF.…”

Section: Nucleotide Activates or Co-activates The Receptor Of Anothermentioning

confidence: 99%

Extracellular ATP and other nucleotides—ubiquitous triggers of intercellular messenger release

Zimmermann

2015

Purinergic Signalling

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Extracellular nucleotides, and ATP in particular, are cellular signal substances involved in the control of numerous (patho)physiological mechanisms. They provoke nucleotide receptor-mediated mechanisms in select target cells. But nucleotides can considerably expand their range of action. They function as primary messengers in intercellular communication by stimulating the release of other extracellular messenger substances. These in turn activate additional cellular mechanisms through their own receptors. While this applies also to other extracellular messengers, its omnipresence in the vertebrate organism is an outstanding feature of nucleotide signaling. Intercellular messenger substances released by nucleotides include neurotransmitters, hormones, growth factors, a considerable variety of other proteins including enzymes, numerous cytokines, lipid mediators, nitric oxide, and reactive oxygen species. Moreover, nucleotides activate or co-activate growth factor receptors. In the case of hormone release, the initially paracrine or autocrine nucleotide-mediated signal spreads through to the entire organism. The examples highlighted in this commentary suggest that acting as ubiquitous triggers of intercellular messenger release is one of the major functional roles of extracellular nucleotides. While initiation of messenger release by nucleotides has been unraveled in many contexts, it may have been overlooked in others. It can be anticipated that additional nucleotide-driven messenger functions will be uncovered with relevance for both understanding physiology and development of therapy.

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“…Sensory neurons in dorsal root ganglion (DRG) express P2X receptors (P2XRs), ligand-gated cation channels that are assembled from at least seven different subunits (5,6,10,30). Spinal afferents predominantly display homomeric P2X3 and heteromeric P2X2/3 subtypes, and this system has been shown to be important in several animal models of visceral injury, including the urinary bladder (12, 24) and the colon (42).…”

mentioning

confidence: 99%

Adrenergic signaling mediates mechanical hyperalgesia through activation of P2X3 receptors in primary sensory neurons of rats with chronic pancreatitis

Wang

Zhu

Jin

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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. Adrenergic signaling mediates mechanical hyperalgesia through activation of P2X3 receptors in primary sensory neurons of rats with chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol 308: G710 -G719, 2015. First published January 29, 2015; doi:10.1152/ajpgi.00395.2014.-The mechanism of pain in chronic pancreatitis (CP) is poorly understood. The aim of this study was designed to investigate roles of norepinephrine (NE) and P2X receptor (P2XR) signaling pathway in the pathogenesis of hyperalgesia in a rat model of CP. CP was induced in male adult rats by intraductal injection of trinitrobenzene sulfonic acid (TNBS). Mechanical hyperalgesia was assessed by referred somatic behaviors to mechanical stimulation of rat abdomen. P2XR-mediated responses of pancreatic dorsal root ganglion (DRG) neurons were measured utilizing calcium imaging and whole cell patch-clamp-recording techniques. Western blot analysis and immunofluorescence were performed to examine protein expression. TNBS injection produced a significant upregulation of P2X3R expression and an increase in ATP-evoked responses of pancreatic DRG neurons. The sensitization of P2X3Rs was reversed by administration of ␤-adrenergic receptor antagonist propranolol. Incubation of DRG neurons with NE significantly enhanced ATPinduced intracellular calcium signals, which were abolished by propranolol, and partially blocked by protein kinase A inhibitor H-89. Interestingly, TNBS injection led to a significant elevation of NE concentration in DRGs and the pancreas, an upregulation of ␤ 2-adrenergic receptor expression in DRGs, and amplification of the NE-induced potentiation of ATP responses. Importantly, pancreatic hyperalgesia was markedly attenuated by administration of purinergic receptor antagonist suramin or A317491 or ␤ 2-adrenergic receptor antagonist butoxamine. Sensitization of P2X3Rs, which was likely mediated by adrenergic signaling in primary sensory neurons, contributes to pancreatic pain, thus identifying a potential target for treating pancreatic pain caused by inflammation. chronic pancreatitis; dorsal root ganglion; purinergic receptors; norepinephrine; protein kinase A CHRONIC PANCREATITIS (CP) is a progressive inflammatory disorder characterized by repeated attacks of abdominal pain, fibrosis, and destruction of the glandular pancreas (15,29,39). Pain is a cardinal feature of CP, featured as burning, intermittent, and shooting pain (13). It is, not only the most frequent and dominant symptom of patients with CP, but also the most difficult to treat (1,3,22,35). Our lack of knowledge about what causes pain in pancreatitis has been a serious obstacle to treatment on these patients, with pain frequently relapsing or persisting (1, 31). Basic research of pancreatic nerves and experimental human pain studies have provided evidence that pain processing is abnormal in these patients and in many conditions resembles that seen in neuropathic pain disorders (34). Despite much speculation, little is known about the detailed pathophysiology of pain in ...

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Purinergic Signalling: Pathophysiology and Therapeutic Potential

Cited by 82 publications

References 107 publications

Effect of electroacupuncture on P2X3 receptor regulation in the peripheral and central nervous systems of rats with visceral pain caused by irritable bowel syndrome

Effect of electroacupuncture on P2X3 receptor regulation in the peripheral and central nervous systems of rats with visceral pain caused by irritable bowel syndrome

Extracellular ATP and other nucleotides—ubiquitous triggers of intercellular messenger release

Adrenergic signaling mediates mechanical hyperalgesia through activation of P2X3 receptors in primary sensory neurons of rats with chronic pancreatitis

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