The antihyperalgesic activity of a selective P2X7 receptor antagonist, A-839977, is lost in IL-1αβ knockout mice

Honoré, Prisca; Donnelly‐Roberts, Diana L.; Namovic, Marian T.; Zhong, Chengmin; Wade, Carrie L.; Chandran, Prasant; Zhu, Chang; Carroll, William A.; Pérez-Medrano, Arturo; Iwakura, Yoichiro; Jarvis, Michael F.

doi:10.1016/j.bbr.2009.05.018

Cited by 103 publications

(82 citation statements)

References 41 publications

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“…P2X 7 R involvement in augmented nociceptive signaling was demonstrated previously (8,21,39). Therefore, we assessed the effect of T. spiralis infection upon the response of jejunal afferent fibers to mechanosensitive stimuli in postinfected WT and P2X 7 R 2/2 animals.…”

Section: Discussionmentioning

confidence: 83%

P2X7 Receptor-Dependent Intestinal Afferent Hypersensitivity in a Mouse Model of Postinfectious Irritable Bowel Syndrome

Keating

Pelegrı́n²,

Martínez³

et al. 2011

The Journal of Immunology

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The ATP-gated P2X7 receptor (P2X7R) was shown to be an important mediator of inflammation and inflammatory pain through its regulation of IL-1β processing and release. Trichinella spiralis-infected mice develop a postinflammatory visceral hypersensitivity that is reminiscent of the clinical features associated with postinfectious irritable bowel syndrome. In this study, we used P2X7R knockout mice (P2X7R−/−) to investigate the role of P2X7R activation in the in vivo production of IL-1β and the development of postinflammatory visceral hypersensitivity in the T. spiralis-infected mouse. During acute nematode infection, IL-1β–containing cells and P2X7R expression were increased in the jejunum of wild-type (WT) mice. Peritoneal and serum IL-1β levels were also increased, which was indicative of elevated IL-1β release. However, in the P2X7R−/− animals, we found that infection had no effect upon intracellular, plasma, or peritoneal IL-1β levels. Conversely, infection augmented peritoneal TNF-α levels in both WT and P2X7R−/− animals. Infection was also associated with a P2X7R-dependent increase in extracellular peritoneal lactate dehydrogenase, and it triggered immunological changes in both strains. Jejunal afferent fiber mechanosensitivity was assessed in uninfected and postinfected WT and P2X7R−/− animals. Postinfected WT animals developed an augmented afferent fiber response to mechanical stimuli; however, this did not develop in postinfected P2X7R−/− animals. Therefore, our results demonstrated that P2X7Rs play a pivotal role in intestinal inflammation and are a trigger for the development of visceral hypersensitivity.

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Section: Discussionmentioning

confidence: 83%

P2X7 Receptor-Dependent Intestinal Afferent Hypersensitivity in a Mouse Model of Postinfectious Irritable Bowel Syndrome

Keating

Pelegrı́n²,

Martínez³

et al. 2011

The Journal of Immunology

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“…A role for P2X7Rs in neuropathic pain has also been suggested on the basis that P2X7R mRNA and protein expression are upregulated in spinal microglia follow peripheral nerve injury [43], and pharmacological blockade or genetic deletion of this receptor subtype ameliorates the development of pain hypersensitivity [9,14,22,33,34,49,54]. Recently, genetic variation in P2X7R function has been linked to variations in pain in mice and humans [65].…”

Section: Introductionmentioning

confidence: 99%

P2X4 purinoceptor signaling in chronic pain

Trang

Salter

2012

Purinergic Signalling

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ATP, acting via P2 purinergic receptors, is a known mediator of inflammatory and neuropathic pain. There is increasing evidence that the ATP-gated P2X4 receptor (P2X4R) subtype is a locus through which activity of spinal microglia and peripheral macrophages instigate pain hypersensitivity caused by inflammation or by injury to a peripheral nerve. The present article highlights the recent advances in our understanding of microglia-neuron interactions in neuropathic pain by focusing on the signaling and regulation of the P2X4R. We will also develop a framework for understanding converging lines of evidence for involvement of P2X4Rs expressed on macrophages in peripheral inflammatory pain.

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“…These effects do not appear to be secondary to P2X7-mediated anti-inflammatory effects in models of acute inflammation that are largely driven to prostaglandin E2 [72,73]. P2X7 receptor-selective antagonists also reduce nociception in some, but not all, experimental models of neuropathic pain [67][68][69]).…”

Section: P2x4 Receptorsmentioning

confidence: 99%

“…In experimental models of chronic nociception, A-740003 (compound 37) and A-438079 (compound 36), represent selective and competitive P2X7 antagonists that reduce inflammatory hyperalgesia in rodents [72,73]. These effects do not appear to be secondary to P2X7-mediated anti-inflammatory effects in models of acute inflammation that are largely driven to prostaglandin E2 [72,73].…”

Section: P2x4 Receptorsmentioning

confidence: 99%

P2X receptor antagonists for pain management: examination of binding and physicochemical properties

Gum

Wakefield

Jarvis

2011

Purinergic Signalling

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Enhanced sensitivity to noxious stimuli and the perception of non-noxious stimuli as painful are hallmark sensory perturbations associated with chronic pain. It is now appreciated that ATP, through its actions as an excitatory neurotransmitter, plays a prominent role in the initiation and maintenance of chronic pain states. Mechanistically, the ability of ATP to drive nociceptive sensitivity is mediated through direct interactions at neuronal P2X3 and P2X2/3 receptors. Extracellular ATP also activates P2X4, P2X7, and several P2Y receptors on glial cells within the spinal cord, which leads to a heightened state of neural-glial cell interaction in ongoing pain states. Following the molecular identification of the P2 receptor superfamilies, selective small molecule antagonists for several P2 receptor subtypes were identified, which have been useful for investigating the role of specific P2X receptors in preclinical chronic pain models. More recently, several P2X receptor antagonists have advanced into clinical trials for inflammation and pain. The development of orally bioavailable blockers for ion channels, including the P2X receptors, has been traditionally difficult due to the necessity of combining requirements for target potency and selectivity with suitable absorption distribution, metabolism, and elimination properties. Recent studies on the physicochemical properties of marketed orally bioavailable drugs, have identified several parameters that appear critical for increasing the probability of achieving suitable bioavailability, central nervous system exposure, and acceptable safety necessary for clinical efficacy. This review provides an overview of the antinociceptive pharmacology of P2X receptor antagonists and the chemical diversity and drug-like properties for emerging antagonists of P2X3, P2X2/3, P2X4, and P2X7 receptors. Keywords

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The antihyperalgesic activity of a selective P2X7 receptor antagonist, A-839977, is lost in IL-1αβ knockout mice

Cited by 103 publications

References 41 publications

P2X7 Receptor-Dependent Intestinal Afferent Hypersensitivity in a Mouse Model of Postinfectious Irritable Bowel Syndrome

P2X7 Receptor-Dependent Intestinal Afferent Hypersensitivity in a Mouse Model of Postinfectious Irritable Bowel Syndrome

P2X4 purinoceptor signaling in chronic pain

P2X receptor antagonists for pain management: examination of binding and physicochemical properties

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