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Inhibition of P2X7 receptors by Lu AF27139 diminishes colonic hypersensitivity and CNS prostanoid levels in a rat model of visceral pain

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Abstract

Visceral pain is a prominent feature of various gastrointestinal diseases. The P2X7 receptor is expressed by multiple cell types including dorsal root ganglion satellite glial cells, macrophages, and spinal microglia, all of which have been implicated in nociceptive sensitization. We have used the selective and CNS penetrant P2X7 receptor antagonist Lu AF27139 to explore this receptor’s role in distinct rat models of inflammatory and visceral hypersensitivity. Rats injected with CFA in the hindpaw displayed a marked reduction in hindpaw mechanical threshold, which was dose-dependently reversed by Lu AF27139 (3–30 mg/kg, p.o.). In rats injected with TNBS in the proximal colon, the colorectal distension threshold measured distally was significantly lower than sham treated rats at 7 days post-injection (P < 0.001), indicative of a marked central sensitization. Colonic hypersensitivity was also reversed by Lu AF27139 (10–100 mg/kg) and by the κ-opioid receptor agonist U-50,488H (3 mg/kg, s.c.). Moreover, both Lu AF27139 and U-50,488H prevented a TNBS-induced increase in spinal and brain levels of PGE2 and LTB4, as well as an increase in brain levels of PGF2α and TXB2. Lu AF27139 was well tolerated as revealed by a lack of significant effect on rotarod motor function and coordination at all doses tested up to 300 mg/kg. Thus, P2X7 receptor antagonism is efficacious in a rat model of visceral pain, via a mechanism which potentially involves attenuation of microglial function within spinal and/or supraspinal pain circuits, albeit a peripheral site of action cannot be excluded.

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Data availability

Raw data files are available upon reasonable request from MindImmune Therapeutics https://mindimmune.com/.

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Acknowledgements

We would like to thank Rie Christensen and Kirsten Assing for their expert technical assistance.

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Authors and Affiliations

  1. Neuroinflammation Disease Biology Unit Lundbeck Research USA, Paramus, NJ, USA

    Roland G. W. Staal, Adarsh Gandhi, Hua Zhou, Manuel Cajina, Allen Hopper, Suresh Poda, Gamini Chandresana, Stevin H. Zorn, Brian Campbell & Thomas Mӧller

  2. Clinical Research Neurology Lundbeck Research, Valby, Denmark

    Marta Segerdahl

  3. Chemistry and DMPK Lundbeck Research, Valby, Denmark

    Anne-Marie Jacobsen

  4. Neurodegeneration In Vivo Lundbeck Research, Valby, Denmark

    Sara Hestehave & Gordon Munro

  5. Hoba Therapeutics, Ole Maaløes Vej 3, 2200, Copenhagen N, Denmark

    Gordon Munro

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  1. Roland G. W. Staal
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Contributions

Roland Staal: conceptualization, validation, writing — original draft, writing — review and editing, visualization, supervision, project administration; Adarsh Gandhi: methodology, investigation; Hua Zhou: methodology, investigation; Manuel Cajina: methodology, investigation; Anne-Marie Jacobsen: methodology, investigation, formal analysis, writing — original draft; Sara Hestehave: methodology, investigation; Allen Hopper: conceptualization, writing — review and editing, supervision; Suresh Poda: methodology, formal analysis; Gamini Chandrasena: formal analysis; Stevin H. Zorn: conceptualization, visualization, project administration, writing — review and editing; Brian Campbell: project administration; Märta Segerdahl: conceptualization; Thomas Möller: conceptualization; Gordon Munro: conceptualization, validation, writing — original draft, writing — review and editing, visualization, supervision.

Corresponding author

Correspondence to Gordon Munro.

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Experiments were performed in accordance with Danish legislation (Law no. 474 of May 15th, 2014 and Order no. 88 of January 30, 2013) regulating experiments on animals, which is in compliance with the European Directive 2010/63/EU with specific protocols approved by the Danish Council for Animal Experiments.

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Staal, R.G.W., Gandhi, A., Zhou, H. et al. Inhibition of P2X7 receptors by Lu AF27139 diminishes colonic hypersensitivity and CNS prostanoid levels in a rat model of visceral pain. Purinergic Signalling 18, 499–514 (2022). https://doi.org/10.1007/s11302-022-09892-0

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  • DOI: https://doi.org/10.1007/s11302-022-09892-0

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