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Protease activated receptor 2 (PAR2) activation causes migraine-like pain behaviors in mice

Shayne N Hassler1, Fatima B Ahmad1, Carolina C Burgos-Vega1

  • 11 School of Brain and Behavioral Sciences, University of Texas at Dallas, TX, USA.

Cephalalgia : an International Journal of Headache
|June 1, 2018
PubMed
Abstract

Insights

Protease activated receptor 2 (PAR2) activation in the meninges triggers migraine-like pain by stimulating nociceptors. Blocking PAR2 or using sumatriptan alleviates this pain, suggesting PAR2 is a potential therapeutic target for migraines.

Area of Science:

  • Neuroscience
  • Immunology
  • Pharmacology

Background:

  • Migraine pain is often caused by activated meningeal nociceptors.
  • Mast cell degranulation is implicated in migraine pathophysiology, releasing proteases that activate protease-activated receptors (PARs).

Purpose of the Study:

  • To investigate if protease activated receptor 2 (PAR2) generates nociceptive input from the meninges.
  • To explore PAR2's role in migraine pathophysiology using pharmacological agents and knockout mice.

Main Methods:

  • Primary trigeminal and dural cell cultures underwent calcium imaging after exposure to a PAR2 agonist (2at-LIGRL-NH2).
  • Wild-type and PAR2 knockout mice were assessed for hypersensitivity and grimace behavior after dural application of 2at-LIGRL-NH2 or a mast cell degranulator (compound 48-80).
  • Behavioral experiments included administering a PAR2 antagonist (C391) or sumatriptan.

Main Results:

  • 2at-LIGRL-NH2 induced calcium signaling in trigeminal neurons, dural fibroblasts, and meningeal afferents.
  • Dural application of 2at-LIGRL-NH2 or compound 48-80 caused dose-dependent grimace behavior and mechanical allodynia.
  • These migraine-like responses were attenuated by the PAR2 antagonist C391 and in PAR2 knockout mice, and also by sumatriptan.

Conclusions:

  • Functional PAR2 receptors are present on dural afferents and fibroblasts.
  • Activation of dural PAR2 elicits migraine-like behavioral responses.
  • PAR2 may link immune cells to meningeal nociceptor activation, driving migraine pain and representing a potential therapeutic target.
Keywords:
Protease activated receptor 2 (PAR2)dural nociceptormast cellmigrainetrigeminal nerve

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