Role of PAR-2 Receptors in Migraine Using a Novel, Translatable Injury-Free Preclinical Model

Caroline Kopruszinski, PhD

AHSAM 2020 - Oral session
Published on October 2, 2020 | NEW

4 minute listen

7 minute read

Key messages

  • A novel, injury-free, preclinical model of migraine demonstrated chronic stress induced transient allodynia and a persistent state of “latent sensitization” when exposed to umbellulone.
  • Blockade of PAR-2 receptors prevented umbellulone-induced allodynia in stress-primed animals.
  • PAR2 is an important contributor to migraine etiology and targeting PAR-2 receptors may represent a novel strategy to prevent migraine.
  • Background

    What do we already know about this topic?
  • Findings

    What does this study add?
  • Perspectives

    How does this study impact clinical practice?
  • Expert commentary

    by Andrew Russo, PhD

Key messages

  • A novel, injury-free, preclinical model of migraine demonstrated chronic stress induced transient allodynia and a persistent state of “latent sensitization” when exposed to umbellulone.
  • Blockade of PAR-2 receptors prevented umbellulone-induced allodynia in stress-primed animals.
  • PAR2 is an important contributor to migraine etiology and targeting PAR-2 receptors may represent a novel strategy to prevent migraine.

Background

What do we already know about this topic?

  • Migraine pain is thought to ultimately require activation of nociceptors in the cranial meninges.
  • This process likely involves dural mast cell (MC) degranulation and secretion of inflammatory mediators, cytokines, chemokines and proteases that activate nociceptors.
  • Tryptase, the most abundant MC protease, has been shown to stimulate additional MC as well as trigeminal nociceptors by activating the protease-activated receptors 2 (PAR-2) receptor.1,2
  • Mast cell or neuronal PAR-2 receptors may, therefore, represent a novel target for migraine treatment.

How was this study conducted?

  • In-vivo study conducted in 6-week-old female C57BL/6 mice injected with a fully humanized PAR-2 monoclonal antibody (mAb) either 72 hours before the first restraint-stress, or 72 hours before umbellulone inhalational exposure, to determine the contribution of PAR-2 receptors in preventing (a) restraint stress-induced sensitization and (b) allodynia induced by inhalational umbellulone.
  • To induce the injury-free migraine model, mice were submitted to three days of restraint stress, and tactile frequency of response was evaluated over the next two weeks.
  • Fourteen days after the last restraint stress, mice were exposed to inhalational umbellulone oil (0.01M), for 30 min under isofluorane anesthesia (2%), followed by tactile response frequency assessment.

Findings

What does this study add?

  • Stress-induced transient allodynia resolved by day 14. 
  • Inhalational umbellulone reinstated allodynia only in animals previously primed with stress.
  • Treatment with PAR-2 mAb before restraint stress priming, did not prevent stress-induced allodynia or the stress-induced priming that was revealed by umbellulone exposure.
  • In contrast, administration of the PAR-2 mAb before the umbellulone exposure in animals previously primed with stress prevented tactile allodynia.

Perspectives

How does this study impact clinical practice?

  • The results suggest that in stress-exposed animals, activation of transient receptor potential ankyrin 1 (TRPA1) may promote degranulation of mast cells and consequent activation of neuronal and mast cells PAR-2 receptors eliciting allodynia.
  • Targeting PAR-2 receptors may therefore represent a novel strategy to prevent migraine.

Perspectives

How does this study impact clinical practice?

  • The results suggest that in stress-exposed animals, activation of transient receptor potential ankyrin 1 (TRPA1) may promote degranulation of mast cells and consequent activation of neuronal and mast cells PAR-2 receptors eliciting allodynia.
  • Targeting PAR-2 receptors may therefore represent a novel strategy to prevent migraine.

This is a highlights summary of an oral session given at the AHSAM 2020 Virtual Annual Scientific Meeting and presented by:

Caroline Kopruszinski, PhD
Postdoctoral researcher
University of Arizona
Tucson, Arizona

The content is produced by Infomedica, the official reporting partner of ASHAM 2020 Virtual Annual Scientific Meeting. The summary text was drafted by Goldcrest Medical Writing, reviewed by Marco Vercellino, MD, an independent external expert, and approved by Jessica Ailani, MD, FAHS and Mark J. Burish, MD, PhD, the scientific editors of the program.

The presenting authors of the original session had no part in the creation of this conference highlights summary.

In addition, an expert commentary on the topic has been provided by:

Andrew Russo, PhD
University of Iowa, Iowa City, IA, USA

Andrew Russo, PhD
University of Iowa, Iowa City, IA, USA

Andrew Russo is Professor of Molecular Physiology and Biophysics, and Neurology, at the University of Iowa. Dr. Russo received his PhD in Biochemistry from the University of California, Berkeley, followed by postdoctoral training in molecular neurobiology at UCSD. Dr. Russo’s research is focused on how the neuropeptide CGRP contributes to the altered sensory perception and pain of migraine. The lab uses approaches ranging from epigenetics to mouse behavior. The overall goal of his studies is to develop effective diagnostic and therapeutic strategies for migraine and post-traumatic headache.

1. Nassini R, Materazzi S, Vriens J, et al. The ‘headache tree’ via umbellulone and TRPA1 activates the trigeminovascular system, Brain 2012;135:376–390.

2. Benemei S, Appendino G, Geppetti P. Pleasant natural scent with unpleasant effects: cluster headache-like attacks triggered by Umbellularia californica. Cephalalgia 2010;30:744-746.



Headache
Clinical Studies


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