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Expert commentary

by Andrew Russo, PhD

The focus of this abstract is on protease activated receptors or PAR for short. As a starting point, there are mast cells in the meninges that are known to release a devil’s cocktail of inflammatory agents. These agents include serine proteases that can activate the PAR receptors. PARs are a class of transmembrane receptors that have long been implicated in visceral and other pain conditions. A possible role for these receptors in migraine has also been floating around for nearly 15 years since work from the Hargreaves and Levy labs. A recent advance by the Dussor and Price labs was development of a specific agonist of PAR2 that caused nociceptive behaviors of facial sensitivity and grimace in mice. The effects of this agonist were validated with PAR2 knockout mice, a PAR2 antagonist, and sumatriptan treatment. So, where are we now?

The current abstract from the Porreca lab pursued the role of PAR2 using a migraine model involving restraint stress to prime or sensitize the mice to a subsequent migraine trigger. As a trigger they used inhalation of the ketone umbellulone. Umbellulone is noteworthy as a TRPA1 agonist that is the active ingredient of the California Bay Tree, also known as the headache tree. With this combination, they observed periorbital facial tactile sensitivity. Consistent with other studies and models, they found that chronic stress induced transient allodynia as well as a persistent state of “latent sensitization” (priming) that sensitized the mice to a subsequent umbellulone trigger. This trigger was innocuous to non-sensitized mice, but was a trigger to the stress sensitized mice. While not the focus of this study, I think this is a very important point for all migraine studies—migraine patients are sensitive to triggers that do not affect people who do not suffer from migraines. Why? We still do not know, but preclinical models that recapitulate this primed sensitivity are in my opinion closer to the human clinical situation.

Importantly, they then showed that PAR2 blocking antibodies could block the tactile hypersensitivity. As an added benefit they looked at two time points, before and after the stress priming, to narrow down the period of antibody efficacy. Treatment with PAR2 antibody before stress priming, did not prevent the transient stress‐induced allodynia or the allodynia caused by subsequent umbellulone exposure. In contrast, treatment with the PAR2 antibody after stress, but before umbellulone exposure prevented tactile allodynia in the mice.

This is very interesting, but a critical control is missing. Is there still sufficient antibody at the point of umbellulone treatment? In other words, is this a pharmacokinetic finding or a mechanistic finding? Studies on the half-life of the antibody and tests with different antibody doses will easily address this question. In the meantime, we are left with a very promising and exciting finding for migraine therapeutics.

In summary, this study provides data in support of a role of PAR2 in migraine and evidence that PAR2 blocking antibodies may be a therapeutic tool. Beyond the obvious therapeutic significance, an equally important take-home message is that this study with PAR2 provides a good reminder that we should be thinking more about the apparently robust communication that is going on between meningeal immune cells and trigeminal neurons and how that may contribute to migraine pain.

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