Periorbital Nociception in a Progressive Multiple Sclerosis Mouse Model Is Dependent on TRPA1 Channel Activation.

Diéssica Padilha Dalenogare,Gabriela Trevisan,Maria Fernanda Pessano Fialho,Sara Marchesan Oliveira,Sabrina Qader Kudsi,Juliano Ferreira,Romina Nassini,Guilherme Vargas Bochi,Gabriele Cheiran Pereira,Camila Ritter,Fernando Roberto Antunes Bellinaso,Francesco De Logu,Débora Denardin Lückemeyer,Caren Tatiane De David Antoniazzi,Pierangelo Geppetti,Lorenzo Landini

doi:10.3390/ph14080831

Abstract

Headaches are frequently described in progressive multiple sclerosis (PMS) patients, but their mechanism remains unknown. Transient receptor potential ankyrin 1 (TRPA1) was involved in neuropathic nociception in a model of PMS induced by experimental autoimmune encephalomyelitis (PMS-EAE), and TRPA1 activation causes periorbital and facial nociception. Thus, our purpose was to observe the development of periorbital mechanical allodynia (PMA) in a PMS-EAE model and evaluate the role of TRPA1 in periorbital nociception. Female PMS-EAE mice elicited PMA from day 7 to 14 days after induction. The antimigraine agents olcegepant and sumatriptan were able to reduce PMA. The PMA was diminished by the TRPA1 antagonists HC-030031, A-967079, metamizole and propyphenazone and was absent in TRPA1-deficient mice. Enhanced levels of TRPA1 endogenous agonists and NADPH oxidase activity were detected in the trigeminal ganglion of PMS-EAE mice. The administration of the anti-oxidants apocynin (an NADPH oxidase inhibitor) or alpha-lipoic acid (a sequestrant of reactive oxygen species), resulted in PMA reduction. These results suggest that generation of TRPA1 endogenous agonists in the PMS-EAE mouse model may sensitise TRPA1 in trigeminal nociceptors to elicit PMA. Thus, this ion channel could be a potential therapeutic target for the treatment of headache in PMS patients.

Highlights

Licensee MDPI, Basel, Switzerland.The transient receptor potential ankyrin 1 (TRPA1) is widely expressed in mammalian tissues, including the sensory neurons of the trigeminal ganglion (TG) [1,2,3]
The periorbital mechanical threshold of progressive multiple sclerosis (PMS)-EAE mice was 0.0126 ± 0.0002 g; for control it was 0.4273 ± 0.2177 g 14 days p.i., which shows that the PMS induced by experimental autoimmune encephalomyelitis (PMS-EAE)-induced mice had a very low threshold considering that the lowest von Frey filament used was 0.008 g
Differences among groups were considered significant when p values were less than 0.05 (p < 0.05), using the GraphPad Prism 6.0 software. This model of PMS-EAE caused periorbital mechanical allodynia (PMA) and this measure could be used to explore novel mechanisms for the control of facial nociception, such as that found in headache and migraine

Summary

Introduction

The transient receptor potential ankyrin 1 (TRPA1) is widely expressed in mammalian tissues, including the sensory neurons of the trigeminal ganglion (TG) [1,2,3]. TRPA1 is involved in acute and chronic pain generation, and its activation is mediated by several exogenous and endogenous agonists [1,4,5,6]. The main TRPA1 endogenous agonists produced by the inflammatory process and oxidative stress are hydrogen peroxide (H2 O2 ). 4-hydroxynonenal (4-HNE) [1,7]. These agonists present increased levels in different.

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