Hemokinin-1 as a Mediator of Arthritis-Related Pain via Direct Activation of Primary Sensory Neurons

Éva Borbély; Ágnes Hunyady; Krisztina Pohóczky; Maja Payrits; Bálint Botz; Attila Mócsai; Alexandra Berger; Éva Szőke; Zsuzsanna Helyes

doi:10.3389/fphar.2020.594479

Hemokinin-1 as a Mediator of Arthritis-Related Pain via Direct Activation of Primary Sensory Neurons

Front Pharmacol. 2021 Jan 13:11:594479. doi: 10.3389/fphar.2020.594479. eCollection 2020.

Authors

Éva Borbély^{1

2}, Ágnes Hunyady^{1

2}, Krisztina Pohóczky^{1

2

3}, Maja Payrits^{1

2}, Bálint Botz^{1

4}, Attila Mócsai⁵, Alexandra Berger⁶, Éva Szőke^{1

2}, Zsuzsanna Helyes^{1

2

7}

Affiliations

¹ János Szentágothai Research Centre and Centre for Neuroscience, University of Pécs, Pécs, Hungary.
² Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Pécs, Hungary.
³ Department of Pharmacology, Faculty of Pharmacy, University of Pécs, Pécs, Hungary.
⁴ Department of Medical Imaging, Medical School, University of Pécs, Pécs, Hungary.
⁵ Department of Physiology, Semmelweis University, Budapest, Hungary.
⁶ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
⁷ PharmInVivo Ltd., Pécs, Hungary.

Abstract

The tachykinin hemokinin-1 (HK-1) is involved in immune cell development and inflammation, but little is known about its function in pain. It acts through the NK1 tachykinin receptor, but several effects are mediated by a yet unidentified target. Therefore, we investigated the role and mechanism of action of HK-1 in arthritis models of distinct mechanisms with special emphasis on pain. Arthritis was induced by i.p. K/BxN serum (passive transfer of inflammatory cytokines, autoantibodies), intra-articular mast cell tryptase or Complete Freund's Adjuvant (CFA, active immunization) in wild type, HK-1- and NK1-deficient mice. Mechanical- and heat hyperalgesia determined by dynamic plantar esthesiometry and increasing temperature hot plate, respectively, swelling measured by plethysmometry or micrometry were significantly reduced in HK-1-deleted, but not NK1-deficient mice in all models. K/BxN serum-induced histopathological changes (day 14) were also decreased, but early myeloperoxidase activity detected by luminescent in vivo imaging increased in HK-1-deleted mice similarly to the CFA model. However, vasodilation and plasma protein extravasation determined by laser Speckle and fluorescent imaging, respectively, were not altered by HK-1 deficiency in any models. HK-1 induced Ca²⁺-influx in primary sensory neurons, which was also seen in NK1-deficient cells and after pertussis toxin-pretreatment, but not in extracellular Ca²⁺-free medium. These are the first results showing that HK-1 mediates arthritic pain and cellular, but not vascular inflammatory mechanisms, independently of NK1 activation. HK-1 activates primary sensory neurons presumably via Ca²⁺ channel-linked receptor. Identifying its target opens new directions to understand joint pain leading to novel therapeutic opportunities.

Keywords: arthritic pain; experimental arthritis; in vivo optical imaging; neuroinflammation; primary sensory neuron; tachykinin.