Journal
FRONTIERS IN PHARMACOLOGY
Volume 11, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2020.594479
Keywords
experimental arthritis; arthritic pain; primary sensory neuron; neuroinflammation; tachykinin; in vivo optical imaging
Categories
Funding
- Janos Bolyai Research Scholarship of The Hungarian Academy of Sciences
- University of Pecs Faculty of Pharmacy [GYTKKA-2020-01]
- New National Excellence Program of the Ministry for Innovation and Technologies from the National Research, Development and Innovation Fund [UNKP-20-4-II-PTE-465]
- New National Excellence Program of the Ministry for Innovation and Technology [UNKP-20-5-PTE-540]
- Elvonal program from the Hungarian National Agency for Research, Development and Innovation [KKP 129954]
- [EFOP-3.6.2-16-2017-00008]
- [2017-1.2.1-NKP-2017-00002]
- [EFOP-3.6.1.-16-2016-0004]
- [GINOP 2.3.2-15-2016-00050]
- [17886-4/23018/FEKUTSTRAT]
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This research reveals that HK-1 plays a role in arthritic pain primarily through cellular, rather than vascular inflammatory mechanisms, independently of NK1 activation. HK-1 activates primary sensory neurons presumably via a Ca2+ channel-linked receptor. Identifying the specific target of HK-1 opens up new avenues to understand joint pain and develop novel therapeutic approaches.
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.
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