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Hemokinin-1 is an important mediator of pain in mouse models of neuropathic and inflammatory mechanisms.

Hunyady, Ágnes and Hajna, Zsófia Réka and Gubányi, Tímea and Scheich, Bálint and Kemény, Ágnes and Gaszner, Balázs and Borbély, Éva and Helyes, Zsuzsanna (2019) Hemokinin-1 is an important mediator of pain in mouse models of neuropathic and inflammatory mechanisms. BRAIN RESEARCH BULLETIN, 147. pp. 165-173. ISSN 0361-9230

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Abstract

The Tac4 gene-derived hemokinin-1 (HK-1) is present in pain-related regions and activates the tachykinin NK1 receptor, but with binding site and signaling pathways different from Substance P (SP). NK1 receptor is involved in nociception, but our earlier data showed that it has no role in chronic neuropathic hyperalgesia, similarly to SP. Furthermore, NK1 antagonists failed in clinical trials as analgesics due to still unknown reasons. Therefore, we investigated the role of HK-1 in pain conditions of distinct mechanisms using genetically modified mice. Chronic neuropathic mechanical and cold hyperalgesia after sciatic nerve ligation were determined by dynamic plantar aesthesiometry and withdrawal latency from icy water, motor coordination on the accelerating Rotarod. Peripheral nerve growth factor (NGF) production was measured by ELISA, neuronal and glia cell activation by immunohistochemistry in pain-related regions. Acute somatic and visceral chemonocifensive behaviors were assessed after intraplantar formalin or intraperitoneal acetic-acid injection, respectively. Resiniferatoxin-induced inflammatory mechanical and thermal hyperalgesia by aesthesiometry and increasing temperature hot plate. Chronic neuropathic mechanical and cold hypersensitivity were significantly decreased in HK-1 deficient mice. NGF level in the paw homogenates of intact mice were significantly lower in case of HK-1 deletion. However, it significantly increased under neuropathic condition in contrast to wildtype mice, where the higher basal concentration did not show any alterations. Microglia, but not astrocyte activation was observed 14 days after PSL in the ipsilateral spinal dorsal horn of WT, but not HK-1-deficient mice. However, under neuropathic conditions, the number of GFAP-positive astrocytes was significantly smaller in case of HK-1 deletion. Acute visceral, but not somatic nocifensive behavior, as well as neurogenic inflammatory mechanical and thermal hypersensitivity were significantly reduced by HK-1 deficiency similarly to NK1, but not to SP deletion. We provide evidence for pro-nociceptive role of HK-1, via NK1 receptor activation in acute inflammation models, but differently from SP-mediated actions. Identification of its targets and signaling can open new directions in pain research.

Item Type: Article
Additional Information: Megosztott elsőszerzőség Hunyady Á és Hajna Zs között Megosztott utolsószerzőség Borbély É és Helyes Zs között Funding Agency and Grant Number: National Brain Research Program [2017-1.2.1-NKP-2017-00002, GINOP-2.3.2-15-2016-00050, EFOP-3.6.2-16-2017-00008, EFOP-3.6.1-16-2016-00004, EFOP-3.6.3-VEKOP-16-2017-00009] Funding text: This study was sponsored by National Brain Research Program 2017-1.2.1-NKP-2017-00002, GINOP-2.3.2-15-2016-00050 ("PEPSYS: Complexity of peptidergic signalization and its role in systemic diseases"), EFOP-3.6.2-16-2017-00008 ("The role of neuro-inflammation in neurodegeneration: from molecules to clinics"), EFOP-3.6.1-16-2016-00004 and EFOP-3.6.3-VEKOP-16-2017-00009. Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary János Szentágothai Research Centre, Centre for Neuroscience, University of Pécs, Hungary Department of Medical Biology, Medical School, University of Pécs, Hungary Department of Anatomy, Medical School, University of Pécs, Hungary Export Date: 13 May 2019 CODEN: BRBUD Correspondence Address: Helyes, Z.; Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Szigeti u. 12, Hungary; email: zsuzsanna.helyes@aok.pte.hu Export Date: 10 September 2019 CODEN: BRBUD
Uncontrolled Keywords: TACHYKININS; FORMALIN TEST; microglia; NGF; writhing test; NK1 receptor; partial sciatic nerve ligation; resiniferatoxin-induced hypersensitivity;
Subjects: R Medicine / orvostudomány > R1 Medicine (General) / orvostudomány általában
SWORD Depositor: MTMT SWORD
Depositing User: MTMT SWORD
Date Deposited: 25 Sep 2019 12:39
Last Modified: 25 Sep 2019 12:39
URI: http://real.mtak.hu/id/eprint/101193

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