We discovered two theoretically new transmitter mechanisms in chronic neuropathic pain, stress and depression: the inhibitory neuromodulator somatostatin via its sst4 receptor and the excitatory tachykinin hemokinin-1 (HK-1). Furthermore, we described a novel regulatory function of the capsaicin-sensitive peptidergic sensory system in pain and stress-related disorders. We investigate the central sensitization mechanisms, glia-neurone interactions and nociception-stress pathways in pain models in relation to 4 main mediators/targets: a) Transient Receptor Potential Ankyrin 1 and Vanilloid 1 (TRPA1/TRPV1) activation and semicarbazide-sensitive amine-oxidase (SSAO) products, b) pituitary adenylate-cyclase activating polypeptide (PACAP) and its receptors, c) somatostatin sst4 receptor, and d) HK-1 structurally related to substance P.
We initiated a preclinical development project of our SSAO inhibitor, as a novel drug candidate for the treatment of neuropathic pain.
Somatostatin is released from the activated capsaicin-sensitive sensory nerves and mediates potent analgesic actions comparable to that of morphine, predominantly through its Gi-protein-coupled sst4 receptor. Sst4 is an excellent target for novel analgesics, since despite the sst2, sst3 and sst5 receptors, it does not mediate endocrine actions. We also provided strong proof of concept evidence that sst4 activation directly inhibits nociceptive neuronal activity. Sst4 is expressed in brain areas involved in pain, stress and depression, such as the cortex, striatum, hippocampus, amygdala, and the dorsal horn of the spinal cord. One of our major findings is that sst4 is not only an important target to inhibit central pain sensitization, but also to induce potent anti-anxiety and anti-depressant actions. Therefore, we initiated the synthesis of small molecule sst4 agonists for drug developmental purposes.
HK-1 has a broad range of central pain-producing and stress/depression-inhibiting actions that are not similar to those of substance P and independent of the tachykinin NK-1 receptor activation. Identification of its target and signalling mechanisms might open new perspectives in tachykinin research.
Neuropathic mechanisms are involved in the pathophysiology of chronic pain states resulting from injury, inflammation, rheumatologic diseases and bone cancer. Due to the not sufficient effectivity and/or severe side effects of the presently available drugs (opioids and adjuvant analgesics), as well as some special features, the management is very problematic. Therefore, there is an urgent need to understand the pathological sensitization mechanisms, identify novel drug targets and develop new compounds acting at them.
The main significances of our project are a) identifying and characterizing theoretically novel targets for chronic neuropathic pain and depression, and b) opening new drug developmental perspectives.
- Helyes Zs PI (2016-2020): TOXI-COOP GINOP 2.2.1-15-2016-00020 R+D Competitiveness and Excellence Collaborations „Development of a novel, multi-target analgesic: pharmacodynamic, preclinical and phase I clinical studies”
- Helyes Zs & Pinter E PIs (2016-2020): PEPSYS GINOP-2.3.2-15-2016-00050 – “Complexity of peptidergic signalization and its role in systemic diseases”
- Helyes Zs PI (2016-2020): STAY ALIVE GINOP-2.3.2-15-2016-00048 – “Excellence of R+D Strategic Centres: Improving the severity and lethality parameters of life-threatening diseases from a translational approach”
- Helyes Zs PI (2017-2020): EFOP-3.6.2 “Investigation of neuroinflammaotory and neurodegenerative mechanisms from the molecule to bedsite” –“Exploring neuroinflammatory mechanisms in central sensitization related to pain”
- Helyes Zs PI (2018-2020): NAP-2 “Neuropeptide-mediated novel mechanisms to inhibit central sensitization in chronic neuropathic pain, stress and depression: translational approaches and drug developmental perspectives”
- Helyes Zs PI (2017-2020): SZKK Core Facility Development EFOP-3.6.1-16-2016-00004
For infrastructure development:
- “Nano-bioimaging: nagy idő- és térbeli felbontású képalkotó eljárások fejlesztése és alkalmazása a biomedicinában”: Kutatási infrastruktúra megerősítése - nemzetköziesedés, hálózatosodás (GINOP-2.3.3-15) infrastructure development (Abraham I consortium leader, Helyes Zs PI, altogether 3 105 095 EUR)
- GINOP-233 ECRIN infrastructure development (University of Pecs & University of Szeged, Helyes Zs PI, for our team: 283 440 EUR)
- GINOP-233 Bioimaging infrastructure development (University of Debrecen & University of Pecs, Helyes Zs PI, for our team: 159 235 EUR)