Research groups
Molecular Pharmacology Research Group
Zsuzsanna Helyes (professor) E-mail:
Tel.: +36 (72) 536-000 (ext: 35591, 35386)
Research interest

Capsaicin-sensitive sensory nerve endings induce systemic inhibitory efferent effects through the release of anti-inflammatory and analgesic somatostatin in addition to mediating pain and hyperalgesia. We investigate the complexity of the role, activation and sensitization of these sensory nerve endings in a variety of animal models, with a focus on chronic disease models. We study the activation mechanisms of the ion channels and receptors in the neuronal membrane, the roles of the neuropeptides and other mediators released from these neurons, immune cells and glial cells, as well as the role of the semicarbazide-sensitive amine oxidase enzyme (SSAO) in pain. We aim to elucidate the functions, specific target molecules and signalling mechanisms of somatostatin, pituitary adenylate cyclase-activating polypeptide (PACAP) and the tachykinin hemokinin-1 (HK-1) in neuronal, vascular, immune and glial functions, neurodegenerative and neuroinflammatory processes.
We have discovered two novel transmitter mechanisms in chronic neuropathic pain, stress and depression: the inhibitory neuromodulatory somatostatin via the sst4 receptor and the stimulatory HK-1. We have described a novel regulatory function of the capsaicin-sensitive peptidergic sensory system in stress-induced alterations, mainly in pain. In pain models, we investigate central sensitization mechanisms, glia-neuron interactions and nociception-stress pathways in relation to 4 main mediators/targets: a) transient receptor potential Ankyrin 1 and Vanilloid 1 (TRPA1/TRPV1) activation and SSAO products, b) PACAP and its receptors, c) somatostatin sst4 receptor and d) HK-1.
We started the clinical development project of our novel multi-target SSAO inhibitor analgesic candidate for neuropathic pain therapy.
Somatostatin is released from the activated capsaicin-sensitive sensory nerves and mediates analgesic effects, primarily through the Gi-protein-coupled sst4 receptor. Sst4 is a promising target for the development of novel analgesic and anti-inflammatory drugs, since unlike sst2, sst3 and sst5 receptors, it does not mediate endocrine effects. We also provided 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 dorsal horn of the spinal cord. In addition to being an important target for inhibiting central pain perception, sst4 also has anti-anxiety and anti-depressant effects. We are currently working on the synthesis and testing of small molecule sst4 agonist drug candidates within the framework of the National Laboratory for Drug Research and Development in collaboration with our industrial partner Algonist Gmbh.
HK-1 has a broad range of central analgesic and stress/depression inhibitory effects independently of the tachykinin NK-1 receptor activation. Identification of the target and signalling mechanisms might provide novel drug development perspectives. This reasearch is conducted by Éva Borbély’s group within her OTKA project. Éva Szőke's group has demonstrated that lipid microdomains (lipid rafts) of the sensory nerve endings membrane surrounding TRPV channels may be important targets for peripheral analgesia. We are investigating the effects of several lipid raft modifying compounds, including cholesterol depleting cyclodextrins, in primary sensory neuron cultures and mouse models.
We also focus on identifying peripheral and central sensitization mechanims in chronic primary pain conditions like Complex Regional Pain Syndrome, fibromyalgia, low back pain and non-inflammatory arthritis in patients and animal models using multi-omics approach (peripheral blood mononuclear cells, plasma), brain imaging (fMRI, manganase-enhanced magnetic resonance imaging), clinical and psychological assessments.

Clinical relevance

Neuropathic pain, Complex Regional Pain Syndrome, Rheumatoid arthritis, Fibromyalgia, Migraine, COPD

Flow cytometer
CO2 incubator
Eppendorf and Hettich centrifuge
Cell dimension Ca-imaging system
TRICARB Beta counter
Leica microtome
Biological Safety Cabinets 
Luna cell counter
Biomarker Tissue Lyser
Perkin Elmer AlphaLisa
Nikon microscopre
Olympus microscope
Plethysmograph for detection of respiratory function
Plethysmometer for odema measurement
Dynamic Plantar Aesthesiometer
Bioseb Dynamic Weight Bearing test
Randall-Selitto Analgesimeter
Increasing temperature hot plate
Increasing temperature water bath
Fluorescence Molecular Tomograph
IVIS LUMINA luminescent imaging
Animal smoke exposure device
Morris water maze
Elevated plus maze
Y maze
Radial arm maze
Light-dark boksz
Open filed test
Chronic animal models
Fluorescence microscopy
In vivo optical imaging
Luminescence imaging
Transgenic technology
RNA scope
cell viability assay
cAMP assay
fluorescence Ca-imaging
radioisotope Ca-uptake experiment
ELISA assay
invasion assay
cytokine detectio
receptor cloning
gene silencing
in silico modelling
animal models of acute, chronic and neuropathic pain
animal models of inflammatory diseases
behavioural tests
acute stress models
chronic stress models
animal models of depression
animal models of anxiety
Representative publications
Analgesic effects of the novel semicarbazide-sensitive amine oxidase inhibitor SZV 1287 in mouse pain models with neuropathic mechanisms: Involvement of transient receptor potential vanilloid 1 and ankyrin 1 receptors. Horváth, Á., Tékus, V., Bencze, N., Szentes, N., Scheich, B., Bölcskei, K., Szőke, É., Mócsai, A., Tóth-Sarudy, É., Mátyus, P., Pintér, E., & Helyes, Z.
Pharmacological research ()
Activity of botulinum toxin type A in cranial dura: implications for treatment of migraine and other headaches. Lacković, Z., Filipović, B., Matak, I., & Helyes, Z.
British journal of pharmacology ()
Somatostatin receptor subtype 4 activation is involved in anxiety and depression-like behavior in mouse models. Scheich, B., Gaszner, B., Kormos, V., László, K., Ádori, C., Borbély, É., Hajna, Z., Tékus, V., Bölcskei, K., Ábrahám, I., Pintér, E., Szolcsányi, J., & Helyes, Z.
Neuropharmacology ()
Capsaicin-sensitive sensory nerves exert complex regulatory functions in the serum-transfer mouse model of autoimmune arthritis Borbély, É., Botz, B., Bölcskei, K., Kenyér, T., Kereskai, L., Kiss, T., Szolcsányi, J., Pintér, E., Csepregi, J. Z., Mócsai, A., & Helyes, Z.
Brain, behavior, and immunity ()
Impaired defense mechanism against inflammation, hyperalgesia, and airway hyperreactivity in somatostatin 4 receptor gene-deleted mice. Helyes, Z., Pintér, E., Sándor, K., Elekes, K., Bánvölgyi, A., Keszthelyi, D., Szoke, E., Tóth, D. M., Sándor, Z., Kereskai, L., Pozsgai, G., Allen, J. P., Emson, P. C., Markovics, A., & Szolcsányi, J.
Proceedings of the National Academy of Sciences of the United States of America ()

TKP2021-EGA-16 Studying brain function and disease using a multidisciplinary approach 2022-2025

National Brain Research Program 3.0 2022-

RRF-2.3.1-21-2022-00015 National Laboratory for Drug Research and Development 2022-2026

OKTA Dr. Szőke Éva OTKA NKFIHA K 138936 A Investigation of the role of lipid raft in TRP ion channel activation: analyses of new analgesic mechanisms 2021-2024

OTKA Dr. Helyes Zsuzsanna NKFIH K 138046 Identification of pain sensitization mechanisms in rheumatoid arthritis 2021-2025

TKP2021-EGA-13  National Research, Development and Innovation Fund of Hungary 2022-2025

ELKH projekt: Cooperation in internationally recognised biomedical research area 2021-2022

 ELKH-PTE Chronic Pain Research Group 2022-2026

OTKA Dr Borbély Éva NKFIH FK 137951: Investigation of the regulatory role of hemokinin-1 in mouse models of depression and its comorbidities