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