Persistent pain results in suffering and poor quality of life. In addition, the lack of proper control of persistent pain may lead to the development of physical and mental disabilities, which further devastate the patient’s quality of life. The main goal of our research activities is to identify pivotal mechanisms in neuronal processing of information induced by various persistent painful conditions, which could be used to develop new pain killers. Hence, our activities will ultimately improve patients’ quality of life.
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Journal articleNagy I, Suosa-Valente J, Varga A, et al., 2017,
Inflammation of peripheral tissues and injury to peripheral nerves induce diferring effects in the expression of the calcium-sensitive anandamide synthesising enzyme and related molecules in ratprimary sensory neuron
, Journal of Comparative Neurology, Vol: 525, Pages: 1778-1796, ISSN: 1096-9861Elevation of intracellular Ca2+ concentration induces the synthesis of N0arachydonoylethanolamine (anandamide) in a sub0population of primary sensory neurons. N0acylphosphatidylethanolamine phospholipase D (NAPE0PLD) is the only known enzyme, which synthesises anandamide in a Ca2+0dependent manner. NAPE0PLD mRNA, as well as anandamide's main targets, the excitatory transient receptor potential vanilloid type 1 ion channel (TRPV1) and the inhibitory cannabinoid type 1 (CB1) receptor and the main anandamide0hydrolysing enzyme fatty acid amide hydrolase (FAAH) are all expressed by sub0populations of nociceptive primary sensory neurons. Thus, NAPE0PLD, TRPV1, the CB1 receptor and FAAH could form an autocrine signalling system, which could shape the activity of a major sub0population of nociceptive primary sensory neurons, hence contribute to the development of pain. While the expression patterns of TRPV1, the CB1 receptor and FAAH have been comprehensively elucidated, little is known about NAPE0PLD expression in primary sensory neurons under physiological and pathological conditions. We report that NAPE0PLD is expressed by about a third of primary sensory neurons, the overwhelming majority of which also express nociceptive markers as well as the CB1 receptor, TRPV1 and FAAH. Inflammation of peripheral tissues and injury to peripheral nerves induce differing but concerted changes in the expression pattern of NAPE0PLD, the CB1 receptor, TRPV1 and FAAH. Together these data indicate the existence of the anatomical basis for an autocrine signalling system, in a major proportion of nociceptive primary sensory neurons, and that alterations in that autocrine signalling by peripheral pathologies could contribute to the development of both inflammatory and neuropathic pain.
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Journal articleTorres-Perez JV, Santha P, Varga A, et al., 2017,
Phosphorylated histone 3 at serine 10 identifies activated spinal neurons and contributes to the development of tissue injury-associated pain
, Scientific Reports, Vol: 7, ISSN: 2045-2322Transcriptional changes in superficial spinal dorsal horn neurons (SSDHN) are essential in the development and maintenance of prolonged pain. Epigenetic mechanisms including post-translational modifications in histones are pivotal in regulating transcription. Here, we report that phosphorylation of serine 10 (S10) in histone 3 (H3) specifically occurs in a group of rat SSDHN following the activation of nociceptive primary sensory neurons by burn injury, capsaicin application or sustained electrical activation of nociceptive primary sensory nerve fibres. In contrast, brief thermal or mechanical nociceptive stimuli, which fail to induce tissue injury or inflammation, do not produce the same effect. Blocking N-methyl-D-aspartate receptors or activation of extracellular signal-regulated kinases 1 and 2, or blocking or deleting the mitogen- and stress-activated kinases 1 and 2 (MSK1/2), which phosphorylate S10 in H3, inhibit up-regulation in phosphorylated S10 in H3 (p-S10H3) as well as fos transcription, a down-stream effect of p-S10H3. Deleting MSK1/2 also inhibits the development of carrageenan-induced inflammatory heat hyperalgesia in mice. We propose that p-S10H3 is a novel marker for nociceptive processing in SSDHN with high relevance to transcriptional changes and the development of prolonged pain.
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Journal articleWhite JPM, Cibelli M, Urban L, et al., 2016,
TRPV4: MOLECULAR CONDUCTOR OF A DIVERSE ORCHESTRA
, Physiological Reviews, Vol: 96, Pages: 911-973, ISSN: 1522-1210Transient receptor potential vanilloid type 4 (TRPV4) is a calcium-permeable nonselective cation channel, originally described in 2000 by research teams led by Schultz (Nat Cell Biol 2: 695–702, 2000) and Liedtke (Cell 103: 525–535, 2000). TRPV4 is now recognized as being a polymodal ionotropic receptor that is activated by a disparate array of stimuli, ranging from hypotonicity to heat and acidic pH. Importantly, this ion channel is constitutively expressed and capable of spontaneous activity in the absence of agonist stimulation, which suggests that it serves important physiological functions, as does its widespread dissemination throughout the body and its capacity to interact with other proteins. Not surprisingly, therefore, it has emerged more recently that TRPV4 fulfills a great number of important physiological roles and that various disease states are attributable to the absence, or abnormal functioning, of this ion channel. Here, we review the known characteristics of this ion channel's structure, localization and function, including its activators, and examine its functional importance in health and disease.
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Journal articleSousa-Valente J, Andreou AP, Urban L, et al., 2014,
Transient receptor potential ion channels in primary sensory neurons as targets for novel analgesics
, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 171, Pages: 2508-2527, ISSN: 0007-1188- Author Web Link
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- Citations: 69
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Journal articleMistry S, Paule CC, Varga A, et al., 2014,
Prolonged exposure to bradykinin and prostaglandin E2 increases TRPV1 mRNA but does not alter TRPV1 and TRPV1b protein expression in cultured rat primary sensory neurons
, NEUROSCIENCE LETTERS, Vol: 564, Pages: 89-93, ISSN: 0304-3940- Author Web Link
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- Citations: 11
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Journal articleVeress G, Meszar Z, Muszil D, et al., 2012,
Characterisation of cannabinoid 1 receptor expression in the perikarya, and peripheral and spinal processes of primary sensory neurons.
, Brain Structure & Function -
Journal articleFidalgo AR, Cibelli M, White JPM, et al., 2011,
Systemic inflammation enhances surgery-induced cognitive dysfunction in mice
, NEUROSCIENCE LETTERS, Vol: 498, Pages: 63-66, ISSN: 0304-3940- Author Web Link
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- Citations: 101
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Journal articleWhite JPM, Calcott G, Jenes A, et al., 2011,
Xenon reduces activation of transient receptor potential vanilloid type 1 (TRPV1) in rat dorsal root ganglion cells and in human TRPV1-expressing HEK293 cells
, LIFE SCIENCES, Vol: 88, Pages: 141-149, ISSN: 0024-3205- Author Web Link
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- Citations: 5
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Journal articleWhite JPM, Cibelli M, Fidalgo AR, et al., 2011,
Extracellular signal-regulated kinases in pain of peripheral origin
, EUROPEAN JOURNAL OF PHARMACOLOGY, Vol: 650, Pages: 8-17, ISSN: 0014-2999- Author Web Link
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- Citations: 14
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Journal articleWhite JPM, Urban L, Nagy I, 2011,
TRPV1 Function in Health and Disease
, CURRENT PHARMACEUTICAL BIOTECHNOLOGY, Vol: 12, Pages: 130-144, ISSN: 1389-2010- Author Web Link
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- Citations: 42
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