19 results found
Ponzoni L, Melzi G, Marabini L, et al., 2021, Conservation of mechanisms regulating emotional-like responses on spontaneous nicotine withdrawal in zebrafish and mammals., Prog Neuropsychopharmacol Biol Psychiatry, Vol: 111
BACKGROUND: Nicotine withdrawal syndrome is a major clinical problem. Animal models with sufficient predictive validity to support translation of pre-clinical findings to clinical research are lacking. AIMS: We evaluated the behavioural and neurochemical alterations in zebrafish induced by short- and long-term nicotine withdrawal. METHODS: Zebrafish were exposed to 1 mg/L nicotine for 2 weeks. Dependence was determined using behavioural analysis following mecamylamine-induced withdrawal, and brain nicotinic receptor binding studies. Separate groups of nicotine-exposed and control fish were assessed for anxiety-like behaviours, anhedonia and memory deficits following 2-60 days spontaneous withdrawal. Gene expression analysis using whole brain samples from nicotine-treated and control fish was performed at 7 and 60 days after the last drug exposure. Tyrosine hydroxylase (TH) immunoreactivity in pretectum was also analysed. RESULTS: Mecamylamine-precipitated withdrawal nicotine-exposed fish showed increased anxiety-like behaviour as evidenced by increased freezing and decreased exploration. 3H-Epibatidine labeled heteromeric nicotinic acethylcholine receptors (nAChR) significantly increased after 2 weeks of nicotine exposure while 125I-αBungarotoxin labeled homomeric nAChR remained unchanged. Spontaneous nicotine withdrawal elicited anxiety-like behaviour (increased bottom dwelling), reduced motivation in terms of no preference for the enriched side in a place preference test starting from Day 7 after withdrawal and a progressive decrease of memory attention (lowering discrimination index). Behavioural differences were associated with brain gene expression changes: nicotine withdrawn animals showed decreased expression of chrna 4 and chrna7 after 60 days, and of htr2a from 7 to 60 days.The expression of c-Fos was significantly increased at 7 days. Finally, Tyrosine hydroxylase (TH) immunoreactivity increased in dorsal parvocellular pretectal nucleus, but not in p
Torres Perez J, Irfan J, Febrianto MR, et al., 2021, Histone post-translational modification as potential therapeutic targets for pain management, Trends in Pharmacological Sciences, Vol: 42, Pages: 897-911, ISSN: 0165-6147
Effective pharmacological management of pain associated with tissue unmet medical need. Transcriptional modifications in nociceptive pathways are pivotal for the development and the maintenance of pain associated with tissue damage. Accumulating evidence has shown the importance of the epigenetic control of transcription within nociceptive pathways via histone post-translational modifications (PTMs). Hence, histone PTMs could be targets for novel effective analgesics. Here, we discuss the current understanding of histone PTMs in the modulation of gene expression affecting nociception and pain phenotypes following tissue injury. We also provide a critical view of the translational implications of preclinical models and discuss opportunities and challenges of targeting histone PTMs for relieving pain in clinically relevant tissue injuries.
Evans JR, Torres-Perez JV, Miletto Petrazzini ME, et al., 2021, Stress reactivity elicits a tissue-specific reduction in telomere length in aging zebrafish (Danio rerio), SCIENTIFIC REPORTS, Vol: 11, ISSN: 2045-2322
Torres-Perez JV, Brennan CH, 2021, Restoring Wnt/beta-catenin pathway as potential therapeutics for Williams syndrome-associated anxiety disorders, 2000 Meeting of the British-Pharmacological-Society (PHARMACOLOGY), Publisher: WILEY, Pages: 447-448, ISSN: 0007-1188
Ponzoni L, Teh M-T, Torres-Perez JV, et al., 2020, Increased Response to 3,4-Methylenedioxymethamphetamine (MDMA) Reward and Altered Gene Expression in Zebrafish During Short- and Long-Term Nicotine Withdrawal, MOLECULAR NEUROBIOLOGY, Vol: 58, Pages: 1650-1663, ISSN: 0893-7648
Friston D, Junttila S, Borges Paes Lemes J, et al., 2020, Leptin and fractalkine: novel subcutaneous cytokines in burn injury, Disease Models and Mechanisms, Vol: 13, ISSN: 1754-8403
Burn injury is a pathology underpinned by progressive and aberrant inflammation. It is a major clinical challenge to survival and quality of life. While burn injury’s complex local and disseminating pathological processes ultimately stem from local tissue damage, to date relatively few studies have attempted to characterise the local inflammatory mediator profile. Here, cytokine content and associated transcriptional changes were measured in rat skin for three hours immediately following induction of a scald-type (60oC, 2 minutes) burn injury model. Leptin (p = 0.0002) and fractalkine (p = 0.0478) concentrations were significantly elevated post-burn above pre-burn and control site values, coinciding with the development of burn site oedema and differential expression of leptin mRNA (p = 0.0004). Further, gene sequencing enrichment analysis indicated cytokine-cytokine receptor interaction (p = 1.45x10-6). Subsequent behavioural studies demonstrated that, following subcutaneous injection into the dorsum of the paw, both leptin and fractalkine induced mechanical allodynia, heat hyperalgesia and the recruitment of macrophages. This is the first report of leptin’s elevation specifically at the burn site and the first report of fractalkine’s elevation in any tissue post-burn which, together with the functional findings, calls for exploration of the influence of these cytokines on pain, inflammation and burn wound progression. Additionally targeting these signalling molecules represents a therapeutic potential as early formative mediators of these pathological processes.
Torres-Pérez JV, Naeem H, Thompson CL, et al., 2020, Nanoscale mapping reveals functional differences in ion channels populating the membrane of primary cilia, Cellular Physiology and Biochemistry, Vol: 54, Pages: 15-26, ISSN: 1015-8987
BACKGROUND/AIMS: The primary cilium is a nanoscale membrane protrusion believed to act as a mechano-chemical sensor in a range of different cell types. Disruptions in its structure and signalling have been linked to a number of medical conditions, referred to as ciliopathies, but remain poorly understood due to lack of techniques capable of investigating signal transduction in cilia at nanoscale. Here we set out to use latest advances in nanopipette technology to address the question of ion channel distribution along the structure of primary cilium. METHODS: We used glass nanopipettes and Scanning Ion Conductance Microscopy (SICM) to image 3D topography of intact primary cilia in inner medullary collecting duct (IMCD) cells with nanoscale resolution. The high-resolution topographical images were then used to navigate the nanopipette along the structure of each cilium and perform spatially resolved single-channel recordings under precisely controlled mechanical and chemical stimulation. RESULTS: We have successfully obtained first single-channel recordings at specific locations of intact primary cilia. Our experiments revealed significant differences between the populations of channels present at the ciliary base, tip and within extra-ciliary regions in terms of mean conductance and sensitivity to membrane displacement as small as 100 nm. Ion channels at the base of cilium, where mechanical strain is expected to be the highest, appeared particularly sensitive to the mechanical displacement. CONCLUSION: Our results suggest the distribution of ion channels in the membrane of primary cilia is non-homogeneous. The relationship between the location and function of ciliary ion channels could be key to understanding signal transduction in primary cilia.
Friston D, Junttila S, Lemes JBP, et al., 2020, Leptin and fractalkine: Novel subcutaneous cytokines in burn injury., Dis Model Mech
Burn injury is a pathology underpinned by progressive and aberrant inflammation. It is a major clinical challenge to survival and quality of life. While burn injury's complex local and disseminating pathological processes ultimately stem from local tissue damage, to date relatively few studies have attempted to characterise the local inflammatory mediator profile. Here, cytokine content and associated transcriptional changes were measured in rat skin for three hours immediately following induction of a scald-type (60°C, 2 minutes) burn injury model. Leptin (p=0.0002) and fractalkine (p=0.0478) concentrations were significantly elevated post-burn above pre-burn and control site values, coinciding with the development of burn site oedema and differential expression of leptin mRNA (p=0.0004). Further, gene sequencing enrichment analysis indicated cytokine-cytokine receptor interaction (p=1.45x10-6). Subsequent behavioural studies demonstrated that, following subcutaneous injection into the dorsum of the paw, both leptin and fractalkine induced mechanical allodynia, heat hyperalgesia and the recruitment of macrophages. This is the first report of leptin's elevation specifically at the burn site and the first report of fractalkine's elevation in any tissue post-burn which, together with the functional findings, calls for exploration of the influence of these cytokines on pain, inflammation and burn wound progression. Additionally targeting these signalling molecules represents a therapeutic potential as early formative mediators of these pathological processes.
Nagy I, Torres-Perez JV, Adamek P, et al., 2017, The NAv1.7 blocker protoxin II reduces burn injury-induced spinal nociceptive processing, Journal of Molecular Medicine, Vol: 96, Pages: 75-84, ISSN: 0946-2716
Controlling pain in burn-injured patients poses a major clinical challenge. Recent findings suggest that reducing the activity of the voltage-gated sodium channel Nav1.7 in primary sensory neurons could provide improved pain control in burn-injured patients. Here, we report that partial thickness scalding-type burn injury on the rat paw upregulates Nav1.7 expression in primary sensory neurons 3 h following injury. The injury also induces upregulation in phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB), a marker for nociceptive activation in primary sensory neurons. The upregulation in p-CREB occurs mainly in Nav1.7-immunopositive neurons and exhibits a peak at 5 min and, following a decline at 30 min, a gradual increase from 1 h post-injury. The Nav1.7 blocker protoxin II (ProTxII) or morphine injected intraperitoneally 15 min before or after the injury significantly reduces burn injury-induced spinal upregulation in phosphorylated serine 10 in histone H3 and phosphorylated extracellular signal-regulated kinase 1/2, which are both markers for spinal nociceptive processing. Further, ProTxII significantly reduces the frequency of spontaneous excitatory post-synaptic currents in spinal dorsal horn neurons following burn injury. Together, these findings indicate that using Nav1.7 blockers should be considered to control pain in burn injury.
Nagy I, Varga A, Vicente Torres Perez J, 2017, Development of analgesics: a little help from mitogen and stress-activated kinases 1 and 2, Journal of Pharmaceutical Research and Drug Design, Vol: 1
Nagy 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: 1096-9861
Elevation 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.
Torres-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: 2045-2322
Transcriptional 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.
, 2016, EHMTIC 2016 – INVITED SPEAKER ABSTRACTS, Cephalalgia, Vol: 36, Pages: 1-185, ISSN: 0333-1024
Beattie S, Torres-Perez JV, Nagy I, 2016, A post-translational modification in histone is a novel marker for nociceptive activation in primary sensory neurons, Publisher: WILEY, Pages: 432-432, ISSN: 1351-5101
Torres-Perez JV, Chamberlain J, Miedzik AA, et al., 2015, Non-paralytic botulinum chimeras increase the activation threshold of the trigeminovascular system in migraine models, International Headache Congress of the International-Headache-Society, Publisher: SAGE PUBLICATIONS LTD, Pages: 4-4, ISSN: 0333-1024
Andreou AP, Miedzik AA, Chamberlain J, et al., 2015, Nitric oxide signalling in the A11 hypothalamic nucleus facilitates trigeminovascular activation, International Headache Congress of the International-Headache-Society, Publisher: SAGE PUBLICATIONS LTD, Pages: 12-12, ISSN: 0333-1024
, 2015, International Headache Society abstracts., Cephalalgia, Vol: 35, Pages: 1-296
Andreou AP, Chamberlain JH, Torres-Perez JV, et al., 2014, The A11 hypothalamic nucleus is susceptible to nitric oxide signalling, JOURNAL OF HEADACHE AND PAIN, Vol: 15, ISSN: 1129-2369
Nagy I, Friston D, Valente JS, et al., 2014, Pharmacology of the capsaicin receptor, transient receptor potential vanilloid type-1 ion channel., Capsaicin as a Therapeutic Molecule, Editors: Abdel-Salam, Publisher: Springer, Pages: 39-76, ISBN: 978-3-0348-0828-6
The capsaicin receptor, transient receptor potential vanilloid type 1 ion channel (TRPV1), has been identified as a polymodal transducer molecule on a sub-set of primary sensory neurons which responds to various stimuli including noxious heat (> -42 degrees C), protons and vanilloids such as capsaicin, the hot ingredient of chilli peppers. Subsequently, TRPV1 has been found indispensable for the development of burning pain and reflex hyperactivity associated with inflammation of peripheral tissues and viscera, respectively. Therefore, TRPV1 is regarded as a major target for the development of novel agents for the control of pain and visceral hyperreflexia in inflammatory conditions. Initial efforts to introduce agents acting on TRPV1 into clinics have been hampered by unexpected side-effects due to wider than expected expression in various tissues, as well as by the complex pharmacology, of TRPV1. However, it is believed that better understanding of the pharmacological properties of TRPV1 and specific targeting of tissues may eventually lead to the development of clinically useful agents. In order to assist better understanding of TRPV1 pharmacology, here we are giving a comprehensive account on the activation and inactivation mechanisms and the structure-function relationship of TRPV1.
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