A5034556369- Pain Mechanisms and Treatments
- Ion channel regulation and function
- Ion Channels and Receptors
- Neuropeptides and Animal Physiology
- Neurobiology and Insect Physiology Research
- Hereditary Neurological Disorders
- Inflammatory mediators and NSAID effects
- Biochemical Analysis and Sensing Techniques
- Pharmacological Receptor Mechanisms and Effects
- Neuroscience and Neuropharmacology Research
- Cancer, Stress, Anesthesia, and Immune Response
- Gut microbiota and health
- Drug-Induced Adverse Reactions
- Regulation of Appetite and Obesity
- Healthcare and Venom Research
- Exercise and Physiological Responses
- Chemokine receptors and signaling
- Diabetes Treatment and Management
- Sphingolipid Metabolism and Signaling
- Signaling Pathways in Disease
- Circadian rhythm and melatonin
- Fibromyalgia and Chronic Fatigue Syndrome Research
- Engineering and Test Systems
- Cardiac electrophysiology and arrhythmias
- Ion Transport and Channel Regulation
University College London
2014-2021
Wolfson Foundation
2018-2020
Whitechapel Gallery
2018
University of London
2018
University of Cambridge
2011-2015
Addenbrooke's Hospital
2014
It has long been speculated that metabolites, produced by gut microbiota, influence host metabolism in health and diseases. Here, we reveal indole, a metabolite from the dissimilation of tryptophan, is able to modulate secretion glucagon-like peptide-1 (GLP-1) immortalized primary mouse colonic L cells. Indole increased GLP-1 release during short exposures, but it reduced over longer periods. These effects were attributed ability indole affect two key molecular mechanisms On one hand,...
Action potential firing, initiated by HCN2 ion channels, is the basic mechanism underlying neuropathic pain.
Summary Ivabradine is a specific and peripherally restricted blocker of hyperpolarisation-activated cyclic nucleotide-gated ion channels that an effective analgesic in inflammatory neuropathic pain. Previous studies have shown (HCN)–2 regulate the firing frequency nociceptive sensory neurons thus play central role both pain conditions. Here we use ivabradine, clinically approved anti-anginal agent blocks all HCN channel isoforms approximately equally, to investigate effect on block. We show...
In vivo imaging shows that the great majority of somatosensory neurons are modality-specific.
Deletion of SCN9A encoding the voltage-gated sodium channel NaV1.7 in humans leads to profound pain insensitivity and anosmia. Conditional deletion sensory neurons mice also abolishes pain, suggesting that locus analgesia is nociceptor. Here we demonstrate, using vivo calcium imaging extracellular recording, knockout have essentially normal nociceptor activity. However, synaptic transmission from central terminals spinal cord greatly reduced by an opioid-dependent mechanism. Analgesia...
The voltage-gated Na + channel v 1.7 controls the balance of pain-promoting and pain-relieving receptor input.
The ability to detect environmental cold serves as an important survival tool. sodium channels NaV1.8 and NaV1.9, well the TRP channel Trpm8, have been shown contribute sensation in mice. Surprisingly, transcriptional profiling shows that NaV1.8/NaV1.9 Trpm8 are expressed nonoverlapping neuronal populations. Here we used vivo GCaMP3 imaging identify cold-sensing populations of sensory neurons live We find ∼80% responsive down 1 °C do not express NaV1.8, genetic deletion does affect relative...
Patients with neuropathic pain often experience innocuous cooling as excruciating pain. The cell and molecular basis of this cold allodynia is little understood. We used in vivo calcium imaging sensory ganglia to investigate how the activity peripheral cold-sensing neurons was altered three mouse models pain: oxaliplatin-induced neuropathy, partial sciatic nerve ligation, ciguatera poisoning. In control mice, were few number small size. animals allodynia, a set normally silent large diameter...
Stimulus-coupled incretin secretion from enteroendocrine cells plays a fundamental role in glucose homeostasis and could be targeted for the treatment of type 2 diabetes. Here, we investigated expression function transient receptor potential (TRP) ion channels L producing GLP-1. By microarray quantitative PCR analysis, identified trpa1 as an cell–enriched transcript small intestine. Calcium imaging primary model cell line GLUTag revealed responses triggered by TRPA1 agonists...
The importance of Na V 1.7 (encoded by SCN9A ) in the regulation pain sensing is exemplified heterogeneity clinical phenotypes associated with its mutation. Gain-of-function mutations are typically pain-causing and have been inherited erythromelalgia (IEM) paroxysmal extreme disorder (PEPD). IEM usually caused enhanced channel activation, whereas that alter steady-state fast inactivation often lead to PEPD. In contrast, nonfunctional known underlie congenital insensitivity (CIP). Although...
Chronic pain is a major global public health issue causing severe impact on both the quality of life for sufferers and wider economy. Despite significant clinical burden, little progress has been made in terms therapeutic development. A unique approach to identifying new human-validated analgesic drug targets study rare families with inherited insensitivity. Here we have analysed an otherwise normal family where six affected individuals display insensitive phenotype that characterized by...
Background: Sensory neurons play an essential role in almost all pain conditions, and have recently been classified into distinct subsets on the basis of their transcriptomes. Here we analysed alterations dorsal root ganglia (DRG) gene expression using microarrays mouse models related to human chronic pain. Methods: Six different were studied male C57BL/6J mice: (1) bone cancer cell injection intramedullary space femur; (2) neuropathic partial sciatic nerve ligation; (3) osteoarthritis...
The objective of this study was to evaluate efficacy, safety and tolerability the first-in-class, anti-CCL17 monoclonal antibody, GSK3858279, in treating knee osteoarthritis (OA) pain.
<h3>Background</h3> Chronic pain is an unmet need in osteoarthritis (OA) as current therapies have limited analgesia and side effects. The chemokine CCL17 mediates inflammatory blocking (via anti-CCL17 monoclonal antibodies [mAb] or knock-out) reduces joint disease murine arthritis. GSK3858279 a novel, high affinity, human mAb that functionally inhibits CCL17. <h3>Objectives</h3> To present efficacy, safety, pharmacokinetic (PK) immunogenicity data from Part B of first-in-human, 2 part,...
A side effect of bortezomib (a drug used to treat multiple myeloma) is neuropathic pain, probably owing increased sphingolipid synthesis. Fingolimod, a sclerosis, down-regulates receptor and candidate analgesic.
Summary Deletion of SCN9A encoding the voltage-gated sodium channel Na V 1.7 in humans leads to profound pain insensitivity and anosmia. Conditional deletion sensory neurons mice also abolishes suggesting locus analgesia is nociceptor. Here we demonstrate that knockout have essentially normal nociceptor activity using vivo calcium imaging extracellular recording. However, glutamate substance P release from central terminals spinal cord greatly reduced by an opioid-dependent mechanism....
Abstract C–C Motif Chemokine Ligand 17 (CCL17) is a chemokine that binds and signals through the G‐protein coupled CC‐chemokine receptor 4 has been implicated in development of inflammatory arthritic pain. GSK3858279 high‐affinity, first‐in‐class, monoclonal antibody, binding specifically to CCL17 inhibiting downstream signaling. In this phase I, randomized, single‐center, double‐blind, placebo‐controlled, three‐period, incomplete‐block crossover study (NCT04114656), analgesic effects safety...
Summary Neuropathic pain patients often experience innocuous cooling as excruciating pain. The cell and molecular basis of this cold allodynia is little understood. We used in vivo calcium imaging sensory ganglia to investigate the activity peripheral cold-sensing neurons three mouse models neuropathic pain: oxaliplatin-induced neuropathy, partial sciatic nerve ligation ciguatera poisoning. In control mice, were few number small size. animals with allodynia, a set normally silent...
Abstract Opioid receptors signal more effectively in sensory neurons from pain-free mice lacking the voltagegated sodium channel Na v 1.7. Type-A GPCRs are known to be regulated through a specific binding site, occupancy of which diminishes agonist binding. We have used an electrophysiological assay Protein Kinase A activity examine role intracellular on opioid signalling. Phosphorylation 1.8 by activation with db-cAMP is unaffected altered sodium. By contrast, there dose-dependent...