A5032076489- Pain Mechanisms and Treatments
- Gastrointestinal motility and disorders
- Ion Channels and Receptors
- Ion channel regulation and function
- Ion Transport and Channel Regulation
- Neuropeptides and Animal Physiology
- Adenosine and Purinergic Signaling
- Complementary and Alternative Medicine Studies
- Exercise and Physiological Responses
- Sphingolipid Metabolism and Signaling
- Neuroendocrine regulation and behavior
- Vascular anomalies and interventions
- Music Therapy and Health
- Media Influence and Health
- Empathy and Medical Education
- Neuroscience and Neuropharmacology Research
- Extracellular vesicles in disease
- Acupuncture Treatment Research Studies
- Pain Management and Placebo Effect
- Menstrual Health and Disorders
- Inflammation biomarkers and pathways
- Intraperitoneal and Appendiceal Malignancies
- Dialysis and Renal Disease Management
- Single-cell and spatial transcriptomics
- Endometriosis Research and Treatment
University of Cambridge
2017-2024
Age UK
2020-2024
Sir Charles Gairdner Hospital
2023
Lawn Tennis Association
2018-2020
Queen Mary University of London
2014-2018
Pfizer (United Kingdom)
2016-2017
University of Bath
2009
Objective Integration of nutritional, microbial and inflammatory events along the gut-brain axis can alter bowel physiology organism behaviour. Colonic sensory neurons activate reflex pathways give rise to conscious sensation, but diversity division function within these is poorly understood. The identification signalling contributing visceral sensation constrained by a paucity molecular markers. Here we address this comprehensive transcriptomic profiling unsupervised clustering individual...
NaV1.9 regulates normal colonic afferent mechanosensation and is required for hypersensitivity to noxious inflammatory mediators those derived from bowel disease tissues. Chronic visceral pain affects millions of individuals worldwide remains poorly understood, with current therapeutic options constrained by gastrointestinal adverse effects. Visceral strongly associated inflammation distension the gut. Here we report that voltage-gated sodium channel subtype expressed in half gut-projecting...
Voltage-gated sodium channels play a fundamental role in determining neuronal excitability. Specifically, voltage-gated channel subtype NaV 1.7 is required for sensing acute and inflammatory somatic pain mice humans but its significance originating from the viscera unknown. Using comparative behavioural models evoking visceral pathways, we identify requirement regulating (noxious heat threshold) not signalling. These results enable us to better understand mechanisms underlying transduction...
Activation of visceral nociceptors by inflammatory mediators contributes to hypersensitivity and abdominal pain associated with many gastrointestinal disorders. Purine pyrimidine nucleotides (e.g., ATP UTP) are strongly implicated in this process following their release from epithelial cells during mechanical stimulation the gut, immune inflammation. Actions mediated through both ionotropic P2X receptors metabotropic P2Y receptors. receptor activation causes excitation afferents; however,...
Abstract Dysmenorrhea is a common chronic pelvic pain syndrome affecting women of childbearing potential. Family studies suggest that genetic background influences the severity dysmenorrhea, but predisposition and molecular mechanisms underlying dysmenorrhea are not understood. In this study, we conduct first genome-wide association study to identify factors associated with severity. A cohort females European descent (n = 11,891) aged 18 45 years rated their average We used linear regression...
Sensory neurons expressing the GPCR Mrgprd mediate effects of a bioactive lipid to cause abdominal pain.
Ongoing, spontaneous pain is characteristic of inflammatory joint and reduces an individual's quality life. To understand the neural basis pain, we made a unilateral knee injection complete Freund's adjuvant (CFA) in mice, which reduced their natural digging behavior. We hypothesized that sensitization knee-innervating dorsal root ganglion (DRG) neurons underlies this altered test hypothesis, performed electrophysiological recordings on retrograde labeled primary DRG neuron cultures measured...
Objective The development of effective visceral analgesics free deleterious gut-specific side effects is a priority. We aimed to develop reproducible methodology study nociception in human tissue that could aid future target identification and drug evaluation. Design Electrophysiological (single unit) responses afferents mechanical (von Frey hair (VFH) stretch) chemical (bradykinin ATP) stimuli were examined. Thus, serosal (putative nociceptors) used investigate the effect tegaserod,...
BackgroundChronic visceral pain is a defining symptom of many gastrointestinal disorders. The KV7 family (KV7.1–KV7.5) voltage-gated potassium channels mediates the M current that regulates excitability in peripheral sensory nociceptors and central pathways. Here, we use combination immunohistochemistry, gut-nerve electrophysiological recordings both mouse human tissues, single-cell qualitative real-time polymerase chain reaction gut-projecting neurons, to investigate contribution...
Abstract In many research areas scientists are interested in clustering objects within small datasets while making use of prior knowledge from large reference datasets. We propose a method to apply the machine learning concept transfer unsupervised problems and show its effectiveness field single-cell RNA sequencing (scRNA-Seq). The goal scRNA-Seq experiments is often definition cataloguing cell types transcriptional output individual cells. To improve disease- or tissue-specific datasets,...
By studying healthy women who do not request analgesia during their first delivery, we investigate genetic effects on labor pain. Such have normal sensory and psychometric test results, except for significantly higher cuff pressure We find an excess of heterozygotes carrying the rare allele SNP rs140124801 in KCNG4. The variant KV6.4-Met419 has a dominant-negative effect cannot modulate voltage dependence KV2.1 inactivation because it fails to traffic plasma membrane. In vivo, Kcng4 (KV6.4)...
Acid-sensing ion channels (ASICs) are voltage-independent cation that detect decreases in extracellular pH. Dysregulation of ASICs underpins a number pathologies. Of particular interest is ASIC3, which recognised as key sensor acid-induced pain and important the establishment arising from inflammatory conditions, such rheumatoid arthritis. Thus, identification new ASIC3 modulators mechanistic understanding how these compounds modulate could be for development strategies to counteract...
The ability to sense visceral pain during appendicitis is diminished with age leading delay in seeking health care and poorer clinical outcomes. To understand the mechanistic basis of this phenomenon, we examined nociception aged mouse human tissue. Inflamed noninflamed appendixes were collected from consenting patients undergoing surgery for treatment or bowel cancer. Supernatants generated by incubating samples buffer used stimulate multiunit activity intestinal preparations, single-unit...
Abstract Neuropathic pain remains difficult to treat, with drug development hampered by an incomplete understanding of the pathogenesis condition, as well a lack biomarkers. The problem is compounded scarcity relevant human peripheral tissues, including skin, nerves, and dorsal root ganglia. Efforts obtain such samples are accelerating, increasing need for standardisation across laboratories. In this white paper, we report on consensus meeting attended neuropathic experts, designed...
Acid sensing in the gastrointestinal tract is required for gut homeostasis and detection of tissue acidosis caused by ischaemia, inflammation infection. In colorectum, activation colonic afferents low pH contributes to visceral hypersensitivity abdominal pain human disease including during inflammatory bowel disease. The naked mole-rat ( Heterocephalus glaber) shows no pain-related behaviour subcutaneous acid injection cutaneous are insensitive acid, an adaptation thought be a consequence...
Abstract Background and Purpose Abdominal pain is a leading cause of morbidity for people living with gastrointestinal disease. While the vanilloid transient receptor potential 4 (TRPV4) ion channel has been implicated in pathogenesis abdominal pain, relative paucity TRPV4 expression colon-projecting sensory neurons suggests that non-neuronal cells may also contribute to TRPV4-mediated nociceptor stimulation. Experimental Approach Changes murine colonic afferent activity were examined using...
Abstract The development of nonopioid analgesics for the treatment abdominal pain is a pressing clinical problem. To address this, we examined expression G i/o -coupled receptors, which typically inhibit nociceptor activation, in colonic sensory neurons. This led to identification orphan receptor GPR35 as visceral analgesic drug target because its marked coexpression with transient potential ankyrin 1 (TRPA1), mediator noxious mechanotransduction bowel. Building on silico docking...
Background and Purpose Abdominal pain is a leading cause of morbidity for people living with gastrointestinal disease. Whereas the transient receptor potential vanilloid 4 (TRPV4) ion channel has been implicated in pathogenesis abdominal pain, relative paucity TRPV4 expression colon‐projecting sensory neurons suggests that non‐neuronal cells may contribute to TRPV4‐mediated nociceptor stimulation. Experimental Approach Changes murine colonic afferent activity were examined using ex vivo...
Galanin is a neuropeptide expressed by sensory neurones innervating the gastrointestinal (GI) tract. displays inhibitory effects on vagal afferent signaling within upper GI tract, and goal of this study was to determine actions galanin colonic spinal function. Specifically, we sought evaluate effect lumbar splanchnic nerve (LSN) mechanosensitivity noxious distending pressures development hypersensitivity in presence inflammatory stimuli colitis. Using ex vivo electrophysiological recordings...
We sought genetic effects on labour pain by studying healthy women who did not request analgesia during their first delivery. Extensive sensory and psychometric testing were normal in these women, except for significantly higher cuff-pressure pain. found an excess of heterozygotes carrying the rare allele SNP rs140124801 KCNG4. The variant Kv6.4-Met419 exerts a dominant negative effect cannot modulate voltage-dependence K v 2.1 inactivation because it fails to traffic plasma membrane. In...
Abstract Acid sensing in the gastrointestinal tract is required for gut homeostasis and detection of tissue acidosis caused by ischaemia, inflammation infection. In colorectum, activation colonic afferents low pH contributes to visceral hypersensitivity abdominal pain human disease including during inflammatory bowel disease. The naked mole-rat ( Heterocephalus glaber ; NMR) shows no pain-related behaviour subcutaneous acid injection cutaneous are insensitive acid, an adaptation thought be a...