Molecular Nociception Group

The Molecular Nociception Group focuses on genetic approaches to understanding the biology of nociceptors (damage-sensing neurons), somatosensation, pain and touch.

James J Cox PhD, John N Wood FRS, Jing Zhao MD PhD

Our research

The twenty-first century has seen a revolution in our understanding of the receptor systems and regulatory pathways that underlie the responses of nociceptors to the occurrence of tissue damage. This has important implications for human health and disease.

We collaborate with research groups in Europe, the United States, Korea, Japan, and Australia, using transgenic mouse models, natural products, and cloned genes to explore the physiology of pain perception. The systems we study have a broad relevance to understanding how the nervous system works in terms of synaptic plasticity, responses to environmental stimuli, sensation, and behaviour.

Sensory Neurobiology

Lead: Prof. John Wood

Our research team focuses on genetic approaches to understanding the biology of damage-sensing neurons (nociceptors), somatosensation, pain and touch. Pain is still an enormous clinical problem, and new drugs are urgently required for a range of chronic pain syndromes.

Our group combines recombinant DNA technology, electrophysiology, gene targeting and behavioural approaches to explore the channels, receptors, transcription factors and regulatory pathways that control nociceptor excitability.

We collaborate closely with human geneticists and clinicians, using mouse models to unravel molecular mechanisms that underlie pain disorders. We also take part in early-stage drug discovery programmes based on targets we identify in the lab.

As well as providing information about pain pathways, the systems we study have a broad relevance to understanding how the nervous system works, in terms of synaptic plasticity, responses to environmental stimuli, sensation and behaviour.

Light touch (red) and damage-sensing (green and blue) neuron cell bodies from spinal ganglia

Touch sensing neurons (green) are associated with Merkel cells (red)

In the absence of a PDZ protein, light touch can no longer be detected

Resources

Mechanistic Studies of Somatosensory Pathway

Professor John Wood

Professor John N Wood FRS has focussed on mouse models of human pain since leaving the Sandoz Institute in 1995. He has studied sensory neuron-specific genes that are implicated in human pain, particularly the capsaicin receptor, acid sensing ion channels, voltage gated sodium channels and transcription factors. He founded spin-out Ionix Pharmaceuticals in 2000. He is also focusing on the role of the peripheral nervous system in regulation of the immune system and cancer.

Professor James Cox

Professor James Cox investigates the genetic basis of rare human pain disorders such as Channelopathy-associated Insensitivity to Pain (SCN9A/Nav1.7), Familial Episodic Pain Syndrome (TRPA1), Marsili Syndrome (ZFHX2) and FAAH-OUT-associated Human Pain Insensitivity. His team is particularly interested in how long non-coding RNAs regulate key pain genes and the endocannabinoid system. A major goal is to translate genetic findings into new analgesic gene therapies.

Dr Jing Zhao

Dr Jing Zhao is an Associate Professor of Pain Mechanisms in the Molecular Nociception Group at the Wolfson Institute for Biomedical Research, Division of Medicine. Dr Zhao’s background is in medicine. After he obtained his MBBS, he trained and worked as a Gastroenterologist in hospital until he started to study for his PhD in Molecular Neurobiology in Shanghai Medical College, Fudan University in 1995. He graduated in 1998 and received postdoctoral training in the Genetic Engineering Group, Shanghai Institute of Molecular Biochemistry and Cell Biology, Chinese Sciences Academy till 2002. Dr Zhao started to study pain in 2003 when he joined Prof John Wood’s group as a Research Fellow at University College London. Dr Zhao was promoted to Associate Professor in 2013.

Translational research and new drugs

The long-term aim of the Molecular Nociception group is to develop new therapies for pain through understanding mechanisms and defining new analgesic targets. This work has been successful and resulted in some new drugs in the clinic.

P2X3 is an ATP-gated ion channel found in damage sensing neurons. It has a role to play in some pain conditions, including bone pain in preclinical studies. Dr Chen and Dr Akopian cloned the channel and knocked it out to examine function. Antagonists are used at the moment to treat chronic cough in Japan. The compound, Gefapixant, is named in honour of Geoff Burnstock the originator of the purinergic hypothesis and the person who welcomed the Molecular Nociception group to his department some 25 years ago.
Nav1.8 is an unusual tetrodotoxin insensitive voltage-gated sodium channel expressed in damage sensing neurons. The channel was cloned by Dr Akopian and characterized electrophysiologically by Dr Sivilotti. Knockout mice showed a loss of mechanosensation and inflammatory pain and conotoxin antagonists are potent analgesics in mice. Ionix pharmaceuticals was formed by the group to develop antagonists, but no clinical studies were carried out owing to lack of funding. Fortunately Vertex have recently developed an orally active Nav1.8 antagonist named Suzetrigine that has FDA approval and is an excellent analgesic, acting in distinct ways from NSAIDs and opioids.

Nav1.8 neuron function has also been investigated exploiting the complex promoter for Nav1.7 to drive Cre recombinase and examine interactions between sensory neurons and the immune system, where many unsuspected efferent functions have been discovered.

Nav1.7 has an important role in pain, first demonstrated by Mohammed Nassar in mice, and subsequently by James Cox and Geoff Woods in humans. In fact, embryonic loss of function humans are pain free, whilst those with gain of function mutations have ongoing pain conditions. This makes Nav1.7 the best genetically validated pain target. Unfortunately, analgesic drugs also act on the heart and autonomic nervous system and have potentially deadly side effects. The disconnect between genetics and drug studies is explained by compensation that occurs in embryonic nulls (Iseppon), where Nav.1.1 and Nav1.2 compensate for the loss of Nav1.7. Nav1.7 is thus not a useful drug target for analgesic development.

Lab Manager

Sam Gossage

Recent Post-Doctoral Fellows

Sascha R.A. Alles PhD
Ali Bangash MD PhD
Shafaq Sikandar PhD
Ana Luiz PhD
Edward C. Emery PhD
John Linley PhD
Naxi Tian PhD
Manuel Arcangeletti PhD
Federico Iseppon PhD

Recent PhD Students

2014 Sam Shepherd
2014 Alexandros Kanellopoulos
2015 Man-Cheung Lee
2015 Jenny Koenig
2015 Shengnan Li
2016 Sonia Santana-Varela
2019 Larissa de Clauser
2020 Donald MacDonald
2020 Alice Fuller
2023 Rayan Haroun
2023 Clarissa Butti

Selected publications

Embracing cancer complexity: Hallmarks of systemic disease. Swanton C, Bernard E, Abbosh C, André F, Auwerx J, Balmain A, Bar-Sagi D, Bernards R, Bullman S, DeGregori J, Elliott C, Erez A, Evan G, Febbraio MA, Hidalgo A, Jamal-Hanjani M, Joyce JA, Kaiser M, Lamia K, Locasale JW, Loi S, Malanchi I, Merad M, Musgrave K, Patel KJ, Quezada S, Wargo JA, Weeraratna A, White E, Winkler F, Wood JN, Vousden KH, Hanahan D. Cell. 2024 Mar 28;187(7):1589-1616

Tentonin 3 is a pore-forming subunit of a slow inactivation mechanosensitive channel. Pak S, Ryu H, Lim S, Nguyen TL, Yang S, Kang S, Yu YG, Woo J, Kim C, Fenollar-Ferrer C, Wood JN, Lee MO, Hong GS, Han K, Kim TS, Oh U. Cell Rep. 2024 Jun 7;43(6):114334.

Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies. Lischka A, Eggermann K, Record CJ, Dohrn MF, Laššuthová P, Kraft F, Begemann M, Dey D, Eggermann T, Beijer D, Šoukalová J, Laura M, Rossor AM, Mazanec R, Van Lent J, Tomaselli PJ, Ungelenk M, Debus KY, Feely SME, Gläser D, Jagadeesh S, Martin M, Govindaraj GM, Singhi P, Baineni R, Biswal N, Ibarra-Ramírez M, Bonduelle M, Gess B, Romero Sánchez J, Suthar R, Udani V, Nalini A, Unnikrishnan G, Marques W Junior, Mercier S, Procaccio V, Bris C, Suresh B, Reddy V, Skorupinska M, Bonello-Palot N, Mochel F, Dahl G, Sasidharan K, Devassikutty FM, Nampoothiri S, Rodovalho Doriqui MJ, Müller-Felber W, Vill K, Haack TB, Dufke A, Abele M, Stucka R, Siddiqi S, Ullah N, Spranger S, Chiabrando D, Bolgül BS, Parman Y, Seeman P, Lampert A, Schulz JB, Wood JN, Cox JJ, Auer-Grumbach M, Timmerman V, de Winter J, Themistocleous AC, Shy M, Bennett DL, Baets J, Hübner CA, Leipold E, Züchner S, Elbracht M, Çakar A, Senderek J, Hornemann T, Woods CG, Reilly MM, Kurth I. Brain. 2023 Dec 1;146(12):4880-4890.

Chemogenetic Silencing of Na_V1.8-Positive Sensory Neurons Reverses Chronic Neuropathic and Bone Cancer Pain in FLEx PSAM⁴-GlyR Mice. Haroun R, Gossage SJ, Luiz AP, Arcangeletti M, Sikandar S, Zhao J, Cox JJ, Wood JN. eNeuro. 2023 Sep 26;10(9):ENEURO.0151-23.2023.

Gate control of sensory neurotransmission in peripheral ganglia by proprioceptive sensory neurons. Fuller AM, Luiz A, Tian N, Arcangeletti M, Iseppon F, Sexton JE, Millet Q, Caxaria S, Ketabi N, Celik P, Wood JN, Sikandar S. Brain. 2023 Oct 3;146(10):4033-4039.

Molecular basis of FAAH-OUT-associated human pain insensitivity. Mikaeili H, Habib AM, Yeung CW, Santana-Varela S, Luiz AP, Panteleeva K, Zuberi S, Athanasiou-Fragkouli A, Houlden H, Wood JN, Okorokov AL, Cox JJ. Brain. 2023 Sep 1;146(9):3851-3865.

Neutrophils infiltrate sensory ganglia and mediate chronic widespread pain in fibromyalgia. Caxaria S, Bharde S, Fuller AM, Evans R, Thomas B, Celik P, Dell'Accio F, Yona S, Gilroy D, Voisin MB, Wood JN, Sikandar S. Proc Natl Acad Sci U S A. 2023 Apr 25;120(17):e2211631120

Pregabalin Silences Oxaliplatin-Activated Sensory Neurons to Relieve Cold Allodynia. Iseppon F, Luiz AP, Linley JE, Wood JN. eNeuro. 2023 Feb 21;10(2):ENEURO.0395-22.2022

Transcriptomic and proteomic profiling of Na_V1.8-expressing mouse nociceptors. Schmidt M, Sondermann JR, Gomez-Varela D, Çubuk C, Millet Q, Lewis MJ, Wood JN, Zhao J. Front Mol Neurosci. 2022 Oct 11;15:1002842.

Genetic pain loss disorders. Lischka A, Lassuthova P, Çakar A, Record CJ, Van Lent J, Baets J, Dohrn MF, Senderek J, Lampert A, Bennett DL, Wood JN, Timmerman V, Hornemann T, Auer-Grumbach M, Parman Y, Hübner CA, Elbracht M, Eggermann K, Geoffrey Woods C, Cox JJ, Reilly MM, Kurth I. Nat Rev Dis Primers. 2022 Jun 16;8(1):41

A central mechanism of analgesia in mice and humans lacking the sodium channel Na_V1.7. MacDonald DI, Sikandar S, Weiss J, Pyrski M, Luiz AP, Millet Q, Emery EC, Mancini F, Iannetti GD, Alles SRA, Arcangeletti M, Zhao J, Cox JJ, Brownstone RM, Zufall F, Wood JN. Neuron. 2021 May 5;109(9):1497-1512

Silent cold-sensing neurons contribute to cold allodynia in neuropathic pain. MacDonald DI, Luiz AP, Iseppon F, Millet Q, Emery EC, Wood JN. Brain. 2021 Jul 28;144(6):1711-1726