Molecular Nociception Group

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.

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

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.

Resources

• Research Department of Genetics, Evolution and Environment
• Blast a sequence
• Clustal W alignment
• EMBL-EBI
• ExPASy 

Mechanistic Studies of Somatosensory Pathway

Professor John N Wood

Professor Wood FRS has focused 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 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 Associate Professor of Pain Mechanisms. He trained and worked as a Gastroenterologist in hospital before studying a PhD in Molecular Neurobiology at Shanghai Medical College, Fudan University. Following postdoctoral training in the Genetic Engineering Group, Shanghai Institute of Molecular Biochemistry and Cell Biology, Chinese Sciences Academy, Dr Zhao joined Prof John Wood’s group in 2003 and 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.

1. 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.
2.  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.

3. 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

1. Embracing cancer complexity: Hallmarks of systemic disease. Swanton C, Bernard E, Abbosh C, André F ... Wood JN, Vousden KH, Hanahan D. Cell. 2024 Mar 28;187(7): 1589-1616
2. Tentonin 3 is a pore-forming subunit of a slow inactivation mechanosensitive channel. Pak S, Ryu H, Lim S ... Wood JN, et al. Cell Rep. 2024 Jun 7;43(6): 114334.
3. Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies. Lischka A, Eggermann K, Record CJ, Dohrn MF ... Wood JN, Cox JJ,  et al. Brain. 2023 Dec 1;146(12):4880-4890.
4. Chemogenetic Silencing of NaV1.8-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.
5. Gate control of sensory neurotransmission in peripheral ganglia by proprioceptive sensory neurons. Fuller AM, Luiz A, Tian N ... Wood JN, Sikandar S. Brain. 2023 Oct 3;146(10): 4033-4039.
6. Molecular basis of FAAH-OUT-associated human pain insensitivity. Mikaeili H, Habib AM, Yeung CW ... Wood JN, Okorokov AL, Cox JJ. Brain. 2023 Sep 1;146(9): 3851-3865.

7. Neutrophils infiltrate sensory ganglia and mediate chronic widespread pain in fibromyalgia. Caxaria S, Bharde S, Fuller AM ... Wood JN, Sikandar S. Proc Natl Acad Sci U S A. 2023 Apr 25;120(17): e2211631120
8. 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.
9. Transcriptomic and proteomic profiling of NaV1.8-expressing mouse nociceptors. Schmidt M, Sondermann JR, Gomez-Varela D ... Wood JN, Zhao J. Front Mol Neurosci. 2022 Oct 11;15:1002842.
10. 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
11. A central mechanism of analgesia in mice and humans lacking the sodium channel NaV1.7. MacDonald DI, Sikandar S, Weiss J ... Zhao J, Cox JJ, Brownstone RM, Zufall F, Wood JN. Neuron. 2021 May 5;109(9): 1497-1512
12. 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.

Facilities

Related programmes

Researchers within the Wolfson Institute for Biomedical Research contribute to several distinguished taught courses at UCL.

 Group activities