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Research Interest

 

 

The main interest of the Smith lab is to understand the molecular mechanisms by which sensory neurones detect noxious stimuli, so-called nociceptors and how the properties of these neurones change from health to disease.

Nociception versus pain

The International Association for the Study of Pain defines nociception as “the neural process of encoding noxious stimuli”, whereas pain is defined as being more than just the initial sensation of the noxious stimulus, “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” Nociceptors express a range of ion channels and receptors that when activated can result in nociceptor activation. A classic example is the burning sensation evoked by chilli peppers, which is due to a chemical called capsaicin that activates an ion channel called TRPV1.

One important factor to consider in pain research is sex and how this may affect both pain and its treatment. Researchers have traditionally used male animal models, but the Smith Lab supports the need to consider use of males and females when designing a study. Here is a podcast Ewan did with The Naked Scientists about pain and sex, based upon a recent perspective piece in Nature from Prof. Jeffrey Mogil.

Acid sensing

In humans, lemon juice and vinegar both cause a stinging sensation when splashed over a cut in the skin, which is due to their acidic nature. Acid is sensed by a variety of different sensory neurone receptors and the ability of acid to activate sensory neurones and evoke nocifensive behaviour is common to many species of the animal kingdom, as we have recently reviewed.  Tissue acidosis occurs in a variety of different pathological conditions, including some inflammatory states and certain cancers. The Smith Lab has a long-standing interest in how the acid-sensing ion channel (ASIC) family of ion channels function and their contribution towards pain. Recent work from our lab has identified critical domains involved in ASIC activation by acid and investigated species differences in ASIC function. Future research is focused on understanding more about how these ion channels are activated and modulated during inflammatory acidosis and how inflammation itself changes the properties of sensory neurones – why does inflammation cause increased pain sensitivity?

Neuronal excitability

We are also interested in bridging the gap between understanding how sensory neurones are activated in the normal, uninjured state and how their function is altered in conditions that are associated with pain, in particular rheumatoid arthritis and inflammatory bowel disease. By understanding how sensory neurones are activated in pathological conditions, we hope to identify novel avenues for therapeutics. To study the properties of particular sensory neurones we use retrograde tracing techniques: a fluorescent substance is injected into the site of interest (e.g. knee joint, or distal colon) and then travels up the sensory nerve fibres to the cell bodies - we can then use the fluorescence to specifically characterise the function of neurones coming from the site of interest and their functionality changes in disease. For example, in the diagram below, the left image shows fast-blue (LB) labelled lumbosacral neurons, yellow arrows represent FB+ neurones showing expression of the marker of interest, in this case GDNF family receptor alpha-3 (Gfrα3, middle panel) and white arrowheads represent FB+ neurones that do not express the marker of interest. The right panel shows the merged image with the inset showing examples of FB+/Gfrα3+ and FB+/Gfrα3- neurones. Scale bar 50 μm.

DRG - labelled

We have recently published a study using RNA-sequencing to identify 7 subtypes of colonic sensory neurones, which we then validated using scqRT-PCR, immunohistochemistry and Ca2+-imaging - future work will investigate the roles of these sensory neurone subtypes in health and disease. In a collaboration with David Bulmer, Nicolas Cenac and David Hughes, we recently demonstrated that the lipid metabolite 5-oxoETE is found at higher levels in constipation predominant  irritable bowel syndrome and that this drives pain by activating one of the seven colonic sensory neurone subtypes.

We also have recently used retrograde tracing to show that TRPV1 expression increases in knee-innervating sensory neurones in mice during inflammation and that the inflammation-induced decrease in mouse digging behaviour (a measure of how pain affects spontaneous behaviour) is reversed by administration of a TRPV1 antagonist as shown in the figure below (A, experimental timeline; CFA = complete Freund's adjuvant to induce inflammation, B and C, 24-hours after CFA knee injection mice dig for less time and dig fewer burrows, which is reversed by administration of a TRPV1 antagonist, D and E, the antagonist has no effect on the digging behaviour or mice injected with saline). A lay summary of this work is provided here.

 

We have also recently begun to work with human synovial fluid to try to identify substances present in synovial fluid that may drive pain. Our initial findings demonstrate that synovial fluid from patients with osteoarthritis can sensitise mouse knee sensory neurones, whereas synovial fluid from healthy individuals does not, future work will investigate the mechanisms involved, but this method promises to accelerate bench-to-bedside treatments for arthritic conditions. A lay summary of this work can be read here.

Naked mole-rat

The African naked mole-rat (Heterocephalus glaber) is a highly unusual mammal. Like certain ant, bee and termite species, naked mole-rats are eusocial, meaning that they live in large colonies with a sole, breeding female, the queen. Moreover, they are cold-blooded, live for over 25 years (similarly sized mice live for a tenth of the time) are resistant to cancer and as others and we have shown, they have highly unusual nocifensive behaviours, in particular they do not find acid nocifensive. We identified that the molecular basis of the acid insensitivity displayed by naked mole-rats is due to an amino acid alteration in the voltage-gated sodium channel subunit NaV1.7: acid activates naked mole-rat acid sensors, but simultaneously blocks NaV1.7 to such an extent that action potentials are not generated. We have also been involved in studies demonstrating the extreme hypoxia resistance of the naked mole-rat and have further shown how naked mole-rat cortical neurones are resistant to acid-induced cell death due to a decrease in the function of neuronal acid-sensing ion channels. We now aim to conduct further comparative physiology and genetics with the naked mole-rat in order to identify molecules and circuits that can explain other aspects of their “odd” physiology, results from such work will lead to a greater understanding of how “normal” physiology works in other mammals including humans. You can find out more about people across Cambridge who are involved in research with the naked mole-rat, by going to the Naked Mole-Rat Initiative website.

You can read more about the naked mole-rat here, or, if you would prefer to hear me giving a podcast for The Naked Scientist then please click here.