The main interest of the Smith lab is to understand the molecular mechanisms by which sensory neurones detect noxious stimuli, so-called nociceptors. We are particularly interested in how acid activates nociceptors in both physiological and pathophysiological states.
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.
Lemon juice and vinegar are both acidic and both cause a stinging sensation when splashed over a cut in the skin. However, tissue acidosis is a common characteristic of many painful inflammatory conditions such as rheumatoid arthritis. As depicted in the diagram below, many different ion channels are involved in the transduction of acid as a noxious stimulus, including the acid-sensing ion channel (ASIC) family of ion channels. Recent work from our lab has identified critical domains involved in ASIC activation by acid. 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?
We are also interested in bridging the gap between understanding how nociceptors are activated in the normal, uninjured state and how nociceptor function is altered in conditions that are associated with pain, in particular conditions associated with tissue acidosis, such as rheumatoid arthritis. By understanding how nociceptors are activated in pathological conditions, we hope to identify novel avenues for therapeutics.
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 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.
If you would like to hear me giving a podcast for The Naked Scientist then please click here to learn more about naked mole-rats.