The spicy science of chillies

Fiona Russell, Postdoctoral Research Associate in chronic pain at King's College London tells us why react the way we do when munching on chillies Burning mouth, red face, sweating – we are all familiar with the effects of eating hot chilli peppers, but how exactly do chillies cause these effects? The active ingredient in chilli peppers is an oil-based compound called capsaicin. Capsaicin binds to and activates a protein found on the peripheral terminals of sensory nerves. This protein is called Transient Receptor Potential Vanilloid 1 (or TRPV1 for short – pronounced TRiP – V1). Activation of TRPV1 initiates an action potential in the nerve which results in a message being transmitted to the brain, allowing us to sense the presence of capsaicin. TRPV1 is also activated by high temperatures (>43°C). The brain cannot distinguish whether TRPV1 has been activated by heat or by capsaicin, thus both stimuli lead to the feeling of a hot burning sensation. Activation of TRPV1 also causes sensory nerves to release chemicals called neuropeptides. These neuropeptides promote local inflammatory effects such as increased blood flow, plasma leakage from blood vessels and recruitment of white blood cells, thus resulting in redness and swelling. As TRPV1 appears to be activated in a whole host of painful conditions such as arthritis, neuropathic pain and inflammatory bowel disorder, much research was undertaken to develop TRPV1 antagonists in the hope they would be novel pain relieving drugs. However, research faltered when it was discovered that TRPV1 antagonists cause hyperthermia in humans. It is now clear that TRPV1 is involved in thermoregulation and TRPV1 activation leads to a hypothermic response (though perhaps this seems counterintuitive as you feel hot after eating a spicy chilli), but the mechanisms behind this effect are not known. The clinical development of TRPV1 antagonists may have been paused due to the serious hyperthermic side effect, but targeting TRPV1 in a different way has proven to be clinically useful. Repeated administration of a TRPV1 agonist leads to an analgesic response due to the desensitisation of TRPV1 expressing sensory nerves. Thus, creams containing differing concentrations of capsaicin have been developed as topical analgesics for many conditions such as arthritis, post-herpetic neuralgia, diabetic neuropathy and trigeminal neuralgia. Initially, application of the cream results in an intense burning sensation, but repeated administration results in neuropeptide depletion from the sensory nerve and renders the nerve endings non-responsive to further stimuli. This results in pain relief for the patient. This is similar to how people can become desensitised to hot chilli peppers and tolerant to eating spicy curries. It is a reversible effect so continued administration of the capsaicin cream or ingestion of hot chillies is required to maintain desensitisation. Work with TRPV1 and the development of new pain drugs, is not stopping. Newer compounds have been developed that mimic the effects of capsaicin but with a reduced initial burning sensation. Dr. Julie Keeble from King’s College London is currently researching TRPV1 and thermoregulation and explains: ‘If we know exactly how TRPV1 antagonists result in hyperthermia, we can develop new drugs that don’t have this side effect.’  The future for TRPV1 as a drug target is hot.