A rare genetic mutation that leaves people unable to feel pain has pointed drug developers toward a single protein on nerve cells—the sodium channel Nav1.7—as a promising target for new painkillers. The problem is that completely blocking Nav1.7 would also eliminate protective pain, such as the reflex that pulls a hand from a hot stove. Patients in early clinical trials of Nav1.7 inhibitors risk losing all pain sensation, not just the pathological kind. This research aims to find a more precise approach: drugs that silence only specific pain modalities—for example, the mechanical allodynia that makes a light touch feel agonising—while leaving normal pain thresholds intact. The team will identify which subsets of sensory neurons produce distinct pain sensations, find the molecules that detect pain in those neurons, and map how those signals travel to the spinal cord and brain. They will also investigate visceral pain and sympathetically driven pain conditions. If successful, this work could lead to a new generation of painkillers that treat chronic pain without the side effects or addiction risks of opioids, and without leaving patients dangerously numb.
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There is a clinical need for a better understanding of pain in order to develop new drugs. Humans with a loss of sodium channel Nav1.7 expression are pain-free and anosmic, but otherwise normal. Inhibitors of Nav1.7 are potent analgesics in animal models in all types (acute, inflammatory, neuropathic) of pain. Thus Nav1.7 is an excellent analgesic drug target, and drugs are already in phase 2 clinical trials. Importantly, the total analgesia associated with complete Nav1.7 block may be problem atic. It would be better to target drugs at particular pain modalities (e.g. mechanical allodynia where innocuous pressure becomes painful) in order to retain the protecting effects of normal thresholds for other pain modalities (e.g. heat). We and others have shown that different sets of sensory neurons evoke distinct pain sensations. Our major research questions are therefore to; 1) Define further sets of sensory neurons responsible for distinct pain sensations. 2) Identify the sensor y neuron transduction molecules associated with distinct pain sensations. 3) Map the central terminations of modality-specific sets of sensory neurons and use trans-synaptic tracers to map central wiring patterns. 4) Provide mechanistic insights into visceral pain and into sympathetically driven heat pain and neuropathic pain. 5) Define the role of innocuous sensation in pain percepts. This programme of work will allow us to identify new pain modality-specific transduction targets in the p eripheral nervous system, and learn more about central wiring patterns.
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