Title: The role of distinct populations of spinal excitatory interneurons in post-operative pain.
Funder: The Academy of Medical Sciences

Abstract: Specific functional subpopulations of excitatory interneurons within the dorsal horn of the spinal cord are essential for the sensation of pain, and yet our knowledge of how these cells contribute to post-operative pain is limited. We aim to demonstrate a critical role for specific subpopulations of excitatory interneurons in post-operative pain; firstly, by profiling their activity in a mouse model of incisional pain, and secondly, by silencing activity in these neurons and observing the effect on pain behaviours. We will use a sensitive and highly-multiplexed in situ hybridisation approach to quantify expression of mRNAs for activity-dependent genes at the single cell level following incision. Neurons that are activated most strongly are likely those underlying pain behaviours. The molecular identity of active neurons will be determined against our recently developed classification scheme that reflects the complex organisational logic of the dorsal horn. Identifying the cells and circuits involved in post-operative pain in this manner will allow the selection of a specific neuronal population to be investigated in behavioural studies. We will silence activity in neurons using genetically-targeted expression of the novel chemogenetic PSAM4-GlyR receptor followed by the administration of PSEM ligands. The effect of this silencing on pain will be measured using novel and highly translational outcome measures. Silencing will be conducted at post-operative timepoints but also at the time of incision to establish whether this approach has a preventative effect on pain intensity.

Lay abstract: If you go into hospital for an operation, it’s very likely you’ll feel pain afterwards. For some people this pain can be severe and long-lasting. The drugs we currently have to treat this type of pain are often ineffective and can have significant side-effects. This is because they are generally blanket treatments which do not target the specific nerve pathways associated with pain. In order to develop more effective treatments for pain after surgery, we need to have a better understanding of why pain occurs. Pain signals are transmitted from the site of surgery to the brain via nerves. An important site in this nerve pathway is an area at the top of the spinal cord called the superficial dorsal horn. The nerves in this area form circuits which can amplify, and hence worsen, pain. One type of nerve within these circuits, the interneuron, is particularly important in the pain pathway. Our work has already shown that there are several different subtypes interneurons. I want to understand more clearly which subtypes of interneurons appear within these dorsal horn circuits, so that we can specifically target them and develop better pain killers. Firstly, I will ask which of the subtypes of spinal interneuron are most likely to underlie pain by determining which are most active after surgery of the foot in mice. In further experiments, I aim to show the importance of these interneurons in post-operative pain by silencing their activity and observing a reduction in pain after surgery.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL