ENDASCOP: Establishing Neuronal Drivers And the Spinal Circuitry of Osteoarthritis Pain (360G-Wellcome-225856_Z_22_Z)

Osteoarthritis (OA) is a common degenerative condition that frequently affects the knee joint and results in chronic pain. Knee pain is sensed when sensory neurones innervating the joint relay this information into the spinal cord, from where it is propagated to the brain leading to perception. Our understanding of the neuronal substrate driving chronic knee pain is limited, with a distinct lack of knowledge of the spinal circuitry underlying normal or chronic joint pain. Our preliminary data in the destabilisation of the medial meniscus (DMM) model of knee pathology shows that knee-innervating sensory neurones become hyperexcitable as pain behaviour develops, with single-cell RNA-sequencing analysis of these neurones identifying three distinct populations involved in this process. Furthermore, we find that chemogenetic inhibition of knee-innervating sensory neurones normalises joint pain. In this project, we will establish the DMM model in transgenic mouse strains and use viral constructs to both determine the roles of distinct primary afferent populations in OA pain and define the spinal circuitry involved in this condition. Human tissue samples will then be used to replicate our studies in mice, providing a means for understanding how OA pain is generated in patients and opening the door to novel therapeutic treatments.