The cellular heterogeneity of peripheral and central immune alterations in chronic pain states

Abstract

Chronic pain affects more than 20% of people worldwide and is a leading cause of years lost to disability. The nervous and immune systems engage in bidirectional crosstalk in the initiation, maintenance, and resolution of chronic pain. These neuroimmune interactions are associated with changes both in nociception and affective states which contribute to the physical, psychological, and social burdens of chronic pain. Targeting these interacting peripheral and central pathways therapeutically remains challenging, since similar cell types and pathways are commonly associated both with pain chronification and resolution in different contexts. This thesis therefore aims to characterise the heterogeneity of immune responses to chronic pain and unveil specific cell subtypes and their interactions that may underpin the disease. The research in this thesis characterises the peripheral immune environment in humans with migraine and diabetic neuropathic pain using high-parameter single-cell mass cytometry and high-dimensional analysis approaches. The research included here also utilises the chronic constriction injury rat model to investigate the contribution of hippocampal and medial prefrontal microglia and neuronal activation to affective disturbances comorbid with neuropathic pain. In so doing, this research hopes to uncover neuroimmunological substrates of, and therapeutic targets for, the underlying pathology of diverse chronic pain states.