Pain and the immune system

Although classically considered from a neuro-centric vantage point, is now well known that pain involves interaction between the immune and nervous systems. Neuro-immune interactions occur all along the pain axis from the tissues to the peripheral neurons, the dorsal root ganglia, the spinal cord and supraspinal centres. Immune cells from mast cells, macrophages, T cells and B cells, to the Schwann cells of neurons, and the glia cells in the spinal cord and brain, release diverse inflammatory mediators including cytokines and chemokines. Fundamental mechanisms underlying pain enhancement by immune cells are diverse and differ between nociceptive, neuropathic and nociplastic pain conditions. The involvement of the immune system in pain provides enormous potential for interventions to address pain by targeting these mechanisms. These interventions include pharmacological and genetic treatments, as well as non-pharmacological treatments with the potential to impact systemic and CNS immune activity, such as exercise, diet and treatments targeting psychosocial and behavioural features (e.g., sleep and stress). Logically, treatment efficacy should depend on matching the treatment to the relevant neuro-immune mechanism. The aim of this review is to provide a foundation to understand the relevance of neuro-immune interactions to the development and persistence of chronic pain, and its implications for treatment. We provide an overview of the role of neuroinflammation in pain, evidence that this contributes to human pain conditions, and how this can guide matching the right treatments to the right person.