The role of the neuronal microenvironment in sensory function and pain pathophysiology

The high prevalence of pain and the at times low efficacy of current treatments represent a significant challenge to healthcare systems worldwide. Effective treatment strategies require consideration of the diverse pathophysiologies that underlie various pain conditions. Indeed, our understanding of the mechanisms contributing to aberrant sensory neuron function has advanced considerably. However, sensory neurons operate in a complex dynamic microenvironment that is controlled by multidirectional interactions of neurons with non-neuronal cells, including immune cells, neuronal accessory cells, fibroblasts, adipocytes, and keratinocytes. Each of these cells constitute and control the microenvironment in which neurons operate, inevitably influencing sensory function and the pathology of pain. This review highlights the importance of the neuronal microenvironment for sensory function and pain, focusing on cellular interactions in the skin, nerves, dorsal root ganglia, and spinal cord. We discuss the current understanding of the mechanisms by which neurons and non-neuronal cells communicate to promote or resolve pain, and how this knowledge could be used for the development of mechanism-based treatments.