Immune drivers of physiological and pathological pain

Abstract

Physiological pain serves as a warning of exposure to danger and prompts us to withdraw from noxious stimuli to prevent tissue damage. Pain can also alert us of an infection or organ dysfunction and aids in locating such malfunction. However, there are instances where pain is purely pathological, such as unresolved pain following an inflammation or injury to the nervous system, and this can be debilitating and persistent. We now appreciate that immune cells are integral to both physiological and pathological pain, and that pain, in consequence, is not strictly a neuronal phenomenon. Here, we discuss recent findings on how immune cells in the skin, nerve, dorsal root ganglia, and spinal cord interact with somatosensory neurons to mediate pain. We also discuss how both innate and adaptive immune cells, by releasing various ligands and mediators, contribute to the initiation, modulation, persistence, or resolution of various modalities of pain. Finally, we propose that the neuroimmune axis is an attractive target for pain treatment, but the challenges in objectively quantifying pain preclinically, variable sex differences in pain presentation, as well as adverse outcomes associated with immune system modulation, all need to be considered in the development of immunotherapies against pain.

Local keratinocyte-nociceptor interactions enhance obesity-mediated small fiber neuropathy via NGF-TrkA-PI3K signaling axis

“…These data suggest a correlation between the emergence of increased vascular permeability in the skin vasculature and the development of sensory hypersensitivity in DIO mice. Given that immune cells are known to modulate nociceptor terminals in the pathological skin 21 , we observed no significant change in the number of CD45 + immune cells within the epidermis of DIO ear skin, where hypersensitivity in sensory axon terminal was detected (Supplementary Fig. 4v'-b'').…”