Papers of the Week

Back pain is the leading cause of disability worldwide and contributes to significant socioeconomic impacts worldwide. It has been hypothesized that the degenerative intervertebral disc (IVD) contributes to back pain by sensitizing nociceptive neurons innervating the IVD to stimuli that would not be painful to healthy patients; however, the inflammatory signaling networks mediating this sensitization remain poorly understood. A better understanding of the underlying mechanisms of degenerative IVD induced changes in nociception are required to improve our understanding and treatment of back pain. Towards these ends, we developed a novel in vitro model to investigate degenerative IVD induced changes in dorsal root ganglion (DRG) neuron activation by measuring DRG neuron activity following neuron seeding on human degenerative IVD tissue collected from patients undergoing surgical treatment for back pain. Lentiviral CRISPR epigenome editing vectors were built to down-regulate the inflammatory receptors TNFR1, IL1R1, and IL6st in DRG neurons in single-plex and multi-plex. Multiplex CRISPR epigenome editing of inflammatory receptors demonstrated that degenerative IVD tissue drives thermal sensitization through the simultaneous and redundant signaling of IL-6, TNF-α, and IL-1β. This work elucidates redundant signaling pathways in neuron interactions with the degenerative IVD and suggests the need for multiplex targeting of IL-6, TNF-α, and IL-1β for pain modulation in the degenerative IVD.