Degenerative IVD conditioned media and acidic pH sensitize sensory neurons to cyclic tensile strain.

Abstract

Low back pain is among the leading causes of disability worldwide. The degenerative intervertebral disc (IVD) environment contains pathologically high levels of inflammatory cytokines and acidic pH hypothesized to contribute to back pain by sensitizing nociceptive neurons to stimuli that would not be painful in healthy patients. We hypothesized that the degenerative IVD environment drives discogenic pain by sensitizing nociceptive neurons to mechanical loading. To test this hypothesis, we developed an in vitro model that facilitated the investigation of interactions between the degenerative IVD environment, nociceptive neurons innervating the IVD and mechanical loading of the disc; and, the identification of the underlying mechanism of degenerative IVD induced nociceptive neuron sensitization. In our model, rat dorsal root ganglia (DRG) neurons were seeding onto bovine annulus fibrosus tissue, exposed to degenerative IVD conditioned media and/or acidic pH, and subjected to cyclic tensile strain (1 Hz; 1%-6% strain) during measurement of DRG sensory neuron activity via calcium imaging. Using this model, we demonstrated that both degenerative IVD conditioned media and degenerative IVD acidic pH levels induced elevated nociceptive neuron activation in response to physiologic levels of mechanical strain. In addition, interleukin 6 (IL-6) was demonstrated to mediate degenerative IVD conditioned media induced elevated nociceptive neuron activation. These results demonstrate IL-6 mediates degenerative IVD induced neuron sensitization to mechanical loading and further establishes IL-6 as a potential therapeutic target for the treatment of discogenic pain. Data further suggests the degenerative IVD environment contains multiple neuron sensitization pathways (IL-6, pH) that may contribute to discogenic pain.