Figure 4.

Schematic of major interdependent phases leading to disc degeneration and pain. Following initial insult/s, disc cells upregulate expression of inflammatory cytokines and chemokines that include TNF-α, IL-β, IL-6 as well as IL-17 and CCLs. In this inflammatory environment, disc cells express several catabolic molecules like SDC4, ADAMTS-4/5, MMPs. These enzymes promote degradation of predominant extracellular matrix molecules such as aggrecan (ACAN) and collagen II (Col2). Continuous structural breakdown of matrix molecules of the NP and AF results in mechanical instability, annular tears and in many instances herniation. In the second phase of the disease, release of chemokines and cytokines from the degenerated disc enhances activation and infiltration of immunocytes into tissues further amplifying the inflammatory response. Infiltration of immune cells is accompanied by the appearance of microvasculature and nociceptive nerve fibers that arise from the dorsal root ganglion (DRG). In the third phase of the disease, neurogenic factors in particular NGF and BDNF produced by the herniated disc as well as the immunocytes induce expression of the pain associated cation channels like ASIC3 and Trpv1 in the DRGs. In this inflammatory milieu, activation of these channels is likely to promote discogenic pain and reinforce cytokine mediated disc degeneration. Possible sites of pharmacological intervention are indicated.