in this model, CGRP was upregulated in DRG neurons innervating damaged discs. However, direct intradiscal application of etanercept immediately after disc puncture suppressed CGRP expression in DRG neurons innervating injured discs. This finding may further elucidate the mechanism for the effectiveness of etanercept in upregulation of neuropeptide in DRG neurons innervating intervertebral discs.

Nerve growth factor (NGF) and its dual structurally unrelated receptors, tropomyosin-related kinase A (TrkA) or p75 neurotrophin receptor (p75 NTR ), cause the pathogenesis of discogenic pain. To investigate the sensory innervation of injured rat lumbar intervertebral disc (IVD), we examined the expression of neuropeptides such as calcitonin gene-related peptide (CGRP) at dorsal root ganglia (DRG) by inhibiting NGF or its dual receptors. Sprague-Dawley rats with multiply punctured L5-L6 IVD were used. Six experimental groups were prepared: naïve, sham control, and four agent-treated groups with punctured IVD (vehicle, anti-NGF antibody, anti-TrkA antibody, and anti-p75 NTR antibody). Retrograde neurotracer Fluoro-Gold (FG) was applied together except for the naïve group. Their lumbar DRG were harvested and immunolabeled for CGRP. FG-labeled DRG neurons were most prevalent at L1 and L2 DRG, and the proportion of FG-labeled CGRP-immunoreactive DRG neurons in the vehicle group was significantly elevated (p < 0.05) compared with the sham group, while those of antibody-treated groups, especially in the anti-p75 NTR group, significantly decreased compared with the vehicle group (p < 0.05). Direct intradiscal application of antibody to NGF or its receptors suppressed CGRP expression, and p75 NTR antagonism induced the most profound suppression. Lumbar intervertebral disc (IVD) is a source of low back pain. Previous studies demonstrated that degenerative IVD expresses proinflammatory cytokines such as tumor necrosis factor (TNF)-␣ 1 and nerve growth factor (NGF) 2 and induces sensory nerve ingrowth into the injured sites to transmit nociceptive sensation.3 NGF is one of the neurotrophins involved in certain chronic inflammatory or neuropathic pain states. [4][5][6][7][8][9] NGF produced at the inflamed or degenerative site of IVD is one of the causes for discogenic low back pain based on evidence that the significant dominant population of the sensory innervation derived from dorsal root ganglia (DRG) for IVD is sensitive to NGF. 10 We demonstrated that the innervation of L5-L6 IVD consists of multisegmental innervation through paravertebral sympathetic trunks and direct innervation through sinuvertebral nerves on the posterior longitudinal ligament.

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