Calcitonin Gene-Related Peptide (CGRP) as a Potential Therapeutic Target for Discogenic Back Pain

Discogenic back pain is a leading cause of disability worldwide, yet current treatments target symptoms rather than molecular mechanisms. Calcitonin gene-related peptide (CGRP), a neuropeptide involved in neurogenic inflammation, has been identified in intervertebral disc (IVD) tissue, but its impact on human disc cells is not well defined.

Determine whether CGRP induces inflammatory cytokine and neurotrophic factor expression in human annulus fibrosus (AF) and nucleus pulposus (NP) cells, and whether monoclonal antibody via small-molecule blockade attenuates this response.

Basic laboratory study using human IVD cells cultured onto 3-D scaffolds METHODS: Primary AF and NP cells from surgical specimens were treated with recombinant human CGRP for one hour, with or without anti-CGRP antibodies (galcanezumab, erenumab) or small-molecule CGRP inhibitors. AF cells were exposed to inflammatory cytokines (TNF-α and IL-1β) and neurotrophic factors (BDNF and NGF). Expression of IL-6, TNF-α, BDNF and NGF were measured via quantitative PCR and analyzed using one-way ANOVA with mixed effects post hoc (P < 0.05 denotes statistical significance).

CGRP significantly increased IL-6 (2.79 fold, P < 0.001), BDNF (1.70 fold, P = .01) and NGF (1.61 fold, P < 0.001) expression in AF cells, while smaller effects occurred in NP cells. TNF-α and IL-1β significantly downregulated RAMP1 expression in AF cells but they significantly upregulated BDNF. Galcanezumab reduced IL-6 expression from 4.47-fold to 1.26-fold (P = 0.03 vs CGRP), and erenumab suppressed BDNF induction (P = 0.01). Anti-CGRP agents alone had no baseline effect.

CGRP induces inflammatory and neurotrophic signaling in human AF cells, attenuated by molecules that block CGRP.

CGRP represents a promising molecular target for novel therapies addressing discogenic back pain.