Calcitonin gene-related peptide-expressing sensory neurons and spinal microglial reactivity contribute to pain states in collagen-induced arthritis

Nieto, Francisco R.; Clark, Anna K.; Grist, John; Chapman, Victoria; Malcangio, Marzia

Abstract

Objective

To evaluate the contribution of sensory neurons in ankle joints and adjacent tissue to the development of pain in collagen‐induced arthritis (CIA), and to determine the relationship between pain and the appearance of clinical signs.

Methods

Mechanical and heat hypersensitivity and hind paw swelling were assessed in Lewis rats before and until 18 days following collagen immunization. We examined the effect of intrathecal administration of a calcitonin gene‐related peptide (CGRP) antagonist (CGRP8–37) from day 11 to day 18 postimmunization on CIA‐induced hypersensitivity. During CIA development, CGRP and p‐ERK immunoreactivity was quantified in lumbar dorsal root ganglia in which sensory neurons innervating the ankle joint were identified by retrograde labeling with Fluoro‐Gold. Microgliosis in the lumbar dorsal horn was assessed by immunohistochemistry, and release of CGRP evoked by activity of primary afferent fibers was measured using a preparation of isolated dorsal horn with dorsal roots attached.

Results

CIA was associated with mechanical hypersensitivity that was evident before hind paw swelling and that was exacerbated with the development of swelling. Heat hyperalgesia developed along with swelling. Concomitant with the development of mechanical hypersensitivity, joint innervating neurons exhibited enhanced CGRP expression and an activated phenotype (increased p‐ERK expression), and significant microgliosis became evident in the dorsal horn; these peripheral and central changes were augmented further with disease progression. CGRP release evoked by dorsal root stimulation was higher in the dorsal horn on day 18 in rats with CIA compared to control rats. Prolonged intrathecal administration of CGRP8–37 attenuated established mechanical hypersensitivity and reduced spinal microgliosis.

Conclusion

Sensory neuron–derived CGRP sustains mechanical hypersensitivity and spinal microglial reactivity in CIA, suggesting that central mechanisms play critical roles in chronic inflammatory pain. Blockade of these central events may provide pain relief in rheumatoid arthritis patients.

Citation

Nieto, F. R., Clark, A. K., Grist, J., Chapman, V., & Malcangio, M. (2015). Calcitonin gene-related peptide-expressing sensory neurons and spinal microglial reactivity contribute to pain states in collagen-induced arthritis. Arthritis and Rheumatology, 67(6), https://doi.org/10.1002/art.39082

• Journal Article Type: Article
• Acceptance Date: Feb 17, 2015
• Online Publication Date: Feb 23, 2015
• Publication Date: Jun 30, 2015
• Deposit Date: May 23, 2018
• Publicly Available Date: May 23, 2018
• Journal: Arthritis & Rheumatology
• Print ISSN: 2326-5191
• Electronic ISSN: 2326-5205
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 67
• Issue: 6
• DOI: https://doi.org/10.1002/art.39082
• Public URL: https://nottingham-repository.worktribe.com/output/753488
• Publisher URL: https://onlinelibrary.wiley.com/doi/abs/10.1002/art.39082
• Contract Date: May 23, 2018