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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

Authors

Francisco R. Nieto

Anna K. Clark

John Grist

Marzia Malcangio



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 http://eprints.nottingham.ac.uk/id/eprint/51960
Publisher URL https://onlinelibrary.wiley.com/doi/abs/10.1002/art.39082
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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