title: Calcitonin gene-related peptide-expressing sensory neurons and spinal microglial reactivity contribute to pain states in collagen-induced arthritis.
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 (CGRP(8-37) ) 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 CGRP(8-37) attenuated established mechanical hypersensitivity and reduced spinal microgliosis.
  
  
  CONCLUSIONS
  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.
authors.affiliation: King's College London, London, UK.
authors.forename: Francisco R
authors.initials: FR
authors.lastname: Nieto
authors.affiliation: King's College London, London, UK.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Clark
authors.affiliation: King's College London, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Grist
authors.affiliation: University of Nottingham, Nottingham, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Chapman
authors.affiliation: King's College London, London, UK.
authors.forename: Marzia
authors.initials: M
authors.lastname: Malcangio
mesh_terms: D000818:Animals; D000843:Ankle Joint / Q000378:metabolism*; D018771:Arthralgia / Q000209:etiology / Q000378:metabolism*; D001169:Arthritis, Experimental / Q000150:complications / Q000378:metabolism*; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D006930:Hyperalgesia / Q000209:etiology / Q000378:metabolism*; D007278:Injections, Spinal; D017628:Microglia / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D011984:Sensory Receptor Cells / Q000378:metabolism*; D013116:Spinal Cord / Q000166:cytology
chemical_list: D010446:Peptide Fragments; C058636:calcitonin gene-related peptide (8-37); D015740:Calcitonin Gene-Related Peptide