Calcitonin gene-related peptide gene expression in collagen-induced arthritis is differentially regulated in primary afferents and motoneurons: influence of glucocorticoids.
Calcitonin gene-related peptide is involved in peripheral and spinal mechanisms of inflammatory pain. In this paper, we used collagen II-induced arthritis in the rat as a model to investigate the influence of chronic arthritic pain on calcitonin gene-related peptide gene expression in sensory and motor pathways. Additionally, we examined the effect of the glucocorticoid drug budesonide on arthritis-induced changes of calcitonin gene-related peptide expression and constitutive calcitonin gene-related peptide expression. Thirteen days after the immunization with native rat collagen type II rats developed a progressive and chronic polyarthritis which was scored with respect to the degree of swelling and/or redness of the paw and ankle joints. Budesonide significantly attenuated the extent of arthritis. Changes in calcitonin gene-related peptide expression were evaluated by semiquantitative in situ hybridization and immunocytochemistry on day 21 post-immunization. In sensory neurons of dorsal root ganglia of arthritic rats, a significant increase in calcitonin gene-related peptide messenger RNA and protein levels was seen. These increases were completely blocked by budesonide. Also in dorsal root ganglia of non-arthritic rats, budesonide had an effect, with reduced calcitonin gene-related peptide messenger RNA levels below constitutive concentrations. Image analysis of calcitonin gene-related peptide immunoreactivity revealed that changes in calcitonin gene-related peptide expression were due to alterations in calcitonin gene-related peptide expression levels rather than to de novo synthesis or changes in the numbers of calcitonin gene-related peptide expressing neurons. In spinal motoneurons of arthritic rats, marked decreases in calcitonin gene-related peptide messenger RNA and protein levels were measured. These reductions were attenuated by budesonide. The changes in calcitonin gene-related peptide expression in motoneurons correlated with the severity of arthritis in the ipsilateral hind paw. Budesonide had no effects on calcitonin gene-related peptide messenger RNA levels in motoneurons of non-arthritic rats. The opposite regulation of calcitonin gene-related peptide gene expression in primary sensory and spinal somatomotor pathways in collagen-induced arthritis suggests that calcitonin gene-related peptide plays a specific role in both chronic inflammatory pain and arthritis-induced motor dysfunction. The sensitivity of constitutive and inflammation-induced sensory calcitonin gene-related peptide expression to budesonide treatment may indicate that the beneficial effects of steroid treatment in inflammation is partly mediated by down-regulation of calcitonin gene-related peptide in sensory neurons involved in neurogenic inflammation.
Nohr
D
D
Department of Neuroanatomy, University of Düsseldorf, Germany.
Schäfer
M K
MK
Persson
S
S
Romeo
H
H
Nyberg
F
F
Post
C
C
Ekström
G
G
Weihe
E
E
D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019819:Budesonide / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000096:biosynthesis* / Q000235:genetics; D003094:Collagen; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D012333:RNA, Messenger; D019819:Budesonide; D003094:Collagen; D015740:Calcitonin Gene-Related Peptide