Spinal prodynorphin gene expression in collagen-induced arthritis: influence of the glucocorticosteroid budesonide.
Changes in the spinal expression of the opioid precursor and prodynorphin, which has been implicated in the response to peripheral inflammation, were examined with semi-quantitative in situ hybridization histochemistry in rats subjected to collagen II-induced arthritis. The effects of glucocorticosteroid treatment on the basal and inflammation-induced prodynorphin expression were evaluated. Collagen II-induced arthritis caused a 16-fold increase in prodynorphin mRNA levels which comprised all neurons expressing low levels under normal conditions. In the superficial dorsal horn, one group of neurons of a large size reacted with a dramatic increase of prodynorphin mRNA, while another group of small neurons exhibited a moderate elevation of prodynorphin mRNA levels. In the deep dorsal horn of arthritic rats, most prodynorphin neurons were large and showed high prodynorphin mRNA levels. Systemic treatment with the glucocorticosteroid budesonide attenuated the arthritis-induced increase of prodynorphin mRNA expression in a topospecific manner. The budesonide-induced reduction of prodynorphin mRNA levels was more pronounced in the deep dorsal horn than in the superficial dorsal horn. Budesonide treatment of control animals caused a small, but significant increase in prodynorphin mRNA levels in the superficial laminae I/II without affecting prodynorphin mRNA levels in the deep dorsal horn. The degree of arthritis correlated closely with spinal prodynorphin mRNA levels. The tight correlation between severity of arthritis and prodynorphin mRNA levels in non-treated and corticosteroid-treated arthritic rats suggests that spinal prodynorphin expression is a good parameter for the evaluation of the influence of peripheral inflammation and of the efficacy of analgesic/anti-inflammatory drugs in its treatment. Opposite effects of budesonide on basal and inflammation-induced prodynorphin expression may involve a spinal site of action in addition to peripheral anti-inflammatory mechanisms. We suggest that the collagen II-induced arthritis in the rat is an excellent model for human rheumatoid arthritis allowing for the study of molecular plasticity of anti-inflammatory and anti-nociceptive drug action at different levels of the neuroaxis.
Persson
S
S
Department of Pharmaceutical Bioscience, Biomedical Center, Uppsala University, Sweden.
Schäfer
M K
MK
Nohr
D
D
Ekström
G
G
Post
C
C
Nyberg
F
F
Weihe
E
E
D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001168:Arthritis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D019819:Budesonide; D003094:Collagen; D015342:DNA Probes; D004745:Enkephalins / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000502:physiology*; D005938:Glucocorticoids; D006614:Hindlimb / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D017403:In Situ Hybridization; D011282:Pregnenediones / Q000494:pharmacology*; D011498:Protein Precursors / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D013116:Spinal Cord / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D015342:DNA Probes; D004745:Enkephalins; D005938:Glucocorticoids; D011282:Pregnenediones; D011498:Protein Precursors; D012333:RNA, Messenger; D019819:Budesonide; D003094:Collagen; C033660:preproenkephalin