The kappa-opioid agonist, asimadoline, alters cytokine gene expression in adjuvant arthritis.
OBJECTIVE
We have previously found that the kappa-opioid agonist, asimadoline, attenuates adjuvant arthritis in a dose-dependent, antagonist-reversible manner. To elucidate possible mechanisms, we investigated the effects of asimadoline (5 mg/kg/day i.p.) or vehicle on in vivo cytokine expression and T-cell recruitment in adjuvant arthritis.


METHODS
Arthritis severity was assessed every 3-4 days for 21 days. Rats were killed on days 0, 13 and 21 post-induction and synovial membrane and inguinal lymph nodes were removed for mRNA extraction. Changes in cytokine mRNA expression were measured using reverse transcription-polymerase chain reaction (RT-PCR) and densitometry. T cells in joints were quantified by immunohistochemistry.


RESULTS
Asimadoline significantly decreased arthritis severity at day 13, with a concomitant decrease in synovial membrane expression of cytokines interleukin-17 and transforming growth factor-beta (TGF-beta) mRNA at day 13, and no change in T cell numbers in the joints of arthritic rats. By contrast, in the inguinal lymph nodes, expression of tumour necrosis factor was increased at day 13 and TGF-beta mRNA was increased throughout.


CONCLUSIONS
An altered balance, therefore, in the pro- and anti-inflammatory effects of TGF-beta by asimadoline might explain its striking anti-arthritic actions.
Bush
K A
KA
School of Physiology and Pharmacology, University of New South Wales, Australia.
Kirkham
B W
BW
Walker
J S
JS
D000081:Acetamides / Q000494:pharmacology* / Q000627:therapeutic use; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000843:Ankle Joint / Q000187:drug effects / Q000378:metabolism; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D002452:Cell Count; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects*; D007124:Immunoenzyme Techniques; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011759:Pyrrolidines / Q000494:pharmacology* / Q000627:therapeutic use; D012313:RNA / Q000032:analysis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects
D000081:Acetamides; D000316:Adrenergic alpha-Agonists; D016207:Cytokines; D011759:Pyrrolidines; D012333:RNA, Messenger; D012313:RNA; C092095:asimadoline