Substance P and glutamate receptor antagonists improve the anti-arthritic actions of dexamethasone in rats.
OBJECTIVE
Current single drug treatments for rheumatoid arthritis have problems of limited efficacy and/or high toxicity. This study investigates the benefits of individual and combined treatments with dexamethasone and substance P and glutamate receptor antagonists in a rat model of arthritis.


METHODS
Arthritis was induced in rats by unilateral intra-articular injection of Freund's complete adjuvant. Separate groups of rats were subjected to the following treatments 15 min before induction of arthritis: (i) control with no drug treatment; (ii) single intra-articular injection of a NK(1) receptor antagonist RP67580; (iii) single intra-articular injection of a NMDA receptor antagonist AP7 plus a non-NMDA receptor antagonist CNQX; (iv) daily oral dexamethasone; and (v) combined treatment with dexamethasone and all of the above receptor antagonists. Knee joint allodynia, swelling, hyperaemia and histological changes were examined over a period of 7 days.


RESULTS
Treatment with dexamethasone suppressed joint swelling, hyperaemia and histological changes that include polymorphonuclear cell infiltration, synovial tissue proliferation and cartilage erosion in the arthritic rat knees. Treatment with RP67580 or AP7 plus CNQX did not attenuate hyperaemia or histological changes, but reduced joint allodynia and swelling. Co-administration of dexamethasone with these receptor antagonists produced greater inhibition on joint allodynia and swelling than their individual effects.


CONCLUSIONS
The data suggest substance P and glutamate contribute to arthritic pain and joint swelling. The efficacy of dexamethasone in reducing arthritic pain and joint swelling can be improved by co-administration of substance P and glutamate receptor antagonists.
Lam
Francis F Y
FF
School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China. francislam@cuhk.edu.hk
Ng
Ethel S K
ES
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D005620:Freund's Adjuvant; D018698:Glutamic Acid / Q000378:metabolism; D007270:Injections, Intra-Articular; D054833:Isoindoles / Q000494:pharmacology; D007719:Knee Joint / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D064729:Neurokinin-1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000187:drug effects* / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013373:Substance P / Q000378:metabolism; D013997:Time Factors
D000893:Anti-Inflammatory Agents; D018691:Excitatory Amino Acid Antagonists; D054833:Isoindoles; D064729:Neurokinin-1 Receptor Antagonists; D017470:Receptors, Glutamate; D018040:Receptors, Neurokinin-1; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; D013373:Substance P; D018698:Glutamic Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate; D003907:Dexamethasone; D005620:Freund's Adjuvant; C031231:2-amino-7-phosphonoheptanoic acid