Effect of the peripherally selective kappa-opioid agonist, asimadoline, on adjuvant arthritis.
1. Opioids, though widely used as analgesics, have not been seriously considered as therapy for rheumatoid arthritis. The present study evaluated the dose-effect and time-dependence relationships of a new peripherally selective kappa agonist, asimadoline, in rats with adjuvant arthritis. 2. The arthritis was assessed by a pooled severity index combining the comprehensive criteria of oedema, radiography and histological changes, in the hind limbs. Asimadoline was extremely effective in attenuating joint damage (by up to 80%) when administered parenterally (0.5 to 10 mg kg(-1) day(-1), i.p.) throughout the disease or during its early phase; treatment was less successful if confined to the latter stages. Ten fold higher doses were effective orally. 3. Equimolar doses of a peripherally-selective antagonist, naloxone methiodide, and the kappa-selective antagonist, MR2266, fully reversed the peripheral anti-arthritic effects of asimadoline (5 mg kg(-1) day(-1)), indicating that asimadoline acts through peripheral kappa-opioid receptors. However, an equivalent dose of MR2266 did not fully reverse the anti-arthritic effects of the highest dose of asimadoline (40 mg kg(-1) day(-1)), suggesting a loss of kappa-selectivity at this dose. 4. Asimadoline also exhibited analgesic effects (mechanical nociceptive thresholds) in arthritic but not non-arthritic rats, indicating that inflammation is necessary for asimadoline-induced analgesia. 5. These data confirm our previous findings that kappa-opioids possess anti-arthritic properties and that these effects are mediated via peripheral kappa-receptors. The present results are new in showing that the peripherally acting kappa-opioid agonist, asimadoline, is a potent anti-arthritic agent. Such novel drugs, essentially lacking central side effects, herald new treatments for rheumatoid arthritis.
Binder
W
W
School of Physiology and Pharmacology, University of New South Wales, Sydney, Australia.
Walker
J S
JS
D000081:Acetamides / Q000008:administration & dosage / Q000494:pharmacology*; D000284:Administration, Oral; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001169:Arthritis, Experimental / Q000503:physiopathology*; D001575:Benzomorphans / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009270:Naloxone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds; D051381:Rats; D011917:Rats, Inbred Lew; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000037:antagonists & inhibitors; D013997:Time Factors
D000081:Acetamides; D000701:Analgesics, Opioid; D001575:Benzomorphans; D009292:Narcotic Antagonists; D011759:Pyrrolidines; D000644:Quaternary Ammonium Compounds; D017473:Receptors, Opioid, kappa; D009270:Naloxone; C027247:MR 2266; C041269:N-methylnaloxone; C092095:asimadoline