ANTIINFLAMMATORY EFFECTS OF KAPPA-OPIOIDS IN ADJUVANT ARTHRITIS

Current therapies for arthritis are unsatisfactory and cause serious s ide effects and morbidity. It has been postulated that opioid drugs ma y block inflammatory mediators and attenuate the joint damage in adjuv ant arthritis. However, the importance of opioid receptor subtypes inv olved in inflammation remains to be determined because data are confli cting in this regard. The present investigation was designed to test t he effects of both a kappa-agonist, (+/-)U50488H and a kappa-antagonis t, MR2266 on the progression of experimental arthritis. To produce adj uvant arthritis, male Lewis rats were innoculated subcutaneously (s.c. ) with 0.05 ml of Freund's complete adjuvant (10 mg/ml) into the right hind paw. The kappa-opioid agonist, (+/-)U50488H (20 mg/kg/d s.c.) an d the kappa-opioid antagonist, MR2266 (20 mg/kg/d s.c.) were administe red for 3 days during the primary inflammatory phase of adjuvant arthr itis. There were four treatment groups; group I were non-arthritic con trols and received paraffin oil vehicle and opioid injections; group I I were arthritic controls and received adjuvant and saline injections; group III received adjuvant and agonist and group IV received adjuvan t and antagonist. The progression of adjuvant arthritis from day 0 to 24 was monitored by body weight change, hind limb size (ipsilateral an d contralateral) and a total severity score for each clinical observat ion of gait, coat and limb condition. On day 24 histology and radiogra phy of the contralateral limb was performed. There was less soft-tissu e swelling, as judged by time-averaged % change in the volume of the c ontralateral limb, in both agonist (mean +/- se: 82 +/- 5) and antagon ist (77 +/- 4) treated rats compared to untreated arthritic controls ( 99 +/- 5, p<0.05). Other clinical measures of severity were not differ ent between untreated and opioid-treated arthritic rats. However, the joint damage as judged by radiography was lower in kappa agonist treat ed rats (2.6 +/- 0.5, p<0.05) compared to untreated controls (4.1 +/- 0.5) and antagonist treatment (4.4 +/- 0.5). Microscopic pathological scores were also significantly lower in agonist (2.8 +/- 0.3, p<0.05) compared to both antagonist treated rats (4.2 +/- 0.1) and vehicle-tre ated controls (3.6 +/- 0.2). The results of this study show that kappa -opioid receptor agonists but not antagonists attenuate the progressio n of experimental arthritis. These observations have important implica tions for the evaluation and use of kappa-opioid agents in the managem ent of arthritis.