The site of anti-arthritic action of the κ-opioid, U-50,488H, in adjuvant arthritis: Importance of local administration

Abstract

1 Currently available pharmacological therapies treat arthritis inadequately. We have previously found that the kappa (κ)-opioid, U-50,488H (trans-(±)-3,4-dichloro-N-methyl-N-[2-(l-pyrrolid cyclohexyl]benzene-acetamide methane sulphonate), possesses anti-arthritic effects. In light of the finding that opioid receptors in the periphery are upregulated during inflammation, κ-opioids may represent a novel therapy for arthritis. The primary aim and unique feature of the present study is to investigate whether opioids exert their anti-arthritic effects in the periphery. Thus, the dose-effect relationship of a κ-opioid agonist, U-50,488H was compared after both local and distant administration. Further, we tested whether the antiarthritic effects of this drug are stereospecific and receptor-mediated by use of opioid antagonists. 2 Using an adjuvant model of arthritis in male Lewis rats, arthritis was judged by oedema, radiography and histological changes in the contralateral ankle of the hind limb. Treatment with (±)-U-50,488H for 3 days during disease onset and 3 days during established disease significantly attenuated arthritis, but the effects of (±)-U-50,488H on radiology and histology varied according to treatment time. Administration of (±)-U-50,488H during disease onset had a more marked effect on radiography, suggesting that treatment with that drug should be started early to prevent progressive joint destruction. Further, it was found that (±)-U-50,488H, administered for 3 days during the disease onset, either by direct subcutaneous injection into the inflamed paw or at a more distant site into the back of the neck, dose-dependently attenuated arthritic damage as measured by an index which pooled all three variables. More importantly however, (±)-U-50,488H was approximately fourfold more potent as an 'anti-arthritic' agent after local compared to distant subcutaneous injection (ED50; local vs distant: 5.8 ± 1.6 vs 19.5 ± 0.8 mg kg-1). 3 Equivalent doses of the (-)-enantiomer (20 mg kg-1day-1) and the racemate (±) of U-50,488H (40 mg kg-1day-1), elicited a similar attenuation of arthritic parameters while the (+)-enantiomer exacerbated arthritis, suggesting that the anti-arthritic activity lies solely with the (-)-enantiomer. 4 Both the peripherally selective antagonist, naloxone methiodide, and the κ-selective antagonist, MR2266 ((-)-5,9α-diethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorphan) were able to reverse fully the peripheral anti-arthritic effects of U-50,488H, indicating that it exerts its effects through peripheral κ-opioid receptors. 5 Taken together, these results not only confirm our previous findings that demonstrate anti-arthritic effects of U-50,488H but they indicate that the opioid attenuation of experimental arthritis is mediated via peripheral κ-receptors in the arthritic joint. Peripherally acting κ -opioid agonists should lead to new therapies for arthritis.