THE EFFECTS OF PROPOFOL ON MACROSCOPIC AND SINGLE-CHANNEL SODIUM CURRENTS IN RAT VENTRICULAR MYOCYTES

1 Opioids, though widely used as analgesics, have not been seriously c onsidered as therapy for rheumatoid arthritis. The present study evalu ated the dose-effect and time-dependence relationships of a new periph erally selective kappa agonist, asimadoline, in rats with adjuvant art hritis. 2 The arthritis was assessed by a pooled severity index combin ing the comprehensive criteria of oedema, radiography and histological changes, in the hind limbs. Asimadoline was extremely effective in at tenuating 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 it s early phase; treatment was less successful if confined to the latter stages. Ten fold higher doses were effective orally. 3 Equimolar dose s of a peripherally-selective antagonist, naloxone methiodide, and the kappa-selective antagonist, MR2266, fully reversed the peripheral ant i-arthritic effects of asimadoline (5 mg kg(-1) day(-1)), indicating t hat asimadoline acts through peripheral kappa-opioid receptors. Howeve r, an equivalent dose of MR2266 did not fully reverse the anti-arthrit ic effects of the highest dose of asimadoline (40 mg kg(-1) day(-1)), suggesting a loss of kappa-selectivity at this dose. 4 Asimadoline als o exhibited analgesic effects (mechanical nociceptive thresholds) in a rthritic but not non-arthritic rats, indicating that inflammation is n ecessary for asimadoline-induced analgesia. 5 These data confirm our p revious findings that kappa-opioids possess anti-arthritic properties and that these effects are mediated via peripheral kappa-receptors. Th e present results are new in showing that the peripherally acting kapp a-opioid agonist, asimadoline, is a potent anti-arthritic agent. Such novel drugs, essentially lacking central side effects, herald new trea tments for rheumatoid arthritis. 6 Single channel recordings showed th at the mean open time of single sodium channels was dramatically reduc ed by propofol (from 0.50+/-0.02 ms in control to 0.28+/-0.01 ms by 56 mu M propofol and to 0.24+/-0.01 ms by 168 mu M, both significantly d ifferent from control, P < 0.01). Single channel conductance was not c hanged by either concentration of propofol.