UP-202-56, AN ADENOSINE ANALOG, SELECTIVELY ACTS VIA A(1) RECEPTORS TO SIGNIFICANTLY DECREASE NOXIOUSLY-EVOKED SPINAL C-FOS PROTEIN EXPRESSION

The effects of oral administration of UP 202-56, an adenosine analogue , were assessed on carrageenan-induced spinal c-Fos protein expression and peripheral oedema. Three hours after intraplantar injection of ca rrageenan (6 mg/150 mu l of saline), in awake rats, numerous c-Fos-lik e immunoreactive (c-Fos-LI) neurons in the dorsal horn of L4-L5 lumbar segments of the spinal cord (191 +/- 8; 184 +/- 10; 205 +/- 7 c-Fos-L I neurons per 40 mu m section, for carrageenan controls in three exper imental series performed in this study, respectively) and an extensive peripheral oedema were observed. Oral UP 202-56 (10, 30 or 50 mg/kg) dose-dependently reduced the number of carrageenan-induced c-Fos-LI ne urons (r = 0.931, P < 0.0001), with the highest dose of UP 202-56 prod ucing 72 +/- 4% reduction of the total number of carrageenan-induced s pinal c-Fos-LI neurons, and 12 +/- 3% and 33 +/- 6% of reduction of co ntrol carrageenan oedema at paw and ankle levels, respectively. DPCPX (1 mg/kg i.p.), a selective adenosine A(1) receptor antagonist, which injected alone had no effect on carrageenan-induced spinal c-Fos expre ssion and peripheral oedema, blocked the effects of UP 202-56 (30 mg/k g p.o.) on the number of carrageenan-induced c-Fos-LI neurons. In addi tion, DPCPX did not modify the effects of UP 202-56 on carrageenan-ind uced peripheral oedema. DMPX (1 mg/kg i.p.), a somewhat selective aden osine A(2) receptor antagonist, which injected alone had no significan t effect on carrageenan-induced spinal c-Fos protein expression and pe ripheral oedema, did not influence the effects of UP 202-56 (30 mg/kg p.o.) on both carrageenan-induced spinal c-Fos expression and peripher al oedema. Our results demonstrate that UP 202-56 dose-dependently red uced the spinal c-Fos protein expression in carrageenan model of infla mmatory pain. The ability of DPCPX to block the effect of UP 202-56, i n contrast to the lack of effect of DMPX, increased evidence for a pre dominant role of adenosine A(1) receptors activation in the mechanism of action of UP 202-56. These results increase evidence for a role of adenosine in the modulation of nociceptive transmission and support th e antinociceptive action of adenosine analogues, such as UP 202-56, in inflammatory pain processes. (C) 1998 International Association for t he Study of Pain. Published by Elsevier Science B.V.