Peripheral suppression of arthritic pain by intraarticular fadolmidine, an alpha 2-adrenoceptor agonist, in the rat

Earlier results suggest that peripheral alpha(2)-adrenoceptors and opioid receptors may reduce arthritic pain. Fadolmidine is a highly selective alpha(2)-adrenoceptor agonist that has only limited central access after peripheral administration. We assessed the peripheral antinociceptive properties of fadolmidine and the potential contribution of peripheral opioid receptors to its antinociceptive effect in experimental monoarthritis. After induction of monoarthritis in the knee joints of rats, we determined the frequency of vocalization induced by repetitive movement of the knee joint. Fadolmidine and clonidine were administered intraarticularly ipsi- or contralateral to the inflamed joint. Reversal of the fadolmidine-induced effect was attempted with subcutaneous (s.c.) administration of atipamezole, an alpha(2)-adrenoceptor antagonist, and intraarticular administration of naloxone methiodide, an opioid receptor antagonist that does not penetrate the blood-brain barrier. Fadolmidine produced a dose-dependent attenuation of the vocalization response to movement of the inflamed knee joint, and this effect was significantly stronger after ipsi- than contralateral drug administration. Clonidine also produced a dose-dependent attenuation of the vocalization response, but this effect was not significantly different after ipsi- versus contralateral drug administration. Fadolmidine-induced antinociception was reversed by s.c. administration of atipamezole. Furthermore, intraarticular administration of naloxone methiodide into the inflamed, but not the contralateral, joint reversed the antinociceptive effect of fadolmidine independent of whether fadolmidine was administered into the inflamed or contralateral joint. In rats, intraarticular administration of fadolmidine provides a marked suppression of pain-related behavior in arthritis, due to a selective action on peripheral alpha(2)-adrenoceptors and opioid receptors.