Effects of endothelin-1 on inflammatory incapacitation of the rat knee joint

This study assessed the possible local nociceptive and hyperalgesic properties of endothelin-1 (ET-1) in the rat knee-joint incapacitation test, in which animals are placed for 1 min/h on a revolving (3 rpm) metal cylinder and nociception is measured as the time the hindpaw of the injected limb was off the cylinder (i.e., paw elevation time, PET). Carrageenan (Cg; 150 mug/joint), E. coli LPS (1 mug/joint), and ET-1 (120 or 240 pmol/joint) each increased PET persistently, unlike sarafotoxin S6c (120-240 pmol/joint) or PBS. ET-1 (15 and 30 pmol/joint, 30 min before) did not cause incapacitation per se but potentiated PET induced by Cg, increasing the area under the curve (AUC in arbitrary units, 0-6 h) from 105 +/- 9 to 165 +/- 10 and 169 +/- 25, respectively. Prior Cg injection (300 mug/joint, 72 h before) sensitized the joint to incapacitation triggered by restimulation with either Cg (300 mug/joint), LPS (1 mug/joint), or ET-1 (30 pmol/joint). Treatment with bosentan (10 mg/kg i.v., 15 min before joint stimulation) did not affect PET values in naive animals to Cg or LPS, but significantly reduced the upregulated response evoked by restimulation with LPS (but not Cg), from 465 +/- 24 to 290 +/- 49 (AUC 0-12 h). Therefore, ET-1 triggers nociception and hyperalgesia in the naive knee joint of the rat, perhaps via ETA receptors. Although local endogenous ETs may not have a role in inflammatory nociception in the naive joint, they may participate in articular incapacitation induced by restimulation with LPS. This latter finding could be relevant to the etiology of pain associated with chronic arthritic diseases.