ARTICULAR NOCICEPTION INDUCED BY ENDOTHELIN-1, CARRAGEENAN AND LPS INNAIVE AND PREVIOUSLY INFLAMED KNEE-JOINTS IN THE RAT - INHIBITION BY ENDOTHELIN RECEPTOR ANTAGONISTS

Endothelin-1, unlike the selective endothelin ETB receptor agonist sar afotoxin S6c, causes nociception in the rat when injected intraarticul arly into the naive knee-joint. By using selective antagonists, the pr esent study further characterizes the receptors underlying the articul ar nociceptive actions of endothelin-1, as well as the possible contri bution of endogenous endothelins towards nociception induced by carrag eenan or E. coli lipopolysaccharide (LPS) in this tissue. Nociception was evaluated by placing the animal for 1 min each hour on a revolving (3 rpm) cylinder and measuring the increase in time the hindpaw of th e limb affected by the intra-articular (i.a.) injection of the nocicep tive agent, failed to touch its metallic surface (i.e, paw elevation t ime, PET). In naive joints, endothelin-1 (120 pmol) increased the area under the PET curve (AUC 0-6 h, in arbitrary units) from 61 +/- 3 (co ntrol) to 156 +/- 12. This nociceptive effect was reduced by prior int ravenous (i.v.) injection of the mixed ETA/ETB receptor antagonist bos entan (by 54 and 73% with 10 and 30 mg/kg) or i.a. administration of t he selective ETA receptor antagonist BQ-123 (cyclo [D-Asp-Pro-D-Val-Le u]; by congruent to 45% with 10 or 30 nmol), but was unaffected by the selective ETB receptor antagonist BQ-788 cyl-D-1-methoxycarbonyl-tryp tophanil-D-norleucine; 10 nmol). Prior joint challenge with carrageena n (300 mu g) 72 h beforehand (i.e. priming) rendered the joint more se nsitive to nociception induced by either endothelin-1 or sarafotoxin S 6c (15, 30 and 60 pmol). Responses elicited by endothelin (30 pmol) in the primed joint were sensitive to inhibition by either BQ-123 or BQ- 788 (each causing congruent to 80% inhibition at 10 nmol). Priming als o enhanced PET responses to carrageenan itself and to LPS (1 mu g) mar kedly and persistently, increasing the area under the curve (AUC 0-12 h, in arbitrary units) from 241 +/- 19 to 409 +/- 50 and from 312 +/- 40 to 466 +/- 25, respectively (P < 0.05), without changing that measu red following vehicle injection (from 121 +/- 3 to 117 +/- 4). Bosenta n (up to 30 mg/kg, i.v.) failed to modify nociception caused by carrag eenan or LPS in naive joints, by carrageenan in the primed joint, or c ontrol PET responses; LPS-induced nociception in the primed joint, how ever, was inhibited by 52 to 56% by bosentan (3 or 10 mg/kg) or 59% by local injection of the selective endothelin ETB receptor antagonist B Q-788 (10 nmol, i.a.), but was unaffected by the selective endothelin ETA receptor antagonist BQ-123. Thus, nociception induced by endotheli n-1 in the naive joint is mediated largely via endothelin ETA receptor s, whereas both ETA and ETB receptors contribute to its action in the carrageenan-primed joint. Furthermore, LPS-induced nociception in the primed joint is mediated to a large extent via endothelin release and activation of ETB receptors within the joint itself. These findings ma y be relevant to the etiology of pain underlying chronic arthritic dis ease in humans. (C) 1998 International Association for the Study of Pa in. Published by Elsevier Science B.V.