Tumour necrosis factor-alpha mediates carrageenin-induced knee-joint incapacitation and also triggers overt nociception in previously inflamed rat knee-joints

Tumour necrosis factor-alpha (TNF alpha) was studied in the carrageenin (CG ) induced knee-joint incapacitation, and also in mediating recurrent incapa citation response in knee-joints previously exposed to an inflammatory atta ck. CG or TNF alpha intra-articular injection into CG-primed knee-joints in duced an intense and long-lasting (>8 h) peaking incapacitation response. T NF alpha injected in naive joints did not elicit incapacitation. Anti-TNF a lpha serum in situ treatment specifically inhibited CG-induced incapacitati on in naive joints, and also TNF alpha-induced incapacitation in primed joi nts. Hoe-140 (D-Arg(0)[Hyp(3),Thi(5),D-Tic(7),Oic(8)]-bradykinin, a bradyki nin B-2 receptor antagonist, given before CG, abolished incapacitation, but was without effect when injected 3 h after. Hoe-140 given before or after the CG injection in primed joints was without effect, but it produced a par tial inhibitory effect in the early phase (1 h) of TNF alpha-induced incapa citation. Des-Arg(9)[Leu(8)]-bradykinin, a bradykinin B-1 receptor antagoni st, given intra-articularly after CG or TNF alpha, reversed incapacitation either in naive or primed joints. Indomethacin abolished the incapacitation induced by CG in naive joints, but only the 5-lipoxygenase inhibitor MK-88 6 plus indomethacin blocked the response in primed joints. MK-886 did not m odify CG-induced incapacitation in naive joints, but lately reversed CG-ind uced incapacitation in primed joints, and blocked TNF alpha-induced respons e. Substance P or prostaglandin E-2 did not induce incapacitation in either naive or primed joints. Our results support the conclusion that TNF alpha is a mediator of CG-induced inflammatory incapacitation, and is able to ind uce the further release of kinins and leukotrienes, which is suggested to h ave an important role in the maintenance of long-lasting nociceptive respon se. (C) 1999 International Association for the Study of Pain. Published by Elsevier Science B.V.