Antihyperalgesic effect of pentoxifylline on experimental inflammatory pain.

The antihyperalgesic effect of pentoxifylline was investigated in three experimental pain models. Pentoxifylline (0.5-1.6 mg kg(-1)) given 30 min before the stimulus significantly inhibited the writhing response induced by the intraperitoneal (i.p.) administration of either acetic acid (-90%) or zymosan (-83%), but not that of iloprost, in mice, as well as the zymosan-induced articular hyperalgesia in the zymosan arthritis in rats (-50%). Pentoxifylline also inhibited the mechanical hypernociception in rats induced by the intraplantar injection of either carrageenin (-81%), bradykinin (-56%) or tumor necrosis factor alpha (TNF-alpha; -46%), but not that induced by interleukin-1beta (IL-1beta) or prostaglandin E(2) (PGE(2)). Pentoxifylline did not inhibit the nociceptive response in the hot plate test in mice. Further, the antinociceptive effect of pentoxifylline in the writhing test in mice and the zymosan-induced articular hyperalgesia were not reversed by the coadministration of the opioid receptor antagonist naloxone. Thus, pentoxifylline antinociceptive effect is probably not mediated at a central level. Pentoxifylline significantly reduced TNF-alpha (-43%) and IL-1beta (-42%) concentrations in the joint exudates of rats stimulated by intra-articular injection of zymosan and the production of both cytokines (-66 and -86%, respectively) by mouse peritoneal macrophages stimulated in vivo with zymosan as well as the expression of TNF-alpha at the tissue level in carrageenin-injected rat paws. In conclusion, the antinociceptive activity of pentoxifylline is associated with the inhibition of the release of both TNF-alpha and IL-1beta.

Dual effect of nitric oxide in articular inflammatory pain in zymosan-induced arthritis in rats.

The contribution of nitric oxide (NO) to articular pain in arthritis induced by zymosan (1 mg, intra articular) in rats was assessed by measuring articular incapacitation (AI). Systemic treatment with the non-selective NO synthase (NOS) inhibitor L-NAME (10 - 100 mg kg(-1) i.p.) or with the selective iNOS inhibitors aminoguanidine (AG; 10 - 100 mg kg(-1) i.p.) or 1400W (0.5 - 1 mg kg(-1) s.c.) inhibited the AI induced by injection of zymosan 30 min later. Local (intra articular) treatment with the NOS inhibitors (L-NAME or AG, 0.1 - 1 micromol; 1400W, 0.01 (micromol) 30 min before zymosan also inhibited the AI. Systemic or local treatment with the NOS inhibitors (L-NAME; AG, 100 mg kg(-1) i.p. or 0.1 micromol joint(-1); 1400W, 1 mg kg(-1) s.c. or 0.01 micromol joint(-1)), 2 h after zymosan did not affect the subsequent AI. Local treatment with the NO donors SNP or SIN-1, 2 h after zymosan did inhibit AI. L-NAME and AG, given i.p. inhibited nitrite but not prostaglandin E(2) (PGE(2)) levels in the joints. L-NAME (100 mg kg(-1)) but not AG (100 mg kg(-1)) increased mean arterial blood pressure. Neither L-NAME, AG nor the NO donor SIN-1 altered articular oedema induced by zymosan. In conclusion, inhibitors of iNOS decrease pain in zymosan arthritis only when given before the zymosan. This was not due to inhibition of articular PGE(2) release or oedema. NO donors also promoted antinociception in zymosan arthritis without affecting oedema.