The effects of local pentoxifylline and propentofylline treatment on formalin-induced pain and tumor necrosis factor-alpha messenger RNA levels in the inflamed tissue of the rat paw

Abstract

We sought to determine whether local administration of pentoxifylline (PTF) or propentofylline (PPTF), which hinders cytokine production, influences pain threshold and formalin-induced pain behavior in rats or the level of tumor necrosis factor-alpha (TNF-alpha) messenger RNA (mRNA) concentrations in the inflamed paw tissue. PTF (0.5, 1, or 2 mg) and PPTF (1 or 2 mg) injected intraplantarly (i.pl.) had no significant effect on pain threshold. Injection of 0.1 mL of a 12% formalin solution subcutaneously into the dorsal surface of the left hindpaw induced pain behavior (47.6 +/- 4.6 incidents per 5 min), and PTF injected at doses of 1 and 2 mg/100 microL i.pl. before (but not after) formalin was effective in antagonizing (33.6 +/- 2.5 and 23.6 +/- 3.4 incidents per 5 min, respectively) formalin-induced pain behavior. A similar antagonistic effect was observed after PPTF treatment at a dose of 2 mg/100 microL; however, in contrast to PTF, at a later time point (85-90 min) after the formalin challenge, this effect was independent of the scheme of PPTF administration, before or after formalin. The effect of PTF on formalin-induced pain behavior did not parallel paw volume as measured by plethysmometer; however, PTF per se significantly increased the paw volume. Formalin injection significantly increased the TNF-alpha mRNA level in the inflamed tissue of the rat hind paw (150%). PTF administered before, but not after, formalin significantly antagonized (by approximately 40%) the observed increase in the level of TNF-alpha mRNA. Our study demonstrates and provides biochemical evidence that preemptive inhibition of proinflammatory cytokine synthesis by the use of PTF and PPTF, phosphodiesterase, and glial activation inhibitors is useful in antagonizing hyperalgesia in formalin-induced pain. Moreover, local administration of PTF may be a valuable approach to the treatment of inflammatory pain.

Implications: This study demonstrates and provides biochemical evidence that preemptive inhibition of proinflammatory cytokine synthesis by local administration of pentoxifylline and propentofylline is useful in antagonizing hyperalgesia in formalin-induced pain. Moreover, local administration of pentoxifylline could be regarded as a valid approach to the treatment of inflammatory pain.