The l-kynurenine-probenecid combination reduces neuropathic pain in rats

Background l-Kynurenine has antinociceptive effects in acute and inflammatory pain. This study determined the effect of l-kynurenine and its metabolite (kynurenic acid) on rats subjected to neuropathic pain. Methods L5/L6 spinal nerve ligation induced tactile allodynia as measured with von Frey filaments using the up-down method. High-performance liquid chromatography and Western blot analysis determined kynurenic acid levels and expression of kynurenine amino transferase II (KAT II), respectively. Results l-Kynurenine (50-200mg/kg, i.p.) or probenecid (100mg/kg, i.p.) did not affect allodynia in neuropathic rats. In contrast, l-kynurenine (50-200mg/kg, i.p.) in combination with probenecid (100mg/kg, i.p.), an inhibitor of organic anion transport, reversed allodynia. Furthermore, intrathecal kynurenic acid (1-30g) reversed allodynia. Probenecid (100mg/kg, i.p.) supplementation enhanced the maximal antiallodynic effect of intrathecal kynurenic acid (10g). Only the combined administration of l-kynurenine (200mg/kg)/probenecid (100mg/kg) increased the kynurenic acid concentration in cerebrospinal fluid. KAT II is expressed in dorsal root ganglia and dorsal spinal cord. KAT II expression was unchanged by the spinal nerve ligation or l-kynurenine/probenecid combination. The kynurenine/probenecid combination did not affect motor activity. Conclusions l-Kynurenine produces its antiallodynic effect in the central nervous system through kynurenic acid. This effect may result from blockade of N-methyl-d-aspartate receptors. KAT II is expressed in dorsal root ganglion and dorsal spinal cord. Combined l-kynurenine and probenecid therapy has the potential to reduce neuropathic pain in humans.