Recent studies have highlighted the involvement of the
kynurenine pathway in the pathology of
neurodegenerative diseases, but the role of this system in
neuropathic pain requires further extensive research. Therefore, the aim of our study was to examine the role of
kynurenine 3-monooxygenase (Kmo), an
enzyme that is important in this pathway, in a rat model of neuropathy after chronic constriction injury (CCI) to the sciatic nerve. For the first time, we demonstrated that the injury-induced increase in the Kmo
mRNA levels in the spinal cord and the dorsal root ganglia (DRG) was reduced by chronic administration of the microglial inhibitor
minocycline and that this effect paralleled a decrease in the intensity of neuropathy. Further,
minocycline administration alleviated the
lipopolysaccharide (LPS)-induced upregulation of Kmo
mRNA expression in microglial cell cultures. Moreover, we demonstrated that not only indirect inhibition of Kmo using
minocycline but also direct inhibition using Kmo inhibitors (Ro61-6048 and JM6) decreased
neuropathic pain intensity on the third and the seventh days after CCI. Chronic Ro61-6048 administration diminished the
protein levels of IBA-1,
IL-6, IL-1beta and NOS2 in the spinal cord and/or the DRG. Both Kmo inhibitors potentiated the
analgesic properties of
morphine. In summary, our data suggest that in
neuropathic pain model, inhibiting Kmo function significantly reduces
pain symptoms and enhances the effectiveness of
morphine. The results of our studies show that the
kynurenine pathway is an important mediator of
neuropathic pain pathology and indicate that Kmo represents a novel pharmacological target for the treatment of neuropathy.