Diabetes mellitus is a serious debilitating epidemic affecting all social strata, imposing huge health, social and economic burdens. Diabetic
neuropathic pain, an important microvascular complication of
diabetes mellitus, characterized by
allodynia and
hyperalgesia, is recognized as one of the most difficult types of
pain to treat. The development of tolerance, inadequate relief and potential toxicity of classical antinociceptives warrant the investigation of newer agents to relieve this
pain. Reactive
oxygen/
nitrogen species,
cytokines and
matrix metalloproteinases (
MMPs) are implicated in the pathogenesis of
diabetic neuropathy. The present study was designed to explore the effect of
naringenin, a citrus
flavonoid, on
streptozotocin induced diabetic
neuropathic pain in Wistar rats. After 8 weeks of diabetes induction, rats developed neuropathy which was evident from marked
hyperalgesia and
allodynia associated with enhanced oxidative-nitrosative stress, release of inflammatory mediators (TNF-α, TGF-1β), MMP-9 activation and decreased motor nerve conduction velocity. Treatment with
naringenin (25, 50, 100 mg kg-1) for 4 weeks starting from the 5th week of
streptozotocin injection significantly attenuated behavioral, biochemical and molecular changes, along with alterations in motor nerve conduction velocity in a dose-dependent manner. Moreover, diabetic rats treated with
insulin-
naringenin combination produced a more pronounced effect as compared to individual drugs. The major finding of the study is that
insulin alone corrected the
hyperglycemia and partially reversed the
pain response in diabetic rats. However, combination with
naringenin not only attenuated the diabetic condition but also reversed
neuropathic pain through modulation of oxidative-nitrosative stress, inflammatory
cytokine release and
MMP inhibition in the diabetic rats. Modulation of MMP-9 by a natural
flavonoid like
naringenin seems to be a novel approach to target diabetic
neuropathic pain.