Diabetic neuropathic pain, an important microvascular complication in diabetes mellitus, is recognised 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 the newer agents to relieve this pain. Reactive oxygen/nitrogen species, cytokines and apoptosis are implicated in the pathogenesis of diabetic neuropathy. The aim of the present study was to explore the effect of tocotrienol on thermal and mechanical hyperalgesia, allodynia, oxidative-nitrosative stress, inflammation and apoptosis in streptozotocin-induced experimental diabetes. Diabetic rats developed neuropathy which was evident from a marked hyperalgesia and allodynia associated with enhanced nitrosative stress, release of inflammatory mediators (TNF-alpha, IL-1beta, TGF-1beta) and caspase-3. Chronic treatment with tocotrienol (25, 50 and 100 mg/kg body weight; p.o.) for 4 weeks starting from the 4th week of streptozotocin injection significantly attenuated behavioral, biochemical and molecular changes associated with diabetic neuropathy. Moreover, diabetic rats treated with insulin-tocotrienol combination produced more pronounced beneficial effect as compared to their per se groups. 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 tocotrienol not only attenuated the diabetic condition but also reversed neuropathic pain through modulation of oxidative-nitrosative stress, inflammatory cytokine release and caspase-3 in the diabetic rats and thus it may find clinical application to treat neuropathic pain in the diabetic patients.
