Streptozotocin-induced diabetic hyperalgesia in rats is associated with upregulation of toll-like receptor 4 expression

Neuropathic pain is one of the common complications of diabetes mellitus, and current treatments often do not meet medical needs. Toll-like receptor 4 (TLR4) has been implicated as a potential therapeutic target in neuropathic and other pain models. In this study, we investigated whether TLR4 expression in spinal cord would be altered in streptozotocin-induced diabetic rat model, which had persistent mechanical and thermal hypersensitivity. The results showed that the mRNA expression of TLR4 was upregulated in streptozotocin-treated animals. Furthermore, TLR4 expression was associated with both paw-pressure withdrawal threshold toward mechanical stimulus and paw withdrawal latency toward thermal stimulus. The protein levels of TNF-α and IL-1β, two downstream proinflammatory cytokines of TLR4 signaling pathway, were also significantly raised and correlated with mechanical/thermal hypersensitivity in diabetic rats. Together, these data have demonstrated that TLR4 and its signaling pathway are associated with neuropathic pain in a diabetic model. It may imply that TLR4 could be a novel target for treating diabetic neuropathy.

► Role of TLR4 in diabetes-induced hyperalgesia in rats was evaluated.
► Streptozotocin-induced diabetic rats show robust hyperalgesia.
► Association between upregulated TLR4 mRNA expression and neuropathic pain.
► Protein levels of TNF-α and IL-1β are also increased along with hypersensitivity.
► In summary, TLR4 and its signaling pathway are associated with STZ-induced diabetic hyperalgesia in rats.