Effects of Duloxetine on the Toll-Like Receptor 4 Signaling Pathway in Spinal Dorsal Horn in a Rat Model of Diabetic Neuropathic Pain.

ABSTRACT

Objective: Although duloxetine has been approved for clinical therapy for diabetic peripheral neuropathic pain, the exact mechanism underlying the anti-allodynic effects in rat models of diabetes mellitus remains obscure. We attempted to identify whether duloxetine exerts anti-allodynic effects via inhibition of the TLR4-Myd88-dependent pathway in diabetic neuropathic pain (DNP) rats. Methods: An animal model of type 1 diabetic neuropathic pain was induced by intraperitoneal streptozotocin in 108 rats randomized into four groups control, DNP, solvent control + DNP, and DNP + duloxetine. The DNP model establishment was validated, providing the MWT and TWL measurements were less than 80% of the baseline value on d14 after streptozotocin administration. The expressions of TLR4, Myd88, and NF-κB in the spinal dorsal horn were determined 21 days after streptozotocin injection by immunohistochemical assay and Western blot. Results: The results revealed that MWT and TWL in DNP, SC + DNP, and DLX + DNP groups were significantly decreased 14 days after STZ administration vs control (P < 0.05), while the pain thresholds in the DLX + DNP group were partially reversed. The expressions of TLR4, Myd88, and NF-κB in groups C, DNP, and SC + DNP were significantly increased, whereas duloxetine administration significantly downregulated the expressions of TLR4, Myd88, and NF-κB (P < 0.05). Conclusions: Our findings indicated that duloxetine mitigated mechanical and thermal withdrawal thresholds in STZ-injected rats and rescued the overexpression of the TLR4-Myd88-dependent pathway in the spinal dorsal horn in these rats. Whether these changes directly contributed to the reduction of thermal and mechanical withdrawal behavior needs to be further explored.