Tizanidine exerts anti-nociceptive effects in spared nerve injury model of neuropathic pain through inhibition of TLR4/NF-κB pathway

Recently, α2-adrenoceptors (α2-AR) agonists have been shown to have anti-nociceptive effects and thus may become a promising therapeutic strategy for neuropathic pain. tizanidine is a highly selective α2-AR agonist, but the effect mechanism of tizanidine in neuropathic pain remains largely unknown. The present study investigated whether tizanidine has anti-nociceptive effects in spared nerve injury (SNI) model of neuropathic pain in rats, as well as explored the underlying molecular mechanism. We found that the rats in SNI group showed significantly higher mechanical and thermal hyperalgesia, accompanied with increased production of proinflammatory cytokines including interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α), as well as the activation of Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling. PDTC, an inhibitor of TLR4/NF-κB signaling, could significantly attenuate the SNI-induced mechanical and thermal hyperalgesia and the production of proinflammatory cytokines. Moreover, treatment with tizanidine also attenuated the SNI-induced mechanical and thermal hyperalgesia, suppressed production of the proinflammatory cytokines, and inhibited the activation of TLR4/NF-κB pathway, which could be reversed by pretreatment with BRL44408, a selective α2-AR antagonist. Taken these findings together, we demonstrated that tizanidine has anti-nociceptive effects on neuropathic pain via inhibiting the production of proinflammatory cytokines through suppressing the activation of TLR4/NF-κB p65 signaling pathway.