Nrf2/HO-1 signaling pathway participated in the protection of hydrogen sulfide on neuropathic pain in rats

Abstract

Neuropathic pain is evoked by aberrant sensory processing in the peripheral or central nervous system, which is characterized by persistent pain, tactile allodynia, or hyperalgesia. Neuroinflammation is associated with the initiation and maintenance of persistent pain in both the peripheral and central nervous systems. Hydrogen sulfide plays important regulatory roles in different physiological and pathological conditions. Therefore, we investigated the effect of hydrogen sulfide on allodynia, hyperalgesia and cytokine release in rats with neuropathic pain and the related regulatory mechanism. Neuropathic pain was established by chronic constriction injury (CCI) of the sciatic nerve in rats. Nuclear factor erythroid-2 (NF-E2)-related factor 2 (Nrf2) siRNA, hemin, Sn-protoporphyrin (SnPP)-IX and/or NaHS were administered to rats with neuropathic pain, and the spinal cord was collected to detect the expression of Nrf2, hemeoxygenase-1 (HO-1), nuclear factor-kappa B (NF-κb) and the cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and high mobility group box (HMGB)-1 by Western blot (WB) analysis, reverse transcription polymerase chain reaction (RT-PCR), immunofluorescence or enzyme-linked immunosorbent assay (ELISA). Mechanical allodynia, thermal hyperalgesia and the number of paw lifts were measured at different time points after operation. In the present research, neuropathic pain induced Nrf2 and HO-1 expression in the microglial cells of the spinal cord; Nrf2 and HO-1 were necessary to alleviate the hyperalgesia of CCI-induced rats; NaHS mitigated the hyperalgesia and allodynia induced by the CCI operation; and NaHS mitigated the excessive release of the cytokines TNF-α, IL-1β, IL-6 and HMGB1 via the Nrf2/HO-1 pathway in the microglial cells of the spinal cord. These results indicated that NaHS exhibited antinociceptive and anti-inflammatory effects that were associated with the activation of the Nrf2/HO-1 pathway in the spinal cord of rats with neuropathic pain.

Keywords: Hyperalgesia; Inflammation; NaHS; Neuropathic pain; Nrf2.