Involvement of endoplasmic reticulum stress in formalin-induced pain is attenuated by 4-phenylbutyric acid

Abstract

BackgroundEndoplasmic reticulum (ER) stress is involved in many neurological and inflammatory responses. Peripheral inflammatory responses can induce central sensitization and trigger inflammatory pain. However, there is little research on the relationship between ER stress and inflammatory pain. In this study, we examined whether the ER stress response is involved in peripheral inflammatory pain using a formalin-induced rat pain model.MethodsRats were divided into the following five groups: control, formalin, formalin + vehicle, formalin + 4-phenylbutyric acid (4-PBA) (40 mg/kg) and formalin + 4-PBA (100 mg/kg). Formalin-induced pain was assessed behaviorally by recording licking activity. The expression levels of immunoglobulin-binding protein (BIP), activating transcription factor-6 (ATF6), phosphorylated inositol-requiring enzyme-1 (p-IRE1), phosphorylated protein kinase RNA-like ER kinase (p-PERK) and c-fos were quantitatively assessed by Western blot, and the distribution of BIP, ATF6 and c-fos in the lumbar enlargement of spinal cord were identified by immunohistochemistry in spinal dorsal horn slices. In addition, the concentrations of nitric oxide (NO) and prostaglandin E2 (PGE2) in the spinal cord were tested by biochemical measurement and enzyme-linked immunosorbent assay (ELISA), respectively.ResultsIntraperitoneal injection of 4-PBA at the dose of 100 mg/kg before formalin injection significantly decreased nociceptive behavior in the second phase compared with control, formalin, formalin + vehicle and formalin + 4-PBA (40 mg/kg) (P<0.05). Western blot showed that formalin injection significantly upregulated the expression of BIP, ATF6, p-PERK and c-fos in the spinal cord. This upregulation was reduced by peritoneal injection of 4-PBA (P<0.05), while expression of p-IRE1 was not altered by formalin treatment. Immunohistochemistry revealed markedly increased staining density for BIP, ATF6 and c-fos in the superficial spinal dorsal horn after formalin injection. This was significantly decreased by administration of 4-PBA (P<0.05). Compared with the formalin + vehicle group, 4-PBA inhibited the release of NO and PGE2 in the spinal cord (P<0.05).ConclusionThese results suggest that ER stress is involved in formalin-induced inflammatory pain and that inhibition of ER stress may attenuate central sensitization induced by peripheral inflammatory stimulation.

Resveratrol alleviates nuclear factor‐κB‐mediated neuroinflammation in vasculitic peripheral neuropathy induced by ischaemia–reperfusion via suppressing endoplasmic reticulum stress

“…ER stress constitutes a specific set of intracellular signalling pathways in response to the accumulation of unfolded or misfolded proteins triggered by a variety of conditions, such as infection, burn, trauma, inflammatory diseases and neurological disorders . Moreover, the accumulated evidence supports the concept that ER stress is critically involved in the peripheral mechanisms of diabetic neuropathy and inflammatory pain . The unfolded‐protein response (UPR) following ER stress is a self‐protective mechanism that initially tries to restore the normal function of ER.…”

“…34 Moreover, the accumulated evidence supports the concept that ER stress is critically involved in the peripheral mechanisms of diabetic neuropathy and inflammatory pain. [20][21][22][23] The unfolded-protein response (UPR) following ER stress is a self-protective mechanism that initially tries to restore the normal function of ER. However, unresolved ER stress can lead to cellular dysfunction and apoptosis.…”

“…Based on the anti‐inflammatory property of resveratrol, we hypothesized that resveratrol may alleviate VPN induced by IR through suppressing the activation of NF‐κB signalling in the sciatic nerve. Moreover, it has been shown that the adaptive cellular mechanism of endoplasmic reticulum (ER) stress has emerged as a fundamental pain regulator and potential therapeutic target in certain types of peripheral neuropathies . We therefore also examined whether a modulating ER stress pathway is involved in the protective effects of resveratrol.…”

“…Moreover, it has been shown that the adaptive cellular mechanism of endoplasmic reticulum (ER) stress has emerged as a fundamental pain regulator and potential therapeutic target in certain types of peripheral neuropathies. [20][21][22][23] We therefore also examined whether a modulating ER stress pathway is involved in the protective effects of resveratrol.…”

Antioxidant Effects ofBerchemia berchemiaefoliain Nerve Pain Models

“…A few XO inhibitors (allopurinol and febuxostat) have been clinically used (Ye et al, 2016). A variety of other antioxidants have also been used as analgesic drug candidates (Zhou et al, 2017). This experimental results show that the water fraction of this material has a strong antioxidant capacity (Fig.…”