Induction of high mobility group box-1 in dorsal root ganglion contributes to pain hypersensitivity after peripheral nerve injury

Abstract

Pro-inflammatory cytokine high mobility group box-1 (HMGB-1) is involved in inflammation in the central nervous system, but less is known about its biological effects in the peripheral nervous system. In the present study, the role of HMGB-1 in the primary afferent nerve was investigated in the context of the pathophysiology of peripheral nerve injury-induced pain hypersensitivity. Real-time PCR confirmed an increase in HMGB-1 mRNA expression in the dorsal root ganglion (DRG) and spinal nerve at 1 day after spinal nerve ligation (SNL). Induction of HMGB-1 mRNA was observed in both injured L5 and uninjured L4. Immunohistochemistry for HMGB-1 revealed that SNL-induced HMGB-1 expression in the primary afferent neurons and satellite glial cells (SGCs) in the DRG, and in Schwann cells in the spinal nerve. Up-regulation of HMGB-1 was associated with translocation of its signal from the nucleus to the cytoplasm. Injection of HMGB-1 into the sciatic nerve produces transient behavioural hyperalgesia. Neutralizing antibody against HMGB-1 successfully alleviated the mechanical allodynia observed after SNL treatment. Receptor for advanced glycation end products (RAGE), one of the major receptors for HMGB-1, was expressed in the primary afferent neurons and SGCs in the DRG, as well as in Schwann cells in the spinal nerve. These results indicate that HMGB-1 is synthesized and secreted into the DRG and spinal nerve, and contributes to the development of neuropathic pain after nerve injury. Blocking HMGB-1/RAGE signalling might thus be a promising therapeutic strategy for the management of neuropathic pain.

H2Treatment Attenuated Pain Behavior and Cytokine Release Through the HO-1/CO Pathway in a Rat Model of Neuropathic Pain

“…High-mobility group box 1 (HMGB1) has been identified as a potent inflammatory mediator. Shibasaki et al showed that nerve injury induced HMGB1 release in the peripheral nerve, which led to the process of pain hypersensitivity [44]. HMGB1 was responsible for pain hypersensitivity in DRG, which contributed to the IL-1β expression in the spinal cord, thereby modulating spinal excitatory synaptic transmission and pain responses [45]; HMGB1 has also been found to activate immunocytes and the release of inflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IL-8, which were associated with hyperalgesia and allodynia in CCI rats [46].…”

Recombinant human soluble thrombomodulin prevents peripheral HMGB1‐dependent hyperalgesia in rats

“…There is evidence for involvement of exogenous and endogenous HMGB1 in pain processing (Chacur et al, 2001;Tong et al, 2010;Feldman et al, 2012). In particular, HMGB1 present in the DRG and spinal cord appears to participate in the pathogenesis of neuropathic pain (Shibasaki et al, 2010;Kuang et al, 2012;Ren et al, 2012).…”

Pattern recognition receptors in chronic pain: Mechanisms and therapeutic implications

“…Weak RAGE immunoreactivity has been observed in intact peripheral nerve axons, DRG neuronal cell bodies and spinal nerve bundles in rodents and following peripheral nerve injury and experimental models of diabetes, RAGE is upregulated in these sites (Juranek et al, 2013;Rong et al, 2004b;Shibasaki et al, 2010). In human tissues, RAGE is found in nerve bundles associated with the microvasculature, and an increased level of RAGE protein expression has been reported in sural nerve biopsy from diabetic patients (Bierhaus et al, 2004) (Table 2).…”