The persistent release of HMGB1 contributes to tactile hyperalgesia in a rodent model of neuropathic pain

Feldman, Polina; Due, Michael R.; Ripsch, Matthew S.; Khanna, Rajesh; White, Fletcher A.

doi:10.1186/1742-2094-9-180

Cited by 96 publications

(110 citation statements)

References 48 publications

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“…Feldman et al used a tibial nerve injury (TNI) model to reveal the mechanism by which HMGB1 contributes to neuropathic pain (18). TNI induced redistribution of HMGB1 from the nucleus to cytoplasm of sensory neurons in rat DRG and cell lines, without changing total protein content, a finding that is consistent with the release mechanism of HMGB1 proposed in other cell types (19).…”

Section: Hmgb1 and Neuropathic Painsupporting

confidence: 61%

“…Glycyrrhizin Tibial nerve injury Mechanical hyperalgesia (18) involved in pathophysiological rather than physiological pain. Shibasaki et al showed that HMGB1 was induced in the peripheral nerve in response to nerve injury and suggested that it contributed to the development of pain hypersensitivity, as revealed by antiHMGB1 anti body treatment in the neuropathic pain model (14).…”

Section: Hmgb1 and Neuropathic Painmentioning

confidence: 99%

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HMGB1 as a Potential Therapeutic Target for Neuropathic Pain

et al. 2013

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Abstract. Neuropathic pain, which is intolerable and persistent, arises as a direct consequence of a lesion or disease affecting the somatosensory system and can be debilitating for the affected patients. Accumulating evidence from animal studies has revealed the potential molecular basis for neuropathic pain, resulting in many promising therapeutic targets. While efforts at drug discovery have been made, conventional pharmacotherapy, including the use of opioid analgesics, is still insufficient for the relief of neuropathic pain. Therefore, novel target molecules that may lead to the development of promising analgesics are eagerly anticipated for improved treatment of neuropathic pain. In various insults such as sepsis and ischemia, highmobility group box 1 (HMGB1) is released extracellularly to induce inflammation. HMGB1 was originally identified as a ubiquitous nuclear protein, but emerging evidence has suggested that HMGB1 also plays a role in neuroinflammation as a proinflammatory mediator. These findings suggest that HMGB1 may be involved in the pathology of neuropathic pain. In fact, some reports demonstrate an involve ment of HMGB1 in the development and maintenance of neuropathic pain in experimental animals. Here, we overview the characteristics of HMGB1 as a proinflammatory mediator and show the promise of HMGB1 as a therapeutic target for neuropathic pain.

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Section: Hmgb1 and Neuropathic Painsupporting

confidence: 61%

Section: Hmgb1 and Neuropathic Painmentioning

confidence: 99%

HMGB1 as a Potential Therapeutic Target for Neuropathic Pain

et al. 2013

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“…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).…”

Section: Resultsmentioning

confidence: 99%

“…Intrathecal administration of the neutralizing antibody against HMGB1 prevents or reverses the neuropathic pain/allodynia (Shibasaki et al, 2010;Ren et al, 2012) and bone cancer pain (Tong et al, 2010). Acute direct application of HMGB1 causes hyperexcitability of dissociated nociceptive DRG neurons isolated from rats (Feldman et al, 2012) and hypersensitivity of sciatic nerves to mechanical stimuli in rats (Chacur et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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

Tanaka

Seki

Ishikura

et al. 2013

British J Pharmacology

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BACKGROUND AND PURPOSEHigh-mobility group box 1 (HMGB1), a nuclear protein, is actively or passively released during inflammation. Recombinant human soluble thrombomodulin (rhsTM), a medicine for treatment of disseminated intravascular coagulation (DIC), sequesters HMGB1 and promotes its degradation. Given evidence for involvement of HMGB1 in pain signalling, we determined if peripheral HMGB1 causes hyperalgesia, and then asked if rhsTM modulates the HMGB1-dependent hyperalgesia. EXPERIMENTAL APPROACHMechanical nociceptive threshold and swelling in rat hindpaw were determined by the paw pressure test and by measuring paw thickness, respectively, and HMGB1 levels in rat hindpaw plantar tissue, dorsal root ganglion (DRG) and serum were determined by Western blotting or ELISA. KEY RESULTSIntraplantar (i.pl.) administration of HMGB1 rapidly evoked paw swelling and gradually caused hyperalgesia in rats. Systemic administration of rhsTM abolished HMGB1-induced hyperalgesia, and partially blocked paw swelling. LPS, administered i.pl., rapidly produced mild paw swelling, and gradually caused hyperalgesia. The anti-HMGB1 neutralizing antibody abolished LPS-induced hyperalgesia, but partially inhibited paw swelling. rhsTM at a high dose, 10 mg kg , abolished the LPS-induced hyperalgesia, but not paw swelling. HMGB1 levels greatly decreased in the hindpaw, but not DRG. Serum HMGB1 tended to increase after i.pl. LPS in rats pretreated with vehicle, but not rhsTM. CONCLUSION AND IMPLICATIONSThese data suggest that peripheral HMGB1 causes hyperalgesia, and that rhsTM abolishes HMGB1-dependent hyperalgesia, providing novel evidence for therapeutic usefulness of rhsTM as an analgesic. AbbreviationsAPC, activated protein C; DRG, dorsal root ganglion; HMGB1, high-mobility group box 1; RAGE, receptors for advanced glycation end products; rhsTM, recombinant human soluble thrombomodulin; TLR4, toll-like receptor-4; TM, thrombomodulin; TM-D, thrombomodulin domain

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“…76 The specific ASIC3 antagonist APETx2 77 inhibited Ca 2 þ influx, indicating a critical role of ASIC3 in sensory neuron excitation. Further, APETx2 was shown to reduce acid-induced inflammatory pain due to complete Freund's adjuvant 78 and slower the progression of osteoarthritis.…”

mentioning

confidence: 99%

Acidic microenvironment and bone pain in cancer-colonized bone

Yoneda¹,

Hiasa²,

Nagata³

et al. 2015

BoneKEy Reports

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Solid cancers and hematologic cancers frequently colonize bone and induce skeletal-related complications. Bone pain is one of the most common complications associated with cancer colonization in bone and a major cause of increased morbidity and diminished quality of life, leading to poor survival in cancer patients. Although the mechanisms responsible for cancer-associated bone pain (CABP) are poorly understood, it is likely that complex interactions among cancer cells, bone cells and peripheral nerve cells contribute to the pathophysiology of CABP. Clinical observations that specific inhibitors of osteoclasts reduce CABP indicate a critical role of osteoclasts. Osteoclasts are proton-secreting cells and acidify extracellular bone microenvironment. Cancer cell-colonized bone also releases proton/lactate to avoid intracellular acidification resulting from increased aerobic glycolysis known as the Warburg effect. Thus, extracellular microenvironment of cancer-colonized bone is acidic. Acidosis is algogenic for nociceptive sensory neurons. The bone is densely innervated by the sensory neurons that express acid-sensing nociceptors. Collectively, CABP is evoked by the activation of these nociceptors on the sensory neurons innervating bone by the acidic extracellular microenvironment created by bone-resorbing osteoclasts and bone-colonizing cancer cells. As current treatments do not satisfactorily control CABP and can elicit serious side effects, new therapeutic interventions are needed to manage CABP. Understanding of the cellular and molecular mechanism by which the acidic extracellular microenvironment is created in cancer-colonized bone and by which the expression and function of the acid-sensing nociceptors on the sensory neurons are regulated would facilitate to develop novel therapeutic approaches for the management of CABP.

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The persistent release of HMGB1 contributes to tactile hyperalgesia in a rodent model of neuropathic pain

Cited by 96 publications

References 48 publications

HMGB1 as a Potential Therapeutic Target for Neuropathic Pain

HMGB1 as a Potential Therapeutic Target for Neuropathic Pain

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

Acidic microenvironment and bone pain in cancer-colonized bone

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