Spinal high‐mobility group box‐1 induces long‐lasting mechanical hypersensitivity through the toll‐like receptor 4 and upregulation of interleukin‐1β in activated astrocytes

Abstract

Intrathecal treatment with recombinant high‐mobility group box‐1 (rHMGB1) in naïve mice leads to a persistent and significantly decreased hind paw withdrawal threshold to mechanical stimuli, suggesting that spinal HMGB1 evokes abnormal pain processing. By contrast, repeated intrathecal treatment with anti‐HMGB1 antibody significantly reverses hind paw mechano‐hypersensitivity in mice with a partial sciatic nerve ligation (PSNL). By contrast, the cellular mechanism by which spinal HMGB1 induces neuropathic pain has yet to be fully elaborated. The current study tested the hypothesis that spinal HMGB1 could induce mechanical hypersensitivity through the activation of specific receptor in glial cells. Intrathecal pretreatment with toll‐like receptor (TLR) 4 inhibitors, but not TLR5, receptor for advanced glycation end‐products and C‐X‐C chemokine receptor type 4 inhibitors, prevented rHMGB1‐evoked mechanical hypersensitivity. Activation of spinal astrocytes appears to be crucial for the mechanism of action of rHMGB1 in naïve mice, as intrathecal pretreatment with astrocytic inhibitors prevented the rHMGB1‐induced mechanical hypersensitivity. Interleukin‐1β (IL‐1β) was up‐regulated within activated astrocytes and block of TLR4 prevented the upregulation of IL‐1β. Interleukin‐1β appears to be secreted by activated astrocytes, as IL‐1β neutralizing antibody prevented rHMGB1‐induced mechanical hypersensitivity. Furthermore, intrathecal pretreatment with either MK801 or gabapentin prevented the rHMGB1‐induced mechanical hypersensitivity, suggesting roles for spinal glutamate and the N‐methyl‐d‐aspartate receptor in the mediation of rHMGB1‐induced mechanical hypersensitivity. Thus, the current findings suggest that spinal HMGB1 upregulates IL‐1β in spinal astrocytes through a TLR4‐dependent pathway and increases glutamatergic nociceptive transduction. These spinal mechanisms could be key steps that maintain neuropathic pain.

Toll-Like Receptor 4 (TLR4)/Opioid Receptor Pathway Crosstalk and Impact on Opioid Analgesia, Immune Function, and Gastrointestinal Motility

“…There is also other evidence demonstrating the critical role of HMGB1 in abnormal pain processing. Intrathecal, intraplantar, and perineural injection of HMGB1 produced mechanical hypersensitivity ( 62 , 84 , 85 ). HMGB1 is a multifunctional protein that interacts with a variety of receptors.…”

“…HMGB1 is a multifunctional protein that interacts with a variety of receptors. Tolerance, hyperalgesia, and allodynia have been shown to involve HMGB1 activating the RAGE, TLR4, and TLR5 signaling pathways (60,61,84,86).…”

Role of high‐mobility group box 1 and its modulation by thrombomodulin/thrombin axis in neuropathic and inflammatory pain

“…Interestingly, the HMGB1/TLR4 axis is also pro‐nociceptive in the spinal cord, since i.t. administration of HMGB1 or ds‐HMGB1 causes TLR4‐dependent mechanical hyperalgesia/allodynia (Agalave et al, 2014; Morioka et al, 2019). Likewise, visceral nociception appears to involve the HMGB1/TLR4 axis in the peripheral tissue, because intravesical infusion of ds‐HMGB1 produces TLR4‐dependent abdominal mechanical hypersensitivity, that is, referred hyperalgesia/allodynia, in mice (F. Ma et al, 2017).…”

Role of HMGB1 in Chemotherapy-Induced Peripheral Neuropathy

“…In 2001, it was reported for the first time that injection of HMGB1 around the sciatic nerve induced mechanical allodynia in rats [90]. Recently, increasing evidence has unveiled the pro-nociceptive role of HMGB1 in the peripheral tissue and spinal cord [16,18,29,80,89], and demonstrated that endogenous HMGB1 is involved in the pathogenesis of various types of intractable pain [11,15], including inflammatory pain [28,29,80], visceral pain [19,20,30,32], neuropathic pain [23,31,76,91,92], cancer pain [33], and post-stroke pain [34]. Endogenous HMGB1 also appears to play a key role in the development of CIPN in rats or mice treated with cancer chemotherapeutics, such as paclitaxel, oxaliplatin, and vincristine, considering the complete prevention of CIPN by inactivation of HMGB1 with HMGB1-nAb or TMα (Figure 2 and Table 1) [8][9][10][11].…”