Role of Extracellular Damage-Associated Molecular Pattern Molecules (DAMPs) as Mediators of Persistent Pain

Kato, Jungo; Svensson, Camilla I.

doi:10.1016/bs.pmbts.2014.11.014

Cited by 74 publications

(68 citation statements)

References 193 publications

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“…Spinal TLR4 systems have been implicated in this transition as the IT delivery of a TLR4 antagonist (LPS-RS) prevented the transition to a chronic pain state in WT mice (Christianson et al, 2011). This role of spinal TLR4 in the evolution of a persistent pain state is consistent with the observation that delivery of TLR4 ligands will initiate a long-lasting change in tactile thresholds (Feldman et al, 2012; Tse et al, 2014; Liu et al, 2012; Kato & Svensson, 2015; Agalave & Svensson, 2015; Agalave et al, 2014), and that TLR4 ligands are reported to be associated with disease severity in humans (Ke et al, 2015). As will be noted below, the issue has several complicating factors, not the least of which is that the role of the spinal TLR4 receptor displays sex-dependent effects.…”

Section: Discussionsupporting

confidence: 85%

“…Increased levels of IL-1β have been linked to the development of persistent pain (Watkins et al, 1994; Lu et al, 2014; Yan et al, 2014), and may be responsible for the tactile allodynia seen in the current experiments. However, the convergent outcomes of TLR4-deficient animals and the effects of TAK-242, suggest that the late “Phase 3” of the formalin model reflects an engagement of TLR4 signaling, presumably through a triggered release of endogenous TLR4 ligands known to induce pain-like behaviors in animals (Feldman et al, 2012; Tse et al, 2014; Liu et al, 2012; Kato & Svensson, 2015; Agalave & Svensson, 2015; Agalave et al, 2014). …”

Section: Discussionmentioning

confidence: 99%

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Systemic TAK-242 prevents intrathecal LPS evoked hyperalgesia in male, but not female mice and prevents delayed allodynia following intraplantar formalin in both male and female mice: The role of TLR4 in the evolution of a persistent pain state

Woller

Ravula

Tucci

et al. 2016

Brain, Behavior, and Immunity

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Objective Pain resulting from local tissue injury or inflammation typically resolves with time. Frequently, however, this pain may unexpectedly persist, becoming a pathological chronic state. Increasingly, the innate and adaptive immune systems are being implicated in the initiation and maintenance of these persistent conditions. In particular, Toll-like receptor 4 (TLR4) signaling has been shown to mediate the transition to a persistent pain state in a sex-dependent manner. In the present work, we explored this contribution using the TLR4 antagonist, TAK-242. Methods Male and female C57Bl/6 mice were given intravenous (IV), intrathecal (IT), or intraperitoneal (IP) TAK-242 prior to IT delivery of lipopolysaccharide (LPS), and tactile reactivity was assessed at regular intervals over 72-hours. Additional groups of mice were treated with IP TAK-242 prior to intraplantar formalin, and flinching was monitored for 1-hour. Tactile reactivity was assessed at 7-days after formalin delivery. Results LPS evoked TNF release from male and female macrophages and RAW267.4 cells, which was blocked in a concentration dependent fashion by TAK-242. In vivo, IT LPS evoked tactile allodynia to a greater degree in male than female mice. TAK-242, given by all routes, prevented development of IT LPS-induced tactile allodynia in male animals, but did not reverse their established allodynia. TLR4 deficiency and TAK-242 treatment attenuated IT LPS-induced allodynia in male, but not female mice. In the formalin model, pre-treatment with TAK-242 did not affect Phase 1 or Phase 2 flinching, but prevented the delayed tactile allodynia in both male and unexpectedly in female mice (Phase 3). Conclusions Together, these results suggest that TAK-242 is a TLR4 antagonist that has efficacy after systemic and intrathecal delivery and confirms the role of endogenous TLR4 signaling in triggering the development of a delayed allodynia in both male and female mice.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Systemic TAK-242 prevents intrathecal LPS evoked hyperalgesia in male, but not female mice and prevents delayed allodynia following intraplantar formalin in both male and female mice: The role of TLR4 in the evolution of a persistent pain state

Woller

Ravula

Tucci

et al. 2016

Brain, Behavior, and Immunity

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“…Recent studies implicate HMGB1 in mediating pain both at the organ level and at the central nervous system level (for a review see Kato J & Svensson CI) [6]. Pain hypersensitivity was elicited when HMGB1 was injected into sciatic nerve and anti-HMGB1 treatment alleviated mechanical allodynia after injury, but the nociceptive signaling pathway is still unclear [21].…”

Section: Discussionmentioning

confidence: 99%

“…HMGB1 is actively secreted in response to inflammatory signals, acting as a pro-inflammatory molecule in addition to its passive release from necrotic cells in various organs [6]. The extracellular activities of HMGB1 depend on the redox state of HMGB1 resulting in activation of different HMGB1 receptors.…”

Section: Introductionmentioning

confidence: 99%

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Disulfide high mobility group box-1 causes bladder pain through bladder Toll-like receptor 4

Kouzoukas

Meyer-Siegler

et al. 2017

BMC Physiol

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BackgroundBladder pain is a prominent symptom in several urological conditions (e.g. infection, painful bladder syndrome/interstitial cystitis, cancer). Understanding the mechanism of bladder pain is important, particularly when the pain is not accompanied by bladder pathology. Stimulation of protease activated receptor 4 (PAR4) in the urothelium results in bladder pain through release of urothelial high mobility group box-1 (HMGB1). HGMB1 has two functionally active redox states (disulfide and all-thiol) and it is not known which form elicits bladder pain. Therefore, we investigated whether intravesical administration of specific HMGB1 redox forms caused abdominal mechanical hypersensitivity, micturition changes, and bladder inflammation in female C57BL/6 mice 24 hours post-administration. Moreover, we determined which of the specific HMGB1 receptors, Toll-like receptor 4 (TLR4) or receptor for advanced glycation end products (RAGE), mediate HMGB1-induced changes.ResultsDisulfide HMGB1 elicited abdominal mechanical hypersensitivity 24 hours after intravesical (5, 10, 20 μg/150 μl) instillation. In contrast, all-thiol HMGB1 did not produce abdominal mechanical hypersensitivity in any of the doses tested (1, 2, 5, 10, 20 μg/150 μl). Both HMGB1 redox forms caused micturition changes only at the highest dose tested (20 μg/150 μl) while eliciting mild bladder edema and reactive changes at all doses. We subsequently tested whether the effects of intravesical disulfide HMGB1 (10 μg/150 μl; a dose that did not produce inflammation) were prevented by systemic (i.p.) or local (intravesical) administration of either a TLR4 antagonist (TAK-242) or a RAGE antagonist (FPS-ZM1). Systemic administration of either TAK-242 (3 mg/kg) or FPS-ZM1 (10 mg/kg) prevented HMGB1 induced abdominal mechanical hypersensitivity while only intravesical TLR4 antagonist pretreatment (1.5 mg/ml; not RAGE) had this effect.ConclusionsThe disulfide form of HMGB1 mediates bladder pain directly (not secondary to inflammation or injury) through activation of TLR4 receptors in the bladder. Thus, TLR4 receptors are a specific local target for bladder pain.

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S100B has pleiotropic effects on vaso‐occlusive manifestations in sickle cell disease

et al. 2020

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Role of Extracellular Damage-Associated Molecular Pattern Molecules (DAMPs) as Mediators of Persistent Pain

Cited by 74 publications

References 193 publications

Systemic TAK-242 prevents intrathecal LPS evoked hyperalgesia in male, but not female mice and prevents delayed allodynia following intraplantar formalin in both male and female mice: The role of TLR4 in the evolution of a persistent pain state

Systemic TAK-242 prevents intrathecal LPS evoked hyperalgesia in male, but not female mice and prevents delayed allodynia following intraplantar formalin in both male and female mice: The role of TLR4 in the evolution of a persistent pain state

Disulfide high mobility group box-1 causes bladder pain through bladder Toll-like receptor 4

S100B has pleiotropic effects on vaso‐occlusive manifestations in sickle cell disease

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