Downregulation of adenosine and adenosine A1 receptor contributes to neuropathic pain in resiniferatoxin neuropathy

Kan, Hung‐Wei; Chang, Chin-Hong; Lin, Chih-Lung; Lee, Yi‐Chen; Hsieh, Sung‐Tsang; Hsieh, Yu-Lin

doi:10.1097/j.pain.0000000000001246

Cited by 26 publications

(31 citation statements)

References 47 publications

(85 reference statements)

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“…DPN mice exhibited an antiparallel fashion of IENF reduction and ATF3 upregulation; that is, DPN extensively affected the neuronal soma and their peripheral terminals. ATF3 upregulation has been associated with increased ATP, which sensitized the P2X3 purinociceptor,11 and reduced adenosine, which mediated the antinociceptive effect 12,32. The susceptible small-diameter neurons have created further challenges in distinguishing the contributions made by changing intracellular signaling molecules.…”

Section: Discussionmentioning

confidence: 99%

Activating transcription factor 3 modulates protein kinase C epsilon activation in diabetic peripheral neuropathy

Chang¹,

Kan²,

Hsieh³

2019

JPR

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BackgroundSkin denervation that develops in patients with diabetes mellitus as a neuropathic manifestation is known as diabetic peripheral neuropathy (DPN). Skin denervation is parallel to neuronal injuries that alter intracellular signaling. To date, the correlation between nerve injury and the activation of intracellular responses to neuropathic manifestations has not been elucidated; specifically, whether activating transcription factor 3 (ATF3) is responsible for neuronal injury and a critical molecule that modulates the activation of intracellular protein kinase C epsilon (p-PKCε) and pain development in DPN is a crucial question.MethodsTo address, ATF3 knockout (atf3−/− group, C57/B6 genetic background) and wild-type mice (atf3+/+ group) received a single dose of streptozotocin (200 mg/kg) to generate a mouse model of DPN.ResultsBoth atf3+/+ and atf3−/− mice exhibited hyperglycemia and the same pathology of skin denervation at posttreatment month 2, but only atf3+/+ mice developed thermal hyperalgesia (P<0.001) and mechanical allodynia (P=0.002). The atf3+/+ group, but not the atf3−/− group, had preferential ATF3 upregulation on p-PKCε(+) neurons with a ratio of 37.7%±6.1% in p-PKCε(+):ATF3(+) neurons (P<0.001). In addition, B-cell lymphoma-extra large (Bcl-XL), an antiapoptotic Bcl2 family protein, exhibited parallel patterns to p-PKCε (ie, Bcl-XL upregulation was reversed in atf3−/− mice). These two molecules were colocalized and increased by approximately two-fold in the atf3+/+ group compared with the atf3−/− group (30.0%±3.4% vs 13.7% ± 6.2%, P=0.003). Furthermore, linear analysis results showed that the densities of p-PKCε and Bcl-XL had a reverse linear relationship with the degrees of thermal hyperalgesia and mechanical allodynia.ConclusionCollectively, this report suggested that ATF3 is a critical upstream molecule that modulates p-PKCε and Bcl-XL expression, which consequently mediated the development of neuropathic manifestation in DPN.

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Section: Discussionmentioning

confidence: 99%

Activating transcription factor 3 modulates protein kinase C epsilon activation in diabetic peripheral neuropathy

Chang¹,

Kan²,

Hsieh³

2019

JPR

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“…Notably, the transmembrane isoform of prostatic acid phosphatase (PAP) was previously documented in microdomains (Quintero et al, 2007); PAP has ectonucleotidase properties (Sowa et al, 2009) that can hydrolyze extracellular adenosine monophosphate (AMP) to the antinociceptive agonist adenosine (Street and Zylka, 2011; Zylka et al, 2008). The antinociceptive effect of PAP that prevents pain hypersensitivity has been thoroughly documented, and our previous research confirmed that PAP neuropathology results in the loss of antinociception; that is, injured PAP(+) neurons mediate pain hypersensitivity (Wu et al, 2016) through disorder of adenosine signaling (Kan et al, 2018). However, the mechanism involved in this effect remains uncertain and requires further investigation.…”

Section: Introductionmentioning

confidence: 53%

“…(Middle panel) (3) At the acute stage of RTX neuropathy, MβC disrupted the microdomain by depleting cholesterol, which preserves PAP-hydrolyzed PI(4,5)P2 and antinociception despite (4) TRPV1 sensitization and ATF3 upregulation following RTX administration. (Right panel) At the chronic stage, depletion of TRPV1(+) neurons is mildly associated with PAP(+) and A1R(+) neuron depletion; moreover, (5) the residual A1R(+) and PAP(+) neurons are associated with ATF3 upregulation, (6) suppression of PI(4,5)P2 hydrolysis, and (7) reduced availability of adenosine (Kan et al, 2018), which consequently induces pain hypersensitivity.…”

Section: Discussionmentioning

confidence: 99%

Treatment with methyl-β-cyclodextrin prevents mechanical allodynia in resiniferatoxin neuropathy in a mouse model

Lin

Chang

et al. 2018

Biology Open

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Specialized microdomains which have cholesterol-rich membrane regions contain transient receptor potential vanilloid subtype 1 (TRPV1) are involved in pain development. Our previous studies have demonstrated that the depletion of prostatic acid phosphatase (PAP) – a membrane-bound ectonucleotidase – and disordered adenosine signaling reduce the antinociceptive effect. The role of membrane integrity in the PAP-mediated antinociceptive effect in small-fiber neuropathy remains unclear, especially with respect to whether TRPV1 and PAP are colocalized in the same microdomain which is responsible for PAP-mediated antinociception. Immunohistochemistry was conducted on the dorsal root ganglion to identify the membrane compositions, and pharmacological interventions were conducted using methyl-β-cyclodextrin (MβC) – a membrane integrity disruptor that works by depleting cholesterol – in pure small-fiber neuropathy with resiniferatoxin (RTX). Immunohistochemical evidence indicated that TRPV1 and PAP were highly colocalized with flotillin 1 (66.7%±9.7%) and flotillin 2 (73.7%±6.0%), which reside in part in the microdomain. MβC mildly depleted PAP, which maintained the ability to hydrolyze phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and delayed the development of mechanical allodynia. MβC treatment had no role in thermal transduction and neuronal injury following RTX neuropathy. In summary, this study demonstrated the following: (1) membrane cholesterol depletion preserves PAP-mediated antinociception through PI(4,5)P2 hydrolysis and (2) pain hypersensitivity that develops after TRPV1(+) neuron depletion-mediated neurodegeneration following RTX neuropathy is attributable to the downregulation of PAP analgesic signaling.

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“…Interestingly, PAP -/animals show a higher nerve injury-associated pain, similarly to A1 adenosine receptor KO mice which show increased nociceptor response (Wu et al, 2005). In a mouse model of neuropathic pain, where small-diameter sensory nerves are selectively depleted by resiniferatoxin (a capsaicin analogue that acts on TRPV1 receptors) animals showed downregulation of PAP expression leading to increased AMP and reduced adenosine generation (Kan et al, 2018). The exogenous administration of either PAP or adenosine reversed mechanical allodynia, and this effect was inhibited by the A1-receptor antagonist dipropyl-cyclopentylxanthine (DPCPX; Kan et al, 2018).…”

Section: The Neuronal Side Of Purinergic Signaling In Neuropathic Painmentioning

confidence: 99%

“…In a mouse model of neuropathic pain, where small-diameter sensory nerves are selectively depleted by resiniferatoxin (a capsaicin analogue that acts on TRPV1 receptors) animals showed downregulation of PAP expression leading to increased AMP and reduced adenosine generation (Kan et al, 2018). The exogenous administration of either PAP or adenosine reversed mechanical allodynia, and this effect was inhibited by the A1-receptor antagonist dipropyl-cyclopentylxanthine (DPCPX; Kan et al, 2018). Taken together, these results demonstrate that an imbalance in adenosinemediated signaling, which can act autocrinally on sensory neurons and/or paracrinally on surrounding cells contributes to the development of neuropathic pain.…”

Section: The Neuronal Side Of Purinergic Signaling In Neuropathic Painmentioning

confidence: 99%

The role of adenosine and P2Y receptors expressed by multiple cell types in pain transmission

Magni

Ceruti

2019

Brain Research Bulletin

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The role of extracellular nucleotides and nucleosides as signaling molecules in cell-to-cell communication has now been clearly established. This is particularly true in the central and peripheral nervous system, where purines and pyrimidines are involved in both physiological and pathological interactions between neurons and surrounding glial cells. It can be thus foreseen that the purinergic system could represent a new potential target for the development of effective analgesics, also through the normalization of neuronal functions and the inhibition of glial cell activation. Research in the last 15 years has progressively confirmed this hypothesis, but no purinergic-based analgesics have reach the market so far; in the present review we have collected the more recent discoveries on the role of G protein-coupled P2Y nucleotide and of adenosine receptors expressed by both neurons and glial cells under painful conditions, and we have highlighted some of the challenges that must be faced to translate basic and preclinical studies to clinics.

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Downregulation of adenosine and adenosine A1 receptor contributes to neuropathic pain in resiniferatoxin neuropathy

Abstract: This study demonstrates that functional prostatic acid phosphatase is required for maintaining the balance of cellular adenosine analgesia in systemic small-fiber neuropathy.

Cited by 26 publications

References 47 publications

Activating transcription factor 3 modulates protein kinase C epsilon activation in diabetic peripheral neuropathy

Activating transcription factor 3 modulates protein kinase C epsilon activation in diabetic peripheral neuropathy

Treatment with methyl-β-cyclodextrin prevents mechanical allodynia in resiniferatoxin neuropathy in a mouse model

The role of adenosine and P2Y receptors expressed by multiple cell types in pain transmission

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