Role of TRPV1 and ASIC3 in formalin-induced secondary allodynia and hyperalgesia

Martínez-Rojas, Vladimir A.; Barragán-Iglesias, Paulino; Rocha-González, Héctor Isaac; Murbartián, Janet; Granados‐Soto, Vinicio

doi:10.1016/j.pharep.2014.06.011

Cited by 17 publications

(14 citation statements)

References 41 publications

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“…In total, four KChIP proteins (KChIP1-4), sharing expression patterns and functions constitute the KChIP subfamily of NCS proteins. Coexpression of the KChIP proteins remarkably promotes the membrane localization of Kv4 channels, increases current density, slows current inactivation, and speeds recovery from inactivation (An et al, 2000;Takimoto et al, 2002;Jerng et al, 2005;Hu et al, 2006). Reciprocally, the membrane localization of KChIP3, particularly when coexpressed with the Kv4.2 or Kv4.3 channels, was demonstrated in previous studies by our group and others (Takimoto et al, 2002;Ruiz-Gomez et al, 2007;Zhang et al, 2010).…”

Section: Introductionsupporting

confidence: 61%

“…Radiant heat measurement. Thermal hyperalgesia was evaluated by following a thermal stimulus paradigm adapted from Hargreave's published reports (Hargreaves et al, 1988). Before testing, the animals were allowed to acclimatize to their environment for 10 min.…”

Section: Methodsmentioning

confidence: 99%

“…1). In DRG, unlike the other Kv4 auxiliary subunits (KChIP1, KChIP2, and dipeptidyl peptidase like protein 10), KChIP3 exhibited no colocalization with Kv4.3, the major contributor of the subthreshold A type K ϩ current in primary sensory neurons (Kuo et al, 2017), suggesting the unique role of KChIP3 in the periphery.…”

mentioning

confidence: 92%

“…The underlying mechanism is related to the phosphorylation of TRPV1 intracellular domains by multiple protein kinases, which leads to the increased surface localization of the receptor and altered channel kinetics. In contrast, Ca 2ϩ effectors activated after Ca 2ϩ influx via TRPV1, including CaM and phosphatase calcineurin, mediate TRPV1 desensitization (Numazaki et al, 2003;Jung et al, 2004;Rosenbaum et al, 2004;Mohapatra and Nau, 2005;Lishko et al, 2007). Direct associations of CaM with both the intracellular N and C termini of TRPV1 were demonstrated (Rosenbaum et al, 2004;Lishko et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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KChIP3 N-Terminal 31-50 Fragment Mediates Its Association with TRPV1 and Alleviates Inflammatory Hyperalgesia in Rats

Tian

Yang

et al. 2018

J. Neurosci.

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Potassium voltage-gated channel interacting protein 3 (KChIP3), also termed downstream regulatory element antagonist modulator (DREAM) and calsenilin, is a multifunctional protein belonging to the neuronal calcium sensor (NCS) family. Recent studies revealed the expression of KChIP3 in dorsal root ganglion (DRG) neurons, suggesting the potential role of KChIP3 in peripheral sensory processing. Herein, we show that KChIP3 colocalizes with transient receptor potential ion channel V1 (TRPV1), a critical molecule involved in peripheral sensitization during inflammatory pain. Furthermore, the N-terminal 31-50 fragment of KChIP3 is capable of binding both the intracellular N and C termini of TRPV1, which substantially decreases the surface localization of TRPV1 and the subsequent Ca influx through the channel. Importantly, intrathecal administration of the transmembrane peptide transactivator of transcription (TAT)-31-50 remarkably reduces Ca influx via TRPV1 in DRG neurons and alleviates thermal hyperalgesia and gait alterations in a complete Freund's adjuvant-induced inflammatory pain model in male rats. Moreover, intraplantar injection of TAT-31-50 attenuated the capsaicin-evoked spontaneous pain behavior and thermal hyperalgesia, which further strengthened the regulatory role of TAT-31-50 on TRPV1 channel. In addition, TAT-31-50 could also alleviate inflammatory thermal hyperalgesia in rats generated in our study, suggesting that the analgesic effect mediated by TAT-31-50 is independent of endogenous KChIP3. Our study reveals a novel peripheral mechanism for the analgesic function of KChIP3 and provides a potential analgesic agent, TAT-31-50, for the treatment of inflammatory pain. Inflammatory pain arising from inflamed or injured tissues significantly compromises the quality of life in patients. This study aims to elucidate the role of peripheral potassium channel interacting protein 3 (KChIP3) in inflammatory pain. Direct interaction of the KChIP3 N-terminal 31-50 fragment with transient receptor potential ion channel V1 (TRPV1) was demonstrated. The KChIP3-TRPV1 interaction reduces the surface localization of TRPV1 and thus alleviates heat hyperalgesia and gait alterations induced by peripheral inflammation. Furthermore, the transmembrane transactivator of transcription (TAT)-31-50 peptide showed analgesic effects on inflammatory hyperalgesia independently of endogenous KChIP3. This work reveals a novel mechanism of peripheral KChIP3 in inflammatory hyperalgesia that is distinct from its classical role as a transcriptional repressor in pain modulation.

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Section: Introductionsupporting

confidence: 61%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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KChIP3 N-Terminal 31-50 Fragment Mediates Its Association with TRPV1 and Alleviates Inflammatory Hyperalgesia in Rats

Tian

Yang

et al. 2018

J. Neurosci.

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“…According to our previous research, a secondary and long-lasting mechanical allodynic and hyperalgesic response can be observed not only on the ipsilateral but also on the contralateral hind paw. Since sensory receptors in the bilateral area of secondary mechanical allodynia and hyperalgesia are unaffected, these sensory changes might be caused by central sensitization in the spinal cord and brain nucleus of the initial intense nociceptive discharge that follows the formalin injection (4)(5)(6). Various studies suggest that the release of immune substances and proinflammatory cytokines from spinal glia (7,8), and the bilateral signaling via commissural interneurons (9), might, in part, induce the mirror-image pain.…”

Section: Experimental Designmentioning

confidence: 99%

Contribution of Spinal PKCγ Expression to Short- and Long-lasting Pain Behaviors in Formalin-induced Inflamed Mice

Zhao

Yin

et al. 2018

Pain Phys

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Background: Over-expression of spinal protein kinase C γ (PKCγ) contributes to the induction of persistent bilateral hyperalgesia following inflammatory injury, yet the role of spinal PKCγ in short- and long-lasting pain behavior is poorly understood. Objective: This study aimed to characterize the contribution of spinal PKCγ to spontaneous pain and long-lasting bilateral hyperalgesia in formalin-induced inflamed mice using pharmacological inhibition. Study Design: Laboratory animal study. Setting: The study was performed in the Department of Human Anatomy and K.K. Leung Brain Research Centre, Preclinical School of Medicine, the Fourth Military Medical University (Xi’an, China) and the Department of Anesthesiology, Fuzhou General Hospital (Fuzhou, China). Methods: Male mice were unilaterally intraplantarly injected with formalin to induce inflammatory pain. Spontaneous pain behaviors, including flinches and lickings, were recorded by off-line video during the first hour post-injection and counted. Using von Frey tests, longlasting bilateral mechanical paw withdrawal thresholds were determined before injection and at indicated time points thereafter. Temporal expression of spinal PKCγ was observed by immunohistochemical staining. For pharmacological inhibition, mice were treated daily with intrathecal Tat carrier or selective PKCγ inhibitor KIG31-1, from 1 hour prior to 10 days after formalin injection. Spontaneous pain behaviors and long-lasting bilateral mechanical hyperalgesia were assessed. Spinal PKCγ expression was also observed by using immunohistochemical staining and western blot. Results: The number of PKCγ-immunoreactive (ir) spinal neurons was significantly higher at 10 days, but not 2 hours, after formalin intraplantar injection, and accompanied by long-lasting bilateral hyperalgesia. Furthermore, long-lasting bilateral hyperalgesia could be reversed by pharmacological inhibition of over-expressed spinal PKCγ; however, pretreating with intrathecal KIG31-1 showed no antinociceptive effects on short-term spontaneous pain behaviors. Limitations: All results were obtained from the mice and no PKCγ inhibitors were available through clinical practice. Therefore, it remains difficult to draw definitive connections between animal research and human application. Conclusion: Our findings suggest that spinal PKCγ plays a predominant role in long-lasting bilateral hyperalgesia, but not in the spontaneous pain behaviors induced by formalin. Key words: Formalin, spontaneous pain, mechanical hyperalgesia, protein kinase C gamma, KIG31-1, mice

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Analgesic Effects of Danggui-Shaoyao-San on Various “Phenotypes” of Nociception and Inflammation in a Formalin Pain Model

Yin

Zhou

et al. 2015

Mol Neurobiol

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Danggui-Shaoyao-San (DSS) is a traditional Chinese medicine, which has long been used for pain treatment and has been demonstrated to possess anti-oxidative, cognitive enhancement, and anti-depressant effects. In the present study, the effects of aqueous extracts of DSS on spontaneous pain behaviors and long-term hyperalgesia were examined to investigate the anti-nociceptive effects and underlying mechanisms. Single pretreatment of DSS dose-dependently reduced spontaneous flinches/licking time in the second, rather than the first, phase after subcutaneous injection of 5 % formalin into one hindpaw, in doses of 2.4 and 9.6 g/kg. DSS also dose-dependently inhibited FOS and cyclooxygenase-2 (COX-2) expression in both superficial and deep layers within the spinal dorsal horn. Further, DSS reduced hypoalgesia in the injected paw from 1 to 3 days and produced anti-hyperalgesic actions in both the injected paw after 3 days and non-injected paw. These data suggest involvement of enhancement of descending pain inhibition by suppression of 5-HTT levels in the spinal dorsal horn and reduction of peripheral long-term inflammation, including paw edema and ulcers. These findings suggest that DSS may be a useful therapeutic agent for short- and long-term inflammation induced pain, through both anti-inflammatory and suppression of central sensitization mechanisms.

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Role of TRPV1 and ASIC3 in formalin-induced secondary allodynia and hyperalgesia

Abstract: Data suggest that TRPV1 and ASIC3 participate in the development and maintenance of long-lasting secondary allodynia and hyperalgesia induced by formalin in rats. The use of TRPV1 and ASIC3 antagonists by peripheral administration could prove useful to treat chronic pain.

Cited by 17 publications

References 41 publications

KChIP3 N-Terminal 31-50 Fragment Mediates Its Association with TRPV1 and Alleviates Inflammatory Hyperalgesia in Rats

KChIP3 N-Terminal 31-50 Fragment Mediates Its Association with TRPV1 and Alleviates Inflammatory Hyperalgesia in Rats

Contribution of Spinal PKCγ Expression to Short- and Long-lasting Pain Behaviors in Formalin-induced Inflamed Mice

Analgesic Effects of Danggui-Shaoyao-San on Various “Phenotypes” of Nociception and Inflammation in a Formalin Pain Model

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