Ca2+ and calpain mediate capsaicin-induced ablation of axonal terminals expressing transient receptor potential vanilloid 1

Wang, Sheng; Wang, Sen; Asgar, Jamila; Joseph, John; Ro, Jin Y.; Feng, Wei; Campbell, James N.; Chung, Man‐Kyo

doi:10.1074/jbc.m117.778290

Cited by 34 publications

(40 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nociceptive neurons do not regenerate as well as non-nociceptive neurons, and some reports demonstrate that they upregulate pro-death molecules in response to injury ( Kalous and Keast, 2010 ; Hu et al, 2016 ; Berta et al, 2017 ). Furthermore, activation of TRPV1 can ablate TRPV1-expressing neurons and axon terminals ( Mishra and Hoon, 2010 ; Wang et al, 2017 ). Therefore, we considered the possibility that capsaicin induces cell death via TRPV1 and eliminates poorly growing neurons from the population, thereby artificially skewing the distribution of neurons toward better axonal growth.…”

Section: Resultsmentioning

confidence: 99%

TRPV1 Agonist, Capsaicin, Induces Axon Outgrowth after Injury via Ca²⁺/PKA Signaling

Frey¹,

Karney-Grobe²,

Krolak³

et al. 2018

eNeuro

View full text Add to dashboard Cite

Preconditioning nerve injuries activate a pro-regenerative program that enhances axon regeneration for most classes of sensory neurons. However, nociceptive sensory neurons and central nervous system neurons regenerate poorly. In hopes of identifying novel mechanisms that promote regeneration, we screened for drugs that mimicked the preconditioning response and identified a nociceptive ligand that activates a preconditioning-like response to promote axon outgrowth. We show that activating the ion channel TRPV1 with capsaicin induces axon outgrowth of cultured dorsal root ganglion (DRG) sensory neurons, and that this effect is blocked in TRPV1 knockout neurons. Regeneration occurs only in NF200-negative nociceptive neurons, consistent with a cell-autonomous mechanism. Moreover, we identify a signaling pathway in which TRPV1 activation leads to calcium influx and protein kinase A (PKA) activation to induce a preconditioning-like response. Finally, capsaicin administration to the mouse sciatic nerve activates a similar preconditioning-like response and induces enhanced axonal outgrowth, indicating that this pathway can be induced in vivo. These findings highlight the use of local ligands to induce regeneration and suggest that it may be possible to target selective neuronal populations for repair, including cell types that often fail to regenerate.

show abstract

Section: Resultsmentioning

confidence: 99%

TRPV1 Agonist, Capsaicin, Induces Axon Outgrowth after Injury via Ca²⁺/PKA Signaling

Frey¹,

Karney-Grobe²,

Krolak³

et al. 2018

eNeuro

View full text Add to dashboard Cite

show abstract

“…TRPV1 is known to be involved in the perception of inflammatory and thermal pain, especially pain from heat, which exceeds 43°C [ 10 ]. The activation of TRPV1 can further initiate Ca 2+ influx for neuronal depolarization [ 24 , 25 ]. The downregulation of TRPV1 function results in insensitivity to high temperature stimulation, radial heat, and hot-plate tests [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Role of Transient Receptor Potential Vanilloid 1 in Electroacupuncture Analgesia on Chronic Inflammatory Pain in Mice

Yang

Hsieh

Lin

2017

BioMed Research International

View full text Add to dashboard Cite

Chronic inflammatory pain may result from peripheral tissue injury or inflammation, increasing the release of protons, histamines, adenosine triphosphate, and several proinflammatory cytokines and chemokines. Transient receptor potential vanilloid 1 (TRPV1) is known to be involved in acute to subacute neuropathic and inflammatory pain; however, its exact mechanisms in chronic inflammatory pain are not elucidated. Our results showed that EA significantly reduced chronic mechanical and thermal hyperalgesia in the chronic inflammatory pain model. Chronic mechanical and thermal hyperalgesia were also abolished in TRPV1−/− mice. TRPV1 increased in the dorsal root ganglion (DRG) and spinal cord (SC) at 3 weeks after CFA injection. The expression levels of downstream molecules such as pPKA, pPI3K, and pPKC increased, as did those of pERK, pp38, and pJNK. Transcription factors (pCREB and pNFκB) and nociceptive ion channels (Nav1.7 and Nav1.8) were involved in this process. Inflammatory mediators such as GFAP, S100B, and RAGE were also involved. The expression levels of these molecules were reduced in EA and TRPV1−/− mice but not in the sham EA group. Our data provided evidence to support the clinical use of EA for treating chronic inflammatory pain.

show abstract

“…All other chemicals and drugs were purchased from Sigma-Aldrich. To determine the role of calpain, we injected 20 ml of 10 mM MDL28170 (200 nmol), which effectively prevented the ablation of TRPV11 afferents in hindpaw (Wang et al, 2017b).…”

Section: Drugsmentioning

confidence: 99%

“…MDL28170, an inhibitor of calpains, reduced capsaicin-induced ablation of TRPV11 afferent terminals in vitro and in vivo. Importantly, MDL28170 prevented capsaicin-induced thermal hypoalgesia in hindpaw (Wang et al, 2017b). However, it is not known whether such capsaicin-induced calpain-dependent ablation of TRPV11 nerve terminals is necessary for analgesia of neuropathic pain conditions.…”

Section: Introductionmentioning

confidence: 99%

“…However, considering the fact that multiple neuropathic pain conditions are accompanied by reductions in intraepidermal nerve fiber density (Landowski et al, 2016), it is important to determine the causal role for capsaicin-induced ablation of TRPV11 fibers in capsaicin-induced analgesic effects. We recently showed that capsaicin ablates TRPV11 nerve terminals through TRPV1-mediated Ca 21 influx followed by the activation of calpains, which are Ca 21 -dependent proteases (Wang et al, 2017b). MDL28170, an inhibitor of calpains, reduced capsaicin-induced ablation of TRPV11 afferent terminals in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Ablation of TRPV1+ Afferent Terminals by Capsaicin Mediates Long-Lasting Analgesia for Trigeminal Neuropathic Pain

Wang

Bian

Yang

et al. 2020

eNeuro

Self Cite

View full text Add to dashboard Cite

Trigeminal neuropathic pain (TNP) is often resistant to current pharmacotherapy, and there is a pressing need to develop more efficacious treatments. Capsaicin is a pungent ingredient of chili peppers and specifically activates transient receptor potential vanilloid subtype 1 (TRPV1), a Ca 21-permeable ion channel. Topical capsaicin invariably induces burning pain. Paradoxically, the transient pain is often followed by prolonged attenuation of the preexisting pathologic pain from the same region. However, the mechanisms underlying capsaicin-induced analgesia are not well understood. Although the reports of the involvement of TRPV1 and TRPV11 afferents in neuropathic pain are controversial, we recently demonstrated that TRPV1 and TRPV11 afferents are involved in mechanical hyperalgesia in mice with chronic constriction injury of the infraorbital nerve (ION-CCI). Consistently, chemogenetic inhibition of TRPV1-lineage (TRPV1-LN) afferents attenuated mechanical hyperalgesia and ongoing pain. In mice with ION-CCI, we found that a single focal injection of capsaicin into facial skin led to attenuation of mechanical hyperalgesia over two weeks. Capsaicin treatment also attenuated secondary hyperalgesia in extraterritorial mandibular skin. Furthermore, capsaicin treatment decreased ongoing pain. Longitudinal in vivo two-photon imaging of cutaneous nerve fibers showed that such capsaicin-induced analgesia is correlated with cutaneous nerve terminal density. Furthermore, preventing capsaicin-induced ablation of afferent terminals by co-administration of capsaicin with MDL28170, an inhibitor of calpain, abolished capsaicin-induced analgesia. These results suggest that a single focal injection of capsaicin induces long-lasting analgesia for neuropathic pain via selective ablation of TRPV11 afferent terminals and that TRPV11 afferents contribute to the maintenance of TNP.

show abstract

Ca2+ and calpain mediate capsaicin-induced ablation of axonal terminals expressing transient receptor potential vanilloid 1

Cited by 34 publications

References 58 publications

TRPV1 Agonist, Capsaicin, Induces Axon Outgrowth after Injury via Ca²⁺/PKA Signaling

TRPV1 Agonist, Capsaicin, Induces Axon Outgrowth after Injury via Ca²⁺/PKA Signaling

Role of Transient Receptor Potential Vanilloid 1 in Electroacupuncture Analgesia on Chronic Inflammatory Pain in Mice

Ablation of TRPV1+ Afferent Terminals by Capsaicin Mediates Long-Lasting Analgesia for Trigeminal Neuropathic Pain

Contact Info

Product

Resources

About

Ca2+ and calpain mediate capsaicin-induced ablation of axonal terminals expressing transient receptor potential vanilloid 1

Cited by 34 publications

References 58 publications

TRPV1 Agonist, Capsaicin, Induces Axon Outgrowth after Injury via Ca2+/PKA Signaling

TRPV1 Agonist, Capsaicin, Induces Axon Outgrowth after Injury via Ca2+/PKA Signaling

Role of Transient Receptor Potential Vanilloid 1 in Electroacupuncture Analgesia on Chronic Inflammatory Pain in Mice

Ablation of TRPV1+ Afferent Terminals by Capsaicin Mediates Long-Lasting Analgesia for Trigeminal Neuropathic Pain

Contact Info

Product

Resources

About

TRPV1 Agonist, Capsaicin, Induces Axon Outgrowth after Injury via Ca²⁺/PKA Signaling

TRPV1 Agonist, Capsaicin, Induces Axon Outgrowth after Injury via Ca²⁺/PKA Signaling