TRPV1: Receptor structure, activation, modulation and role in neuro-immune interactions and pain

Maximiano, Thaila Kawane Euflazio; Carneiro, Jessica Aparecida; Fattori, Victor; Verri, Waldiceu A.

doi:10.1016/j.ceca.2024.102870

Cited by 12 publications

(4 citation statements)

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“…Then, we examined whether acute IGF-1 could also affect the spikes triggered by TRPV1 channel activation with 1 μM capsaicin. However, high capsaicin concentrations are known to produce acute short-term desensitization, mainly arising from the large Ca 2+ influx through the channel ( Jung et al, 2004 ; Maximiano et al, 2024 ). Indeed, calmodulin binds to both the N- and C-terminal regions of the channel.…”

Section: Resultsmentioning

confidence: 99%

“…In an attempt to elucidate by which mechanisms acute IGF-1 reduces the spike burst evoked by capsaicin, we explored the possible involvement of the Src kinase, a member of the non-receptor tyrosine kinase family, using the specific c-Src kinase inhibitor PP2. Indeed, one of the IGF-1R signaling pathways (canonical) involves the activation of the PI3Kinase, which can activate the downstream Src kinase that binds to, phosphorylates and activates the TRPV1 channel ( Jin et al, 2004 ; Zhang et al, 2005 ; Troncoso et al, 2014 ; Hakuno and Takahashi, 2018 ; Maximiano et al, 2024 ). While inhibition of the Src kinase by PP2 (10 μM) potently reduced the spike burst triggered by capsaicin, it did not alter the IGF-1 depression of capsaicin-evoked spikes [ Figures 5A, B ; n = 14, mean spike frequencies of 3.3 ± 0.7 Hz, 0.5 ± 0.3 Hz and 0.5 ± 0.5 Hz for capsaicin, capsaicin+PP2 and capsaicin+PP2+IGF-1, respectively; one-way ANOVA F (2, 25) = 6.707 with Tukey’s multiple comparisons test: capsaicin vs. capsaicin + PP2, * P = 0.0239; capsaicin vs. capsaicin + PP2 +IGF-1, * P = 0.0118; capsaicin + PP2 vs. capsaicin + PP2 +IGF-1, P = 0.9999].…”

Section: Resultsmentioning

confidence: 99%

“…This result excludes for two reasons the direct involvement of Src kinase in the inhibitory effect of IGF-1 on capsaicin-evoked spike bursts: (a) the Src kinase inhibitor PP2 does not affect the IGF-1 depression of capsaicin-evoked spikes; (b) in principle, one of the IGF-1R signaling pathways (canonical) involves the activation of the PI3Kinase, which can activate the downstream Src kinase. Then, we should expect that IGF-1, like NGF, increases capsaicin-evoked spike burst, since Src kinase binds to, phosphorylates and activates the TRPV1 channel ( Jin et al, 2004 ; Zhang et al, 2005 ; Troncoso et al, 2014 ; Hakuno and Takahashi, 2018 ; Maximiano et al, 2024 ). However, our current-clamp and voltage-clamp experiments clearly showed that IGF-1 has an inhibitory effect both in pairwise and independent measurements (see, Figures 3 , 4 ).…”

Section: Discussionmentioning

confidence: 99%

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Opposite effects of acute and chronic IGF1 on rat dorsal root ganglion neuron excitability

Pastor,

Attali

2024

Front. Cell. Neurosci.

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Insulin-like growth factor-1 (IGF-1) is a polypeptide hormone with a ubiquitous distribution in numerous tissues and with various functions in both neuronal and non-neuronal cells. IGF-1 provides trophic support for many neurons of both the central and peripheral nervous systems. In the central nervous system (CNS), IGF-1R signaling regulates brain development, increases neuronal firing and modulates synaptic transmission. IGF-1 and IGF-IR are not only expressed in CNS neurons but also in sensory dorsal root ganglion (DRG) nociceptive neurons that convey pain signals. DRG nociceptive neurons express a variety of receptors and ion channels that are essential players of neuronal excitability, notably the ligand-gated cation channel TRPV1 and the voltage-gated M-type K+ channel, which, respectively, triggers and dampens sensory neuron excitability. Although many lines of evidence suggest that IGF-IR signaling contributes to pain sensitivity, its possible modulation of TRPV1 and M-type K+ channel remains largely unexplored. In this study, we examined the impact of IGF-1R signaling on DRG neuron excitability and its modulation of TRPV1 and M-type K+ channel activities in cultured rat DRG neurons. Acute application of IGF-1 to DRG neurons triggered hyper-excitability by inducing spontaneous firing or by increasing the frequency of spikes evoked by depolarizing current injection. These effects were prevented by the IGF-1R antagonist NVP-AEW541 and by the PI3Kinase blocker wortmannin. Surprisingly, acute exposure to IGF-1 profoundly inhibited both the TRPV1 current and the spike burst evoked by capsaicin. The Src kinase inhibitor PP2 potently depressed the capsaicin-evoked spike burst but did not alter the IGF-1 inhibition of the hyperexcitability triggered by capsaicin. Chronic IGF-1 treatment (24 h) reduced the spike firing evoked by depolarizing current injection and upregulated the M-current density. In contrast, chronic IGF-1 markedly increased the spike burst evoked by capsaicin. In all, our data suggest that IGF-1 exerts complex effects on DRG neuron excitability as revealed by its dual and opposite actions upon acute and chronic exposures.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Opposite effects of acute and chronic IGF1 on rat dorsal root ganglion neuron excitability

Pastor,

Attali

2024

Front. Cell. Neurosci.

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“…Nociceptors, specialized primary afferent neurons located in the peripheral nervous system (PNS), are adapted to sense danger, recognizing intense mechanical, thermal, and chemical stimuli which modulate ion channels, including sodium channels (Nav1.7, Nav1.8, and Nav1.9) [ 3 ] and/or transient receptor potential (TRP) channels [ 4 , 5 ], creating action potentials towards the spinal cord or trigeminal nuclei and relayed to the brain, to be translated and understood as pain. There are different modalities of pain, such as exacerbated pain (hyperalgesia), or responses to non-noxious stimuli, such as light touch, that can cause pain (allodynia) [ 6 , 7 , 8 , 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

A Narrative Review of the Dorsal Root Ganglia and Spinal Cord Mechanisms of Action of Neuromodulation Therapies in Neuropathic Pain

da Silva,

Martelossi-Cebinelli,

Yaekashi

et al. 2024

Brain Sciences

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Neuropathic pain arises from injuries to the nervous system in diseases such as diabetes, infections, toxicity, and traumas. The underlying mechanism of neuropathic pain involves peripheral and central pathological modifications. Peripheral mechanisms entail nerve damage, leading to neuronal hypersensitivity and ectopic action potentials. Central sensitization involves a neuropathological process with increased responsiveness of the nociceptive neurons in the central nervous system (CNS) to their normal or subthreshold input due to persistent stimuli, leading to sustained electrical discharge, synaptic plasticity, and aberrant processing in the CNS. Current treatments, both pharmacological and non-pharmacological, aim to alleviate symptoms but often face challenges due to the complexity of neuropathic pain. Neuromodulation is emerging as an important therapeutic approach for the treatment of neuropathic pain in patients unresponsive to common therapies, by promoting the normalization of neuronal and/or glial activity and by targeting cerebral cortical regions, spinal cord, dorsal root ganglia, and nerve endings. Having a better understanding of the efficacy, adverse events and applicability of neuromodulation through pre-clinical studies is of great importance. Unveiling the mechanisms and characteristics of neuromodulation to manage neuropathic pain is essential to understand how to use it. In the present article, we review the current understanding supporting dorsal root ganglia and spinal cord neuromodulation as a therapeutic approach for neuropathic pain.

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The synthesis, release, and binding of substance P

Hilliard,

Vink,

Barbe

2025

Substance P

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TRPV1: Receptor structure, activation, modulation and role in neuro-immune interactions and pain

Cited by 12 publications

References 452 publications

Opposite effects of acute and chronic IGF1 on rat dorsal root ganglion neuron excitability

Opposite effects of acute and chronic IGF1 on rat dorsal root ganglion neuron excitability

A Narrative Review of the Dorsal Root Ganglia and Spinal Cord Mechanisms of Action of Neuromodulation Therapies in Neuropathic Pain

The synthesis, release, and binding of substance P

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