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Canna~Fangled Abstracts

The dual role of TRPV1 in peripheral neuropathic pain: pain switches caused by its sensitization or desensitization

By September 9, 2024September 24th, 2024No Comments

 2024; 17: 1400118.
Published online 2024 Sep 9. doi: 10.3389/fnmol.2024.1400118
PMCID: PMC11417043
PMID: 39315294
Ning Gao,# 1 , † Meng Li,# 2 , † Weiming Wang, 1 Zhen Liu,corresponding author 2 , * and Yufeng Guocorresponding author 1 , *
Author information Article notes Copyright and License information PMC Disclaimer

Abstract

The transient receptor potential vanilloid 1 (TRPV1) channel plays a dual role in peripheral neuropathic pain (NeuP) by acting as a “pain switch” through its sensitization and desensitization. Hyperalgesia, commonly resulting from tissue injury or inflammation, involves the sensitization of TRPV1 channels, which modulates sensory transmission from primary afferent nociceptors to spinal dorsal horn neurons. In chemotherapy-induced peripheral neuropathy (CIPN), TRPV1 is implicated in neuropathic pain mechanisms due to its interaction with ion channels, neurotransmitter signaling, and oxidative stress. Sensitization of TRPV1 in dorsal root ganglion neurons contributes to CIPN development, and inhibition of TRPV1 channels can reduce chemotherapy-induced mechanical hypersensitivity. In diabetic peripheral neuropathy (DPN), TRPV1 is involved in pain modulation through pathways including reactive oxygen species and cytokine production. TRPV1’s interaction with TRPA1 channels further influences chronic pain onset and progression. Therapeutically, capsaicin, a TRPV1 agonist, can induce analgesia through receptor desensitization, while TRPV1 antagonists and siRNA targeting TRPV1 show promise in preclinical studies. Cannabinoid modulation of TRPV1 provides another potential pathway for alleviating neuropathic pain. This review summarizes recent preclinical research on TRPV1 in association with peripheral NeuP.

Keywords: TRPV1, peripheral neuropathic pain, molecular mechanisms, sensitization, desensitization

1. Introduction

Neuropathic pain (NeuP) is caused by a lesion or disease affecting the peripheral or central somatosensory nervous system (), as the International Association for the Study of Pain (IASP) defines (). Depending on the lesion location, NeuP is classified into peripheral and central NeuP according the ICD-11 (). The prevalence of NeuP is as high as 7–10% of the general population, which is higher in certain specific populations (; ; ). About 26% of patients with diabetes mellitus and 21% of patients with herpes zoster develop NeuP (). The classic symptoms of NeuP involve positive symptoms such as spontaneous pain, hyperalgesia and allodynia, as well as negative symptoms such as decreased or loss of sensation (; ). Meanwhile, NeuP is often accompanied by different temporal characteristics and pain properties (). NeuP is typically chronic and severe, impacting patients’ psychosocial and healthcare economic costs as well as their quality of life (; ). The management of NeuP is extremely challenging for clinicians due to the refractory treatment (). An epidemiologic survey showed that about 10–20% of patients are not correctly identified () and about 30–60% are not treated appropriately (), which may be related to insufficient information about the pathophysiologic mechanisms of the diseases (). Over the past decades, researchers have begun to investigate the cellular and molecular mechanisms involved in the pathogenesis of NeuP. Studies have revealed that significant mechanisms observed under the NeuP condition, include ectopic activity (), peripheral sensitization (), central sensitization (), impaired inhibitory regulation (), and microglia activation ().

Transient Receptor Potential (TRP) channels is a non-selective cation channels, consisting of a broad range of channels (), which could be categorized into TRPC, TRPV, TRPA, TRPM, TRPP, and TRPML (). The TRP channels are implicated in the transduction of sensory information, including thermosensation (), taste (), hearing (), pain sensation (), etc. The abnormal function of TRP channels may lead to skin (), airway (), endocrine () and gut (). Furthermore, TRP channels are essential molecular components in acute inflammation and chronic pain conditions (). Transient receptor potential channel vanilloid subtype 1 (TRPV1) channel is of the most studied targeting mechanisms in NeuP researches due to its widespread expression in neuronal cells and its critical role in pain perception and modulation (; ). In this review, we provide a systematic overview of TRPV1, with a particular focus on their role and research progress in NeuP.

2. Structure and expression of TRPV1 channel

2.1. Molecular structure

TRPV1 was the first mammalian TRP channel whose structure was determined and cloned (). The TRPV1 protein consists of four subunits, each containing six transmembrane structural domains (S1–S6) and two long intracellular N-terminal and C-terminal (). Four independently folded S1–S4 structural domains surround to form the intervening pore loop region, which constitutes an ion-permeable channel with S5 and S6 (). Single-particle electron cryomicroscopy identified a fourfold symmetric structure of TRPV1, consisting of two regions, a large basket-like domain and a small compact domain, corresponding to the N-terminal, C-terminal region and transmembrane region, respectively (). Dual gating mechanism regulates the opening of TRPV1, where the upper gate is a selectivity filter formed by a funnel-shaped extracellular pore and the lower gate is located in the middle of the S6 helix and is involved in the dilation of a hydrophobic constriction (). Some studies identified allelic variants of TRPV1 in specific populations (), which may be associated with cold sensitivity () and risk of developing knee osteoarthritis ().

2.2. Expression patterns in tissues

TRPV1 is abundantly expressed in peripheral sensory neurons of the dorsal root ganglia (DRG), vagus and trigeminal ganglia (). In addition, TRPV1 is also expressed in the intestinal mucosal epithelium, skin epidermis and immune cells, and others (). As a pain and heat sensor for humans (), it can be activated by a broad range of physical and chemical stimuli such as toxic heat (>43°C), divalent cations, low pH, inflammatory mediators, and animal toxins (). Activation of the channel leads to a large Ca2+ and Na+ influx, generating neuronal depolarization and action potential discharges, which may also lead to calcium overload (; ). The activation of TRPV1 is enhanced when multiple stimuli are present simultaneously (). However, persistent stimulation reduces neuronal excitability, leading to a basic or complete insensitivity to subsequent stimuli, and thus specific desensitization (tachyphylaxis) occurs (Figure 1) (; ). To date, TRPV1 agonists (capsaicin, Resiniferatoxin), as well as antagonists (capsazepine, SB-705498, or NEO6860), have been used for the treatment of migraine, osteoarthritis, atopic dermatitis, and NeuP ().

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Structural and functional overview of TRPV1 activation and desensitization. TRPV1 is composed of three parts: intracellular N and C termini, six transmembrane domains (S1–S6), and a pore loop region formed between S5 and S6. It can be activated by various physical and chemical stimuli, such as noxious heat (>43°C), divalent cations, low pH, inflammatory mediators, and animal toxins. Activation of this channel leads to significant influxes of Ca2+ and Na+, causing neuronal depolarization and action potential discharge. Prolonged stimulation enhances TRPV1 activation, reducing neuronal excitability and resulting in near or complete insensitivity to subsequent stimuli, a phenomenon known as specific desensitization. Additionally, elevated intracellular calcium levels can activate the calcium-dependent protease calpain, which degrades cytoskeletal components within axons, leading to axonal structural damage and functional loss.

3. Mechanisms of NeuP

The pathogenesis of the NeuP is of complexity and has not yet been fully elucidated (). Most of the current potential pathogenic mechanisms center on neuronal cells, encompassing the excitability of primary sensory neurons and the imbalance between excitatory and inhibitory synaptic transmission within the central nervous system (CNS) (). NeuP is typically characterized by ongoing or intermittent spontaneous pain or mechanical allodynia (). Spontaneous pain may be caused by ectopic activity of damaged nerve fibers, and evoked pain primarily involves peripheral and central sensitization (). The reasons for sensitization of nociceptors generally include alteration of ion channels, activation of immune cells, glial-derived mediators, and epigenetic regulation (). At the spinal cord level, the underlying synaptic plasticity is not fully clarified. It has been shown that projection neurons in layer I of the spinal dorsal horn form synaptic connections with nociceptor C as well as Aδ fibers. The nociceptive projection neurons in layer I are activated through a complex neural circuit consisting of excitatory and inhibitory interneurons, which then send out projection fibers to carry that stimulus information to the superior centers (; ). Peripheral nerve impairment via plastic modification of neuronal synapses and networks leads to changes in the balance between synaptic excitation and inhibition in layer I projection neurons, which may be driven in part by changes in excitatory and inhibitory interneurons in layer II or layer III, that may be related to the development and maintenance of pain hypersensitivity responses ().

The mechanisms of central NeuP involve intricate interactions and maladaptive plasticity within spinal and brain circuits related to nociception and antinociception, along with neuronal hyperexcitability and neuro-immune interactions, contributing to the complexity of this condition (). Recently, microglia activation was suggested to be involved in central NeuP pathophysiology, leading to the dysregulation of the MED1/BDNF/TrkB signaling pathway within the CNS following thalamic hemorrhage, which in turn induces pain and depression (). There is also research suggesting that the activation of microglia leads to the reorganization of neural networks within sensory pathways, particularly in the thalamus and primary somatosensory cortex. Microglial depletion can effectively prevent and alleviate mechanical hyperalgesia and abnormal axonal regeneration caused by thalamic hemorrhage ().

Glial cells make up about 70% of the total number of cells in the CNS and comprise a variety of cell types including oligodendrocytes, astrocytes, microglia and satellite cells (). It has been suggested that microglia and astrocytes are the critical cells that contribute to the development of acute and chronic pain following peripheral and central nerve injury (; ). Microglia and astrocytes respond to peripheral input signals and release proinflammatory mediators (), such as cytokines and chemokines, which can sensitize neurons through activation of their cognate receptors, thereby promoting central sensitization and producing allodynia, hyperalgesia and spontaneous pain (). Microglia are the resident immune cells of CNS and can switch between different activation states in response to various stimuli, primarily classified into M1 (pro-inflammatory) and M2 (anti-inflammatory/repair) (). Under pathological conditions, microglia often adopt the M1 phenotype, producing pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, and releasing reactive oxygen species (ROS) and nitric oxide (NO), thereby exacerbating neuroinflammation and neuronal damage (). For example, following spinal cord injury, microglia rapidly switch to the M1 state, aggravating tissue damage through the secretion of these inflammatory mediators (). In contrast, in the presence of anti-inflammatory signals such as IL-4 and IL-10, microglia can polarize to the M2 phenotype (). M2 microglia are involved in tissue repair and the resolution of inflammation, producing anti-inflammatory cytokines, promoting the phagocytosis of debris, and supporting neuronal survival and regeneration. The M2 state is crucial during the recovery process following CNS injury (). Microglia can switch between M1 and M2 states in response to changes in the local microenvironment. Activation of Toll-like receptor 4 (TLR4) drives microglia toward the M1 state, while engagement of anti-inflammatory receptors can induce the M2 phenotype (). In Neup, the persistent activation of M1 microglia is associated with chronic pain conditions. Pro-inflammatory cytokines released by M1 microglia sensitize pain pathways and maintain the pain state (). Conversely, promoting the conversion to the M2 phenotype has been proposed as a therapeutic strategy to alleviate chronic pain (; ).

In addition, an increasing number of studies have explored the mechanisms of NeuP in terms of altered lipid metabolism of neurolemma, inflammatory cellular glucose metabolism, and glial cellular glucose metabolism in recent years. Studies have shown that nerve injury produces sphingosine-1-phosphate (S1P), and spinal dorsal horn pairs drive NeuP through selective activation of S1P receptor subtype 1 in astrocytes (). Reprogramming of glucose metabolism in microglia promotes the shift of microglia to a pro-inflammatory phenotype as well as increased ROS production. Reprogramming of glucose metabolism in glial cells also contributes to hyperalgesia and allodynia in NeuP ().

4. Functions of TRPV1 in pain regulation

In recent years, TRPV1 ion channels have been increasingly reported to be involved in the regulation of a variety of physiopathological processes in living organisms (; ; ), especially for its role as a crucial mechanism in the development of pain (). TRPV1 receptors are highly expressed mainly on C and some Aδ nociception nerves (nociceptor), is a pivotal molecule in mediating both thermosensory and thermal pain sensitization formation (). Injury leads to activation of TRP nociceptors in the periphery and action potentials are conducted along afferent sensory fibers to dorsal horn synapses. Subsequently, the signal crosses the spinal-thalamic lateral fasciculus, the thalamus, and the sensory cortex of the parietal lobe of the thalamocortex to localize the pain (). Activation of TRPV1 in the periaqueductal gray promotes the release of glutamate, which activates antinociceptive neurons in the rostral ventromedial medulla, thereby modulating pain signal transmission and antinociceptive responses in the CNS ().

TRPV1 plays a crucial role in neuroinflammatory responses by sensing stimuli such as high temperatures, acidic environments, and endogenous lipid molecules, leading to calcium influx (; ). This activation of sensory neurons results in the release of inflammatory mediators such as calcitonin gene-related peptide (CGRP) and substance P (). These mediators further activate microglial and astrocytic cells within the CNS, leading to the release of additional pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), IL-1β, and IL-6, which amplify the inflammatory response and increase pain sensitivity (). Additionally, TRPV1 activation exacerbates the inflammatory response through neuro-immune interactions. The inflammatory mediators released by neurons act not only on glial cells but also affect immune cells such as T cells and macrophages (). This leads to the aggregation and activation of these cells at the site of inflammation, releasing more inflammatory mediators and further intensifying the inflammation. Persistent TRPV1 activation may also impact the function of the endogenous opioid system, further influencing pain ().

Many endogenous inflammatory mediators (such as prostaglandin E2 and bradykinin, as well as nerve injury factors like nerve growth factor and TNF-α, etc.) have been shown to act directly or sensitize TRPV1 through secondary messengers and/or protein modifications (; ), leading to allodynia and hyperalgesia (). TRPV1 sensitization is facilitated by kinases such as protein kinase A (PKA), protein kinase C (PKC), and calcium/calmodulin-dependent protein kinase II (CaMKII) (; ). PKC is a prominent participant in pain signaling that can phosphorylate many substrate proteins to regulate the sensitivity of nociceptors (). PKC regulates the activity of TRPV1 channels mainly through two sites, S502 and S800, and phosphorylation of these two sites sensitizes and facilitates the opening of TRPV1 channels to enable calcium ions to flow into the cell (). It was found that PKCε inhibitors completely blocked the enhancement of TRPV1 expression and provided a more significant functional relationship between PKCε and TRPV1 sensitization (). c-AMP-dependent PKA phosphorylates the n-terminus of TRPV1 () and regulates channel sensitization directly through the S116, T144, T370, S502, and S800 sites (; ). Elevated calcium levels in the cell can activate CaMKII, and active CaMKII can directly phosphorylate TRPV1 channels at specific sites Ser 502 and Thr 704 (). Dysregulated lipid metabolism may also impact TRPV1 activation or sensitivity, leading to heightened pain signaling and increased pain perception in neuropathic conditions ().

It is becoming evident that Botulinum neurotoxins (BoNTs) also regulate the expression and function of TRP channels, which may explain their analgesic effects ().

When BoNT-A enters the cell, synaptosomal-associated protein 25 kDa (SNAP25) is cleaved by the protease activity of BoNT-A(1′) (), thereby inhibiting exocytosis. The failure of TRPV1 to translocate to the plasma membrane makes TRPV1 susceptible to ubiquitination and subsequent proteasomal degradation, leading to a decrease in TRPV1 levels, which mediates its antinociceptive effects (). Additionally, estrogen and progesterone can influence pain perception by regulating the expression and function of the TRPV1 receptor (; ). Activation of Sig-1R can enhance the sensitization of TRPV1, leading to increased neuronal response to pain stimuli (). In females, mechanical pain from paclitaxel-induced CIPN is linked to the IL-23/IL-17A/TRPV1 axis (), while male sensory neurons show greater paclitaxel-induced TRPM8 activity compared to females (). An increasing number of studies have highlighted the gender dimorphism in chronic pain ().

5. Role of TRPV1 in mechanisms of NeuP

Hyperalgesia caused by tissue injury or inflammation is typically accompanied with sensitization to TRPV1 channel activity, which is important in the modulation of sensory transmission from primary afferent nociceptors to neurons in the spinal dorsal horn (; ). Preclinical models used for peripheral neuropathic pain research commonly include chronic constriction injury (CCI) of the sciatic nerve, diabetic peripheral neuralgia (DPN), chemotherapy-induced neuropathic pain (CIPN), and etc. (; ). The following section primarily focuses on studies based on these various rodent models of peripheral neuropathic pain.

5.1. Chemotherapy-induced NeuP

The pathological mechanisms of CIPN may be related to affecting the function of ion channels, signaling by neurotransmitters and neuromodulators, inflammatory mediators, transcription factors (), oxidative stress (), and mitochondrial dysfunction (). Moreover, structural brain abnormalities, such as axonopathy, small-fiber degeneration, demyelination, and atrophy, are often detected in the peripheral nerves of individuals with CIPN and rodent models of CIPN (). Platinum- and taxane-derived anticancer drugs, induced neurological damage models are widely applied. Spinal cord expression of TRPV1 receptors has been associated with NeuP induced by the aforementioned chemotherapeutic agents (; ). For instance, Paclitaxel (PTX) induced behavioral hypersensitivity by sensitizing TRPV1 in DRG neurons through TLR4 signaling (; ). TRPV1 has a role in the development of CIPN, and spinal astrocytes and microglia are also engaged in the beginning and maintenance of CIPN (). After the intrathecal injection of the oxaliplatin-treated satellite glial cells-secreted exosomes, mice developed mechanical hypersensitivity, with an increase in the percentage of reactive oxygen species-positive neurons and upregulation of acid-sensing ion channel 3 and TRPV1 expressions in DRG (). TRPV1 is involved in the progression of mechanically allodynia/nociception and thermal hyperalgesia induced by chemotherapeutic agents such as paclitaxel and vincristine (). Inhibition of TRPV1 channels suppresses chemotherapeutic agent-induced mechanical hypersensitivity (; ; ). Zinc significantly decreased paclitaxel-induced NeuP in mice in a TRPV1-dependent manner (), and Decursin promotes the restoration of damaged neuronal networks and inhibits the pain transformation induced by a sudden increase in Ca2+ through the inhibition of TRPV1 (). The overexpression of TRPV1 in DRG neurons and the pain reaction in paclitaxel-treated rats were significantly reduced by pharmacological blockade of TLR4, which indicates that TRPV1 expression and channel activity in CIPN are regulated by TLR4 (). JI017 alleviates neuralgia by inhibiting TRPV1 expression and the activation of astrocytes in the superficial area of the spinal dorsal horn. However, JI017 only attenuated cold nociception while mechanical nociception remained unchanged, which may be related to its low CNS penetration rate (). Resistance to chemotherapeutic agents and subsequent NeuP are the main factors affecting the course of chemotherapy in patients ().  discovered that the development of cisplatin resistance is closely linked to the hyperactivation of the epidermal growth factor receptor (EGFR), driven by a transcriptional upregulation of TRPV1 through NANOG. Additionally, TRPV1 facilitates autophagy-mediated EGF secretion via Ca2+ influx, which in turn activates the EGFR-AKT signaling pathway, contributing to the acquisition of cisplatin resistance (). In addition, small interfering RNA (siRNA)-based therapeutics targeting TRPV1 has been verified in a number of experiments for the treatment of NeuP, including CIPN (). Experimental studies related to the TRPV1 in the CIPN are presented in Table 1.

Table 1

Preclinical evidence relating to TRPV1 and chemotherapy-induced neuropathic pain.

In vivo experiment Cell type Testing technology Intervention References
Animal type Modeling reagents Tissue
C57BL/6 mice Oxaliplatin (6 mg/kg) ② – a, c, d JI017
Male SD rats Paclictaxel (2 mg/kg) ①, ② – a, b, d Puerarin
Male SD rats Cisplatin (2 mg/kg) ①, ④ – a, b, c, g Corydalis saxicola alkaloids
Male SD rats Paclitaxel (2 mg/kg) ①, ② – a, b, c, g Cinobufacini
Male Wistar rats Paclitaxel (2 or 4 mg/kg) ① – a, b, c, d Ruthenium red+ capsazepine
C57BL/6J mice Paclictaxel (4 mg/kg) ① HEK293 Cells a, d, e, i Zinc acetate
C57BL/6J mice Paclitaxel (2 mg/kg) – F11 Cells, HEK293 Cells b Decursin
Male SD rats, ICR mice Paclictaxel (2 mg/kg) ①, ②, ⑤ RBL-2H3 Cells a, b, c, g Quercetin
Male Balb/c mice Vincristine sulfate (75 μg/kg) – PC12 Cells a, c, d, e, g, h Withametelin
Male SD rats Paclictaxel (2 mg/kg) ①, ② RBL-2H3 Cells a, b, f, i Electroacupuncture
C57BL/6NJ mice Oxaliplatin (3 mg/kg) ①, ② HEK293 Cells a, c, d, i –
C57BL/6N mice Oxaliplatin (3 mg/kg) ①, ②, ③, ④ HEK-293, COS-1 Cells a, d, e, i GPR132
Male BALB/C mice Oxaliplatin (3.5 mg/kg) ① HEK293t, K562, LS180, LoVo Cells a, b, c, d, i Carbonic anhydrase inhibitors
C57BL/6j black mice Docetaxel (30 mg/kg) ① SH-SY5Y Cells a, b, e, g, i Melatonin, selenium
NOD-SCID mice – – CaSki, HEK293, Hela, H1299, SiHa, SNU719, AGSGS, SNU668, MKN28, YCC2 Cells b, c, d, e, f, i –

(1) ①, DRG; ②, spinal cord; ③, sciatic nerve; ④, hind paw skin; ⑤, plasma; ⑥, skin. (2) a, behavioral tests; b, Western blotting; c, immunohistochemistry; d, qRT-PCR; e, electrophysiology; f, immunofluorescence; g, biochemical measurements; h, histopathology; i, calcium imaging. (3) SD, Sprague Dawley; ICR, Institute of Cancer Research; JI017, an herb mixture composed of Aconitum carmichaelii, Angelica gigas, and Zingiber officinale.

5.2. Diabetic peripheral neuralgia

Peripheral neuropathy is a common and characteristic complication of diabetes mellitus, causing numbness, tingling, burning pain in the skin, occasionally accompanied by hyperalgesia or allodynia (). Possible mechanisms of DPN include a vicious cycle involving the production of advanced glycation end products (AGEs), activation of PKC, amplification of the polyol pathway, and excessive release of ROS and cytokines (). TRPV1 is linked to diabetes mellitus on multiple fronts, encompassing pancreatic function and insulin secretion, appetite regulation, and energy expenditure or thermogenesis (). Experimental studies related to the TRPV1 in the DPN are presented in Table 2. Hyperglycemia reduces the expression of cannabinoid receptor-1 (CB1) receptors and increases the expression of TRPV1 receptors in the PC12 cell line, leading to greater toxic effects from TRPV1 activation (). Enhanced expression of CGRP may promote injured peripheral nerve regeneration, and activated TRPV1 promotes calcium-dependent release of substance P and CGRP in peripheral nerve endings (). Ropivacaine may exacerbate DPN nerve block by inhibiting TRPV1 expression in the dorsal horn, which in turn decreases CGRP release in the spinal cord (). In vitro, receptor for advanced glycation end-products (RAGE) expression, signaling, and RAGE-induced ROS production contributed to apoptosis of DRG neurons exposed to high glucose conditions (). In contrast, RAGE signaling-mediated TRPV1-associated aberrant responses (in terms of cytoplasmic signaling changes including Ca2+, PCK, and Src kinases) as well as ROS accumulation directly or indirectly results in TRPV1 function impairment, which are one of the contributing factors to DPN in the diabetic pathologic setting (; ). Sensitization of peripheral TRPV1, TRPA1, and TRPC channels in non-peptidergic fibers by hydrogen sulfide synthesized by the cystathionine β-synthase enzyme, leading to hyperalgesia and loss of peripheral nerve fibers in a rat model of diabetes mellitus, was further validated by local peripheral injections of capsazepine, HC-030031, and SKF-96365 blockers (). In addition, using 9-month-old Ins2+/Akita mice,  found that capsaicin activation of TRPV1 in DRG neurons exhibited accelerated current decay, which may provide an explanation for the phenomenon of reduced pain in people with end-stage diabetic peripheral neuropathy in one way.  found that inosine alleviated pain through downregulation of PKC, TRPV1 expression, decreasing Substance P and Transforming growth factor beta in DPN rat model. α-lipoic acid (ALA) may alleviate NeuP in diabetes by regulating TRPV1 expression via affecting NF-κB (). SUMOylation is an important mechanism for protection against endogenous metabolic damage in DPN sensory neurons, and modulation of TRPV1 function through extra-sensory neuronal SUMOylation may yield novel strategies for treating and reversing DPN ().

Table 2

Preclinical evidence relating to TRPV1 and diabetic peripheral neuropathy.

In vivo experiment Cell type Testing technology Intervention References
Animal type Modeling reagents Tissue
Male Wistar rats NA (50 mg/kg), STZ (52.5 mg/kg) ③ – a, c, d, e, g, h Inosine
Female SD rats STZ (65 mg/kg) ① – a, b, e, f ALA
Male SD rats, male ICR mice STZ (55 mg/kg, rats; 150 mg/kg, mice) ①, ②, ⑤ – a, b, c, g Berberine
Male SD rats STZ (60 mg/kg) ②, ③ – a, b, c, e, h Ropivacaine
Wild type Wistar rats, mini pigs STZ (55 mg/kg, rats; 150 mg/kg, mini pigs) ⑥ – a, b, c, g, h Resiniferatoxin cream
SNS-Cre mice, Ubc9fl/fl mice STZ (60 mg/kg) ①, ②, ④ – a, c, g, i –
C57BL/6 mice 25 mM glucose ① – b, c, e Capsaicin
Female Wistar rats STZ (60 mg/kg) ①, ④ – a, b, c, f NaHS
C57BL/6J wild-type and Ins2+/Akita mice 5.5 mM glucose ① – c, e, i Capsaicin
Male SD rats High-sugar and high-fat diet, STZ (35 mg/kg) ① – a, b, d, f A438079

(1) ①, DRG; ②, spinal cord; ③, sciatic nerve; ④, hind paw skin; ⑤, plasma; ⑥, skin. (2) a, behavioral tests; b, Western blotting; c, immunohistochemistry; d, qRT-PCR; e, electrophysiology; f, immunofluorescence; g, biochemical measurements; h, histopathology; i, calcium imaging. (3) ALA, α-lipoic acid; SD, Sprague Dawley; ICR, Institute of Cancer Research; NA, nicotinamide; STZ, streptozotocin.

5.3. Other NeuP

The most common way for creating neuropathy in animals is to cause entire or partial traumatic nerve injury via ligation, transection, or compression (). The key protein phospho-regulating effectors that promote nociceptive sensitization are mitogen-activated protein kinases (MAPK), and additional findings showed that baicalin inhibits TRPV1 up-regulation and extracellular signal-regulated kinase phosphorylation in CCI of the sciatic nerve rats’ DRG (). PHN is common in the elderly and immunocompromised patients (). The resiniferatoxin (RTX)-induced PHN model is a commonly used method of PHN modeling, which depletes TRPV1-expressing primary sensory neurons, causing severe degeneration of C-fiber afferent terminals as well as aberrant sprouting of myelinated afferent fibers in the II layer of the spinal dorsal horn (), which in turn exhibits the distinctive clinical features of PHN, i.e., thermosensory impairments and mechanical allodynia ().  proposed that RTX may stimulate the TRPV1 receptor and its downstream signaling molecules to enhance the expression of netrin-1, and the increased expression of netrin-1 further activates repulsive receptor of netrin-1 (UNC5H2) and deleted in colorectal (DCC) at the central terminus of the remaining myelinated neurons in the DRG to promote myelinated fibers to sprout to the noxious neurons located in the superficial dorsal horn.  found that RTX treatment increased excitatory glutamatergic input from myelinated afferent nerves to the spinal dorsal horn through α2δ-1-dependent enhancement of N-methyl-d-aspartate receptor (NMDAR) activity, thereby causing mechanical allodynia, which further enriched the study of synaptic plasticity in PHN. Experimental studies related to the TRPV1 in the other NeuP are presented in Table 3.

Table 3

Preclinical evidence relating to TRPV1 and other neuropathic pain.

In vivo experiment Cell type Testing technology Intervention References
Animal type Modeling reagents Tissue
Male SD rats CCI of the sciatic nerve ① – a, b, d Baicalin
Male SD rats Laminectomy at T10 + Infinite Horizon Impactor ① – a, b, e, i Capsaicin, AMG9810
Male Wistar rats L5 spinal nerve ligation ①, ②, ④ – a, b, c, d, h RTX
C57bl/6J, TRPV1Cre, R26LSL-tdTomato, R26mT/mG, R26LSL-hM4Di mice CCI of the infraorbital nerve – – a Capsaicin, MDL28170
Male SD rats Tibial and common peroneal nerves ligation+2–3 mm of the nerve were cut distal to the ligation ① – a, b, f, g CRAP
Male SD rats Sciatic nerve ligation ① – a, b, c, d MZF1
Male SD rats RTX (250 μg/kg) ①, ② SH-SY5Y Cells a, b, d, f Capsazepine
Mice RTX (50 μg/kg) ① – a, f, h Adenosine

(1) ①, DRG; ②, spinal cord; ③, sciatic nerve; ④, hind paw skin; ⑤, plasma; ⑥, skin. (2) a, behavioral tests; b, Western blotting; c, immunohistochemistry; d, qRT-PCR; e, electrophysiology; f, immunofluorescence; g, biochemical measurements; h, histopathology; i, calcium imaging. (3) SD, Sprague Dawley; CCI, chronic constriction injury; MZF1, myeloid zinc finger 1; CRAP, Coumarins from Radix angelicae pubescentis; RTX, resiniferatoxin.

6. Association between TRPA1 and TRPV1

There are evidences that TRPA1 and TRPV1 mutually regulate pain signal transduction (; ). TRPA1 is localized to a subset of TRPV1-positive sensory neurons, being present in 30–50% of these neurons. It is rarely detected in neurons that lack TRPV1 expression (; ). In cells co-expressing TRPA1 and TRPV1, these two TRP channels appear to form a complex or a heterogeneous channel at the cell membrane, thereby influencing the function of each other (; ).  utilized selective elimination of the central terminus of TRPV1-expressing nociceptor in wild-type C57Bl/6 mice by intrathecal injection of capsaicin and found that the nociceptive reaction induced by the TRPA1-selective agonist mustard oil was also eliminated. The co-expression of TRPA1 and TRPV1 in nociceptive fibers is crucial for the initiation and progression of chronic pain (). Structurally, TRPA1 and TRPV1 share similar transmembrane domains. However, TRPA1 differs by having an additional pore helix lining the extracellular side of the ion permeation pathway, resulting in two pore helices per subunit (). Studies of IMustard Oil (MO) rapid sensitization in Chinese hamster ovary cells expressing TRPA1 or TRPA1/TRPV1 showed that IMO experienced greater rapid sensitization in the absence of TRPV1. One possible explanation is that TRPV1 stabilizes the membrane surface expression of TRPA1 (). Activation of TRPA1 did not sensitize TRPV1 without the involvement of calcium ions, suggesting that co-expression occurs in a calcium-dependent way. TRPA1 activation leads to enhanced accumulation of cAMP and subsequent stimulation of PKA subunit release, which in turn leads to phosphorylation and sensitization of TRPV1 (). Functional crossover desensitization has also been reported between typical agonists of TRPA1 (allyl isothiocyanate, mustard) and TRPV1 (capsaicin) (). In addition, it was shown that TRPA1 and TRPV1 can form complexes in cell membranes that affect the properties of each other (). The TRPA1 and TRPV1 channels are therefore described as “partners in crime” ().

7. Basic drug targets

7.1. TRPV1 agonists

Capsaicin, a potent agonist of the TRPV1 channel, was extracted from the capsicum genus of spices (). Capsaicin has emerged as a useful tool in the research on pain pathways () and is currently approved for the treatment of PHN, HIV-associated neuropathy and DPN (; ). High concentrations of capsaicin reversibly deactivate TRPV1 receptors, which leads to an analgesic effect (). It has long been recognized that the initial application of capsaicin is painful and, paradoxically, repeated applications produce local analgesic effects (; ). This is a desensitization response induced by prolonged gating of TRPV1 cation channels () that is closely associated with the duration of capsaicin exposure and the external calcium concentration, and which can be considered as a protective mechanism for neurons against calcium overload during repeated TRPV1 stimulation (). Calcium influx following TRPV1 activation leads to channel desensitization. Acute desensitization refers to a rapid decline in the evoked inward current, while tachyphylaxis describes the reduction in current during repeated stimulation (). Compared to the short-term dysfunction induced by low doses of capsaicin, high doses of capsaicin often elicit dysfunction that lasts for months, which may be related to the structural ablation of TRPV1+ nerve endings (). Capsaicin induces calcium influx through TRPV1 channels, leading to the activation of the calcium-dependent protease calpain. Calpain then begins to degrade cytoskeletal components within the axon, resulting in structural damage and loss of function in the axon. Studies have shown that capsaicin-induced TRPV1+ sensory axon ablation is also associated with mitochondrial dysfunction. Inhibiting calcium influx or calpain activity can significantly reduce capsaicin-induced TRPV1+ axon ablation (). Calcineurin, also known as protein phosphatase 2B, is a Ca2+-Calmodulin (CaM) phosphatase that has been shown to dephosphorylate the channel, thereby promoting its desensitization (). Ca2+ influx activates phospholipase C (PLC), leading to the depletion of the agonists Phosphatidylinositol 4,5-bisphosphate (PIP2) and Phosphatidylinositol 4-phosphate (PIP). This reduction in PIP2 and PIP levels limits the channel’ s activity, resulting in its desensitization (; ). These findings not only enhance our understanding of the mechanisms behind capsaicin-induced analgesia but also provide a theoretical foundation for improving the use of capsaicin in pain treatment.

7.2. TRPV1 antagonists and TRPV1-targeted siRNA

TRPV1 antagonists work by blocking the TRPV1 receptor, preventing calcium influx, and thereby inhibiting the transmission of pain signals. However, the preclinical development of TRPV1 antagonists faces challenges, including potential side effects such as thermoregulation abnormalities (). Thereby, the aim of developing TRPV1 antagonists for pain treatment is to create medications that specifically inhibit the activation of TRPV1 channels by pain-inducing agents, without affecting their activation by thermal stimuli (). Subsequently, alternative strategies emerged to target the expression of the TRPV1 channel using genome-editing tools. In a preclinical study, mice treated with TRPV1-targeted siRNA showed a phenotype similar to that of TRPV1 knockout mice (). Research has shown that paratracheal delivery of TRPV1 siRNA suppresses TRPV1 upregulation in the DRG and spinal cord, effectively eliminating CFA-induced inflammation and chemotherapy-induced thermal hyperalgesia and mechanical allodynia (). TRPV1 antagonists, including TRPV1 siRNA, have potential roles in the treatment of neuropathic pain ().

7.3. Cannabinoid modulation

As an integral part of the extended endocannabinoid system (), TRPV1 interacts with endocannabinoids through complex molecular mechanisms, thereby regulating the pathophysiological processes of neuropathic pain (). Firstly, TRPV1 can directly interact with endocannabinoids. For example, Anandamide (AEA) is not only a partial agonist of CB1 receptors but also an agonist of TRPV1. When AEA binds to TRPV1, it leads to the opening of TRPV1 channel, causing Ca2+ influx, which subsequently induces depolarization and the generation of action potentials in sensory neurons (). Secondly, the endocannabinoid system can influence the occurrence and development of neuropathic pain by regulating TRPV1 expression and function. Studies have found that activation of CB1 receptors can inhibit TRPV1 expression and function. For example, treatment with CB1 receptor agonists can reduce TRPV1 expression in sensory neurons, thereby alleviating pain (). This mechanism may be achieved by lowering intracellular cAMP levels and inhibiting PKA activity, which in turn reduces the transcription and translation of the TRPV1 gene (). Additionally, TRPV1 may be involved in the degradation process of endocannabinoids. The degradation of endocannabinoids primarily relies on the enzyme fatty acid amide hydrolase (FAAH) (). For instance, research indicates that increasing doses of a locally injected FAAH inhibitor elevate spinal AEA levels, which in turn produce anti-hyperalgesic and anti-allodynic effects. These effects are achieved through mechanisms that progressively involve the desensitization of TRPV1 channels ().

8. Conclusion and perspectives

TRPV1 plays a dual role in peripheral NeuP, acting as a “switch” for pain through its sensitization and desensitization processes. In CIPN and DPN, the sensitization of TRPV1 channels is a key mechanism. Inhibiting TRPV1 channels can significantly reduce mechanical hypersensitivity and pain. Clinically, capsaicin, a TRPV1 agonist, alleviates pain by inducing receptor desensitization, while TRPV1 antagonists and siRNA targeting TRPV1 show promise in preclinical studies. Cannabinoid modulation of TRPV1 offers another potential pathway for alleviating neuropathic pain. Future research should focus on the immunomodulation and metabolic functions of the TRPV1 receptor, as well as the application of novel gene editing and RNA interference technologies, with the aim of developing more effective pain treatment strategies.

Acknowledgments

The authors appreciate the publications included in this study.

Glossary

AGEs advanced glycation end products
AEA anandamide
ALA α-lipoic acid
BoNTs Botulinum neurotoxins
CaMKII calcium/calmodulin-dependent protein kinase II
CB1 cannabinoid receptor-1
CCI chronic constriction injury
CGRP calcitonin gene-related peptide
CHO Chinese hamster ovary
CIPN chemotherapy-induced neuropathic pain
CRAP Coumarins from Radix angelicae pubescentis
CNS central nervous system
CaM N-methyl-d-aspartate receptor
DCC deleted in colorectal
DPN diabetic peripheral neuralgia
DRG dorsal root ganglion
DCC deleted in colorectal
EGFR epidermal growth factor receptor
FAAH fatty acid amide hydrolase
IASP International Association for the Study of Pain
ICR Institute of Cancer Research
MAPK mitogen-activated protein kinases
MZF1 Myeloid zinc finger 1
NA nicotinamide
NO nitric oxide
NMDAR N-methyl-d-aspartate receptor
NeuP Neuropathic pain
PHN postherpetic neuralgia
PTX Paclitaxel
PLC phospholipase C
PIP2 Phosphatidylinositol 4,5-bisphosphate
PIP Phosphatidylinositol 4-phosphate
PKA protein kinase A
PKC protein kinase C
RAGE receptor for advanced glycation end-products
ROS reactive oxygen species
RTX Resiniferatoxin
S1P sphingosine-1-phosphate
SD Sprague Dawley
siRNA small interfering RNA
STZ streptozotocin
TRP transient receptor potential
TRPV1 transient receptor potential vanilloid 1
TLR4 Toll-like receptor 4
TNF-α tumor necrosis factor-alpha

Funding Statement

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study was funded by High Level Chinese Medical Hospital Promotion Project (Grant no. HLCMHPP2023089) and Science and Technology Innovation Project of China Academy of Chinese Medical Sciences (Grant no. CI2021A02306). The funding agency had no role in the design or conduct of the study.

Author contributions

NG: Conceptualization, Writing – original draft, Writing – review & editing. ML: Conceptualization, Writing – original draft, Writing – review & editing. WW: Conceptualization, Methodology, Software, Validation, Writing – review & editing. ZL: Conceptualization, Investigation, Methodology, Project administration, Writing – review & editing. YG: Conceptualization, Funding acquisition, Investigation, Methodology, Project administration, Writing – review & editing.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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