NLRP3 inflammasome: a key driver of neuroinflammation and a novel therapeutic target for neuropathic pain

Zana Montazeri-Khosh; Ahmad Ebrahimpour; Mahyar Hossein-Zargari; Parsa Taghizadeh-Tabrizi; Mohammad Safari-Sahlabadi; Mohammad Hosein Sheybani-Arani; Nahid Davoodian

doi:10.17085/apm.24132

Anesth Pain Med > Volume 20(4); 2025 > Article

Montazeri-Khosh, Ebrahimpour, Hossein-Zargari, Taghizadeh-Tabrizi, Safari-Sahlabadi, Sheybani-Arani, and Davoodian: NLRP3 inflammasome: a key driver of neuroinflammation and a novel therapeutic target for neuropathic pain

Spinal Pain

Review

Anesthesia and Pain Medicine 2025;20(4):341-356.

Published online: August 22, 2025

DOI: https://doi.org/10.17085/apm.24132

NLRP3 inflammasome: a key driver of neuroinflammation and a novel therapeutic target for neuropathic pain

Zana Montazeri-Khosh¹

, Ahmad Ebrahimpour²

, Mahyar Hossein-Zargari¹

, Parsa Taghizadeh-Tabrizi¹

, Mohammad Safari-Sahlabadi¹

, Mohammad Hosein Sheybani-Arani¹

, Nahid Davoodian^3,⁴

¹Student Research Committee, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran

²Student Research Committee, Faculty of Pharmacy, Hormozgan University of Medical Sciences, Bandar Abbas, Iran

³Endocrinology and Metabolism Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran

⁴Department of Clinical Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran

Corresponding author: Nahid Davoodian, Ph.D. Department of Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas 076, Iran
Tel: 98-76-3371 0373 Fax: 98-76-3366 8478 E-mail: Nahid.Davoodian@hums.ac.ir

Received September 13, 2024 Revised December 10, 2024 Accepted December 11, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Neuropathic pain represents a serious complication arising from a spectrum of disorders that precipitate lesions within the central and peripheral nervous systems. This disabling pain can persist for years, severely diminishing the quality of life of the affected individuals. The treatment options available for neuropathic pain at present have limited efficacy. Moreover, the adverse effects associated with these options restrict their application. The exact etiological mechanisms underlying the pathogenesis of neuropathic pain remain unclear. However, neuroinflammatory processes mediated by the immune system play significant roles in the initiation and progression of neuropathic pain in various models. The nucleotide-binding domain and leucine-rich repeat pyrin-containing protein-3 (NLRP3) inflammasome, a pivotal element of the innate immune system, plays an indispensable role in the pathophysiological mechanisms of central and peripheral neuropathic pain. However, the precise mechanisms facilitating its activation in disparate neuropathic pain conditions remain to be elucidated. Gaining insights into the regulatory mechanisms affecting NLRP3 inflammasome activation in diverse neuropathic pain-associated disorders will aid in developing novel therapeutic avenues. Therefore, this review summarizes the current knowledge on the role of the NLRP3 inflammasome in the pathophysiology of several neuropathic pain-related conditions, such as diabetic neuropathic pain, chemotherapy-induced neuropathic pain, peripheral nerve compression, central nervous system neuropathic pain, radiculopathy, and morphine analgesic tolerance. In addition, this review also discusses the possible use of this inflammasome as a therapeutic target to alleviate the pain-related symptoms of these diseases.

Keywords: Drug tolerance; Immune system; Inflammation; Inflammasomes; Neuralgia; Radiculopathy

INTRODUCTION

Neuropathic pain, defined as disabling pain arising from lesions or diseases that affect the central or peripheral somatosensory system [1], severely compromises the quality of life of patients. Peripheral neuropathic pain, the most prevalent type of neuropathic pain, encompasses several conditions such as post-amputation pain, postherpetic neuralgia, trigeminal neuralgia, painful polyneuropathy, painful radiculopathy, and peripheral neuropathy. Central neuropathic pain, in contrast, is associated with disorders affecting the central nervous system such as multiple sclerosis (MS), stroke, and spinal cord injury (SCI) [2].

Adequate diagnostic criteria and consensus on the definition of neuropathic pain remain to be established; consequently, determining the prevalence of neuropathic pain is difficult [3]. In this regard, a systematic review estimated the prevalence of neuropathic pain by categorizing it into two groups. The prevalence in the first group, which encompassed chronic pain with neuropathic pain characteristics, ranged from 3 to 17%. The prevalence in the second group, which encompassed pain associated with specific conditions, was as follows: postherpetic neuralgia, 3.9-42.0 per 100,000 person-years; trigeminal neuralgia, 12.6-28.9 per 100,000 person-years; and painful diabetic peripheral neuropathy, 15.3-72.3 per 100,000 person-years. Neuropathic pain adversely affects millions globally. Notably, it is more prevalent among older individuals, women, and individuals with lower socioeconomic status [4].

Neuropathic pain is characterized by the presence of clinical signs such as electric-like and burning sensations and pain in response to non-harmful stimulations [5]. Notably, two types of hypersensitivity responses, allodynia and hyperalgesia, have been observed in patients with neuropathic pain. Allodynia is defined as a mechanical hypersensitivity to non-painful stimuli, such as light touch, whereas hyperalgesia is defined as enhanced sensitivity to pain elicited by nociceptive stimuli [2].

The treatment options for neuropathic pain available at present have exhibited limited efficacy; moreover, they are frequently associated with adverse effects that restrict their application. The different pain experiences of patients, the involvement of diverse mechanisms, and the psychological and emotional effects of chronic pain also complicate treatment. Therefore, elucidating the molecular mechanisms involved may aid in developing novel therapeutic options to alleviate this condition [5].

Inflammatory mediators, such as cytokines, chemokines, prostaglandins, nitric oxide, and bradykinins, play significant roles in the pathogenesis of neuropathic pain [6]. The aberrant production of IL-1β, a potent proinflammatory cytokine, has been strongly implicated in the development of inflammation and pain. The suppression of IL-1β signaling pathways can significantly mitigate pain, as evidenced by the findings of multiple animal-based studies [7-9]. Thus, IL-1β is considered a potential therapeutic target for neuropathic pain relief. Inflammasomes mediate one of the main mechanisms regulating the release of IL-1β. Thus, inflammasomes, a group of innate immune system complexes involved in the activation of caspase-1, are a prerequisite for the processing and release of IL-1β [10]. Several types of inflammasomes, especially the nucleotide-binding domain and leucine-rich repeat pyrin-containing protein-3 (NLRP3) have received an increasing amount of attention with respect to their application in the treatment of painful disorders, such as gout [11], diabetic wounds [12], and rheumatoid arthritis [13]. The NLRP3 inflammasome is involved in the pathogenesis of neuropathic pain through its mediating effects on the maturation of IL-1β.

This review provides an overview of the current knowledge on the role of NLRP3 inflammasome in the pathophysiology of several neuropathic pain conditions. In addition, this review also discusses the possibility of using this inflammasome as a therapeutic target to alleviate the pain-related symptoms of these diseases. The electronic databases of PubMed, Google Scholar, and ScienceDirect were searched using the following terms to retrieve relevant articles: neuropathic pain, NLRP3, inflammasome, morphine, and interleukin-1. In addition, the reference lists of the retrieved articles were manually searched to identify relevant studies eligible for inclusion. A total of 112 English-language articles were selected.

NLRP3 INFLAMMASOME ACTIVATION

NLRP3 inflammasome, a receptor and sensor in the innate immune system, regulates and induces inflammation in response to infectious microbes and damage-associated molecular patterns (DAMPs) [14]. The NLRP3 inflammasome comprises three principal elements: NLRP3, which detects danger signals and mobilizes subsequent molecules; caspase-1, which facilitates cytokine secretion and pyroptosis by mediating the maturation of IL-1β and IL-18 cytokines [15] and the cleavage of gasdermin D (GSDMD) [16,17]; and apoptosis-associated speck-like protein, which contains a caspase recruitment domain (ASC), the adaptor protein that links NLRP3 to caspase-1 [18]. The functional regulation of NLRP3 inflammasome occurs in two phases. The expression of crucial inflammasome components is induced by a non-activating "priming" stimulus during the first phase [19]. Subsequently, inflammasome oligomerization is induced by a secondary activating stimulus during the second phase [20]. DAMPs that stimulate different receptors, such as toll-like receptor 4 (TLR4) or cytokine receptors (e.g., tumor necrosis factor receptor), activate the nuclear factor kappa B (NF-κB) signaling pathway that upregulates NLRP3, GSDMD, and pro-IL-1 expression, thereby triggering the priming step. This activation step is driven by different stimuli such as lysosomal destabilization, mitochondrial dysfunction, and ionic flux. These steps result in the assembly of NLRP3 inflammasome components (Fig. 1) [21].

NLRP3 INFLAMMASOME AND DIFFERENT PHENOTYPES OF NEUROPATHIC PAIN

Diabetic neuropathic pain

Diabetes mellitus, a chronic metabolic disorder resulting from defective insulin secretion and signaling pathways [22], is characterized by the presence of chronic hyperglycemia. The chronic hyperglycemic state causes various systemic complications owing to metabolic and vascular dysfunction, such as nephropathy, retinopathy, and neuropathy [23]. A common complication of diabetes mellitus is diabetic neuropathic pain. The etiology of diabetic neuropathic pain remains unknown. However, recent studies have indicated the role of the NLRP3 inflammasome in the inflammatory processes involved in the pathogenesis of this condition.

The aberrant production of reactive oxygen species (ROS) significantly contributes to the development of the complications associated with diabetes [24]. Notably, ROS triggered the dissociation of thioredoxin-interacting protein (TXNIP) from its inhibitor thioredoxin in a diabetic neuropathic pain rat model in a previous study, thereby enabling it to bind with and activate the NLRP3 inflammasome [25]. Moreover, the ROS/TXNIP/NLRP3 pathway induced the phosphorylation of the NR2B subunit of N-methyl-D-aspartate (NMDA) receptors in the spinal cord neurons of the treated animals, resulting in enhanced central sensitization and mechanical allodynia [25]. The epigenetic changes occurring in the TXNIP-coding gene facilitate further activation of the NLRP3 inflammasome in diabetic neuropathic pain. For instance, enhanced expression of ten-eleven translocation methylcytosine dioxygenase 2 (TET2), a DNA demethylase involved in transcriptional activation, was observed in the dorsal root ganglion (DRG) of diabetic mice in the study conducted by Chen et al. [26]. The upregulation of TET2 increases the gene expression of TXNIP, which, in turn, enhances the activation of the NLRP3 inflammasome through the NLRP3/TXNIP axis, thereby enhancing mechanical allodynia in diabetic mice. These findings indicate the involvement of NLRP3 inflammasome in the pathogenesis of diabetic neuropathic pain. Nevertheless, further studies must be conducted in the future to evaluate its therapeutic potential under these conditions.

Chemotherapy-induced neuropathic pain

Treatment with chemotherapeutic and antitumor agents such as paclitaxel, vincristine, oxaliplatin, and bortezomib can lead to the development of chemotherapy-induced neuropathic pain (CINP). CINP is a serious side effect of chemotherapy characterized by the presence of severe allodynia, burning sensation, hyperalgesia, and numbness. Thus, CINP negatively affects the quality of life of patients. No therapeutic agents capable of managing this condition has been developed despite considerable efforts being made over the past few decades [27]. Recent studies have indicated the involvement of NLRP3 inflammasome in the pathology of CINP [28-31]. Consequently, four commonly used chemotherapeutic drugs associated with CINP were selected to elucidate the role of the NLRP3 inflammasome in the underlying molecular mechanisms.

1. Oxaliplatin

Previous studies have suggested the involvement of the peripheral and central inflammatory responses in the pathogenesis of oxaliplatin-induced neuropathic pain [32,33]. Enhanced activity of adenosine kinase in the spinal astrocytes led to a shift in purinergic signaling toward ATP in a mouse model of oxaliplatin-induced CIPN in the study by Wahlman et al. [34].

Notably, enhanced extracellular ATP functions as a DAMP and activates the P2X7 receptor, a purinergic receptor predominantly expressed on immune cells. This results in the activation of the NLRP3 inflammasome and subsequent IL-1β production [34,35]. Mitochondrial dysfunction and ROS production play significant roles in the activation of the NLRP3 inflammasome [21]. Oxaliplatin induced mechanical allodynia with spinal mitochondrial dysfunction and activated the NLRP3 inflammasome cascade in a rat model of CIPN in another study conducted based on these findings. However, a marked reduction in the mitochondrial dysfunction and suppression of the NLRP3 inflammasome pathway was observed following the administration of 2-bromopalmitate, which targets dynamin-related protein 1 (Drp1) [31].

2. Paclitaxel

The mechanism underlying the induction of neuropathic pain through the upregulation of the NLRP3 inflammasome by paclitaxel remains unclear. Notably, paclitaxel induced mechanical allodynia accompanied by increased activation of the NLRP3 inflammasome and mitochondrial damage in the DRG and sciatic nerves of treated rats in a previous study. However, the administration of phenyl-N-tert-butylnitrone, a nonspecific ROS scavenger, markedly mitigated allodynia and suppressed the activation of the NLRP3 inflammasome [28].

3. Vincristine

Vincristine is a chemotherapeutic drug used predominantly in the treatment of leukemia and brain tumor. Peripheral neuropathy is a serious side effect of vincristine; however, the pathophysiological mechanisms are poorly understand [36]. Notably, vincristine can directly induce NLRP3-dependent IL-1β secretion accompanied by the cleavage of caspase-1 in mouse bone marrow-derived macrophages. However, the administration of MCC950, a selective inhibitor of the NLRP3 inflammasome, can prevent the cleavage and release of IL-1β induced by this chemotherapeutic agent [37].

4. Bortezomib

Bortezomib, an anticancer drug with a proteasome-inhibitory effect, has been used in the treatment of multiple myeloma. The administration of bortezomib can also induce persistent neuropathic pain, which primarily manifests as spontaneous pain and mechanical allodynia, in patients with cancer [38]. Significant mechanical allodynia with enhanced NLRP3 inflammasome expression was observed in the DRG of treated mice in a murine model of neuropathic pain induced by bortezomib in the study by Liu et al. [29]. Notably, the administration of bortezomib also increased the recruitment of signal transducer and activator of transcription 3 (STAT3) and the subsequent hyperacetylation of histones on the NLRP3 promoter, thereby inducing the upregulation of NLRP3 mRNA in this area. However, the administration of S3I-201, a selective STAT3 inhibitor, significantly alleviated this negative effect [29].

The findings of these studies suggest that inhibition of the NLRP3 inflammasome could possibly reduce the severity of CINP, which may enable commencement of treatment with increasing doses to completely eradicate cancer. However, further studies must be conducted in the future to elucidate the mechanisms through which the NLRP3 inflammasome is upregulated in different types of CINP.

Peripheral nerve compression

Peripheral nerve compression is a medical syndrome characterized by the entrapment of a specific nerve or squeezing of a nerve owing to repetitive activities or acute tissue injury [39]. Chronic constriction injury (CCI) and spinal nerve ligation (SNL) are the most frequently used animal models for studying the pathophysiology of this syndrome. Notably, enhanced expression of the NLRP3 inflammasome in the animal models of SNL and CCI have been observed in several studies. Moreover, inhibition of the NLRP3 inflammasome reduced the severity of mechanical allodynia and hyperalgesia in treated animals, suggesting the crucial role of the NLRP3 inflammasome in the induction of neuropathic pain through peripheral nerve compression [40-42]. Several studies that examined the association between microRNAs (miRNAs) and the NLRP3 inflammasome in a murine model of CCI to further characterize the molecular mechanisms underlying neuropathic pain revealed that miR-223 [40], miR-185-5p [43], and miR-34C [44] strongly suppress the expression of NLRP3 and significantly reduce neuropathic pain caused by CCI. Similarly, miR-183 negatively regulates the expression of TXNIP, thereby inhibiting the activation of the NLRP3 inflammasome in the spinal cord of CCI rats. NF-κB enhanced the expression of histone deacetylase 2 and subsequent downregulation of miR-183 in a CCI rat model, thereby inducing an inflammatory response and aggravating neuropathic pain in a previous study [45]. In particular, C-X-C chemokine receptor type 4 (CXCR4) and its ligand C-X-C motif ligand 12 (CXCL12) can stabilize TXNIP protein, which results in the activation of the NLRP3 inflammasome [46]. Consistent with this finding, a previous study evaluating the effects of loganin, an iridoid glycoside, revealed that it significantly improved hyperalgesia and mechanical allodynia in a CCI rat model by preventing the activation of the CXCL12/CXCR4-mediated NLRP3 inflammasome in the spinal cord of treated animals [46]. A similar trend was also observed in an animal model of SNL, that is, the upregulation of miR-23a reduced SNL-induced neuropathic pain by targeting CXCR4, thereby suppressing the TXNIP/NLRP3 inflammasome axis [42].

Mitochondrial dysfunction and ROS overproduction have been identified as pivotal factors that are involved in the activation of NLRP3 inflammasome in CCI-induced neuropathic pain [47,48]. Notably, probucol [47] and dexmedetomidine [49] can alleviate CCI-induced neuropathic pain by suppressing the NLRP3 inflammasome through the modulation of the NF-κB signaling and nuclear factor erythroid 2‑related factor 2 (Nrf2) pathways. Similarly, hydrogen-rich saline [50] and carvacrol [48] can also inhibit the NLRP3 inflammasome by increasing autophagy and mitochondrial quality in SNL and CCI rats, respectively. The involvement of the CCAAT/enhancer-binding protein beta (c/EBPb)/C-type lectin domain-containing 7A (Clec7a) axis in the development of CCI-induced neuropathic pain through the activation of the NLRP3 inflammasome in the spinal cord was suggested in the study by Wu et al. [51]. This axis may be a potential target for alleviating neuropathic pain through the amelioration of neuroinflammation [51].

Several studies have investigated the role of NLRP3 in the development of peripheral nerve compression-induced neuropathic pain; however, the involvement of other inflammasomes cannot be disregarded. The potential contribution of the NLRP1 inflammasome to the CCI model of nerve injury [52-54] and depression-like behaviors following CCI [55] have been demonstrated in a few studies. Neuropathic pain was alleviated through the genetic knockout of NLRP1 [52] or inhibition of its activity by curcumin [52], tramadol [54], or aspirin [53] inducing neuroprotective and anti-inflammatory effects in these studies.

The findings of these studies suggest that the NLRP3 inflammasome plays a decisive role in the development of neuropathic pain induced by peripheral nerve compression. Thus, NLRP3 inhibitors may possess the therapeutic potential to alleviate this painful syndrome. However, further studies must be conducted in the future to elucidate the molecular mechanisms through which the NLRP3 inflammasome is upregulated under these conditions.

Central nervous system neuropathic pain

Central neuropathic pain, a type of chronic pain caused by trauma or central nervous system disorders, adversely affects the physical and mental health of patients. The complex etiology of central neuropathic pain remains unknown; however, the involvement of the NLRP3 inflammasome in the onset and development of central neuropathic pain was suggested by several studies [56-58]. Consequently, this review focused on the most prevalent clinical central neuropathic pain, such as SCI, central post-stroke pain (CPSP), and MS, to elucidate the role of the NLRP3 inflammasome in these syndromes.

1. Spinal cord injury

Central neuropathic pain is the most frequent complication of SCI, a debilitating medical disorder. Previous studies have indicated the involvement of the NLRP3 inflammasome in the immune response post-injury [59]. Notably, D-β-hydroxybutyrate, an endogenous ketone body, markedly relieved mechanical and thermal hypersensitivity by improving mitochondrial function and suppressing NLRF3 inflammasome activation in a murine model of SCI in the study by Qian et al. [60]. Inhibition of receptor-interacting protein kinase 3 (RIPK3), an enzyme involved in the inflammatory response, yielded a significant improvement in the severity of mechanical allodynia in SCI rats through the inhibition of the NF-κB signaling pathway and the NLRP3 inflammasome in a previous study [60]. Similarly, other chemical agents such as minocycline [61], trehalose [62], dopamine [63], melatonin [64], and zinc [65] also promote functional recovery after SCI through the inhibition of NLRP3 inflammasome via different mechanisms.

2. Central post-stroke pain

The prevalence of CPSP, the most common type of central neuropathic pain, is significantly higher than that of SCI, MS, and other central nervous system injuries. NLRP3 inflammasome activation induces the formation of cerebral cortex and thalamic lesions, thereby playing a critical role in the occurrence and development of CPSP [66]. Notably, miR-223 negatively regulated the expression of the NLRP3 inflammasome in the thalamic tissue of a mouse model of CPSP in a recent study conducted by Huang et al. [57]. This finding indicates that miR-223 may alleviate CPSP by inhibiting the NLRP3 inflammasome cascade [57]. Hypoxia-inducible factor 1α (HIF-1α), a main regulator of hypoxic response, mediated inflammatory responses by targeting the NLRP3 inflammasome in a model of stroke in a previous study [67]. Consistent with the findings of this study, stellate ganglion block significantly mitigated CPSP by improving the cerebral blood flow and blocking the HIF‑1α/NLRP3 inflammasome pathway following thalamic hemorrhage in the study conducted by Shi et al. [68].

3. Multiple sclerosis

MS, an autoimmune disorder characterized by the formation of demyelinating plaques, impairs the functionality of various regions of the central nervous system. Central neuropathic pain is a frequent and severe symptom reported by patients with MS. The molecular mechanisms underlying central neuropathic pain associated with MS remain unclear; however, the decisive role of the NLRP3 inflammasome in the pathogenesis of MS has been implicated by several studies [69]. The relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE)-mouse model of MS was used to evaluate the role of NLRP3 inflammasome in central neuropathic pain in the study by Khan et al. [58]. Notably, MCC950 treatment, a selective inhibitor of the NLRP3 inflammasome, significantly attenuated mechanical allodynia and disease relapse in the RR-EAE mouse model [58]. Another study also reported the beneficial effect of MCC950 in alleviating mechanical allodynia in a rat model with myelin-oligodendrocyte-glycoprotein (MOG)-induced EAE [70]. Enhanced activation of the NLRP3 inflammasome has also been detected in the spinal cord of rat [70] and mouse models of MOG-induced EAE [70].

These findings suggest that the NLRP3 inflammasome may be a potential therapeutic target that can be used to enhance the quality of life of patients with central neuropathic pain. However, further preclinical studies must be conducted in the future to elucidate the molecular mechanisms underlying NLRP3 inflammasome activation.

Radiculopathy

Radiculopathy is a disease characterized by the presence of pain, muscle weakness, and numbness in the arms or legs owing to the compression of one or more spinal nerve roots. The common causes of mechanical nerve compression, leading to hyperalgesia and nerve inflammation, include the degeneration and herniation of the vertebral column discs [71,72]. Human and animal studies have revealed the presence of various inflammatory mediators in degenerated discs; notably, the levels of these mediators exhibit significant correlations with the grade of degeneration [73]. The NLRP3 inflammasome levels in disc specimens of patients with lumbar disc degeneration (LDD) were proportional to the pain and disc degeneration score in the study conducted by Wang and Zhang [74]. The NLRP3 inflammasome was only expressed in disc microglia in the animal model of LDD; however, depletion of microglial cells from this inflammasome alleviated neuropathic pain and the severity of LDD [74]. Several studies have examined the ability of different molecules and compounds to reduce the inflammatory response, thereby alleviating neuropathic pain. Hydroxytyrosol significantly reduced mitochondrial dysfunction, extracellular matrix degradation, NLRP3 inflammasome activation, and NF-κB signaling pathway in human nucleus pulposus cell in the study by Yu et al. [72]. This effect markedly modulated intervertebral disc (IVD) degeneration. Hydroxytyrosol also ameliorated neuropathic pain by blocking the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway in an animal model of chronic compression of the DRG (CCD) [72]. The protective effects of cortistatin, a cyclic neuropeptide, against IVD degeneration through the inhibition of mitochondrial dysfunction and NLRP3 inflammasome activation was demonstrated in the in vitro and in vivo experiments conducted by Zhao et al. [75]. The analgesic efficacy of fullerol, a strong antioxidant compound, in ameliorating mechanical hyperalgesia by targeting the NLRP3 inflammasome in the DRG of a mouse model of radiculopathy was observed in another study [76]. Bay11-7082, an inhibitor of NF-κB signaling, significantly alleviated mechanical allodynia and hyperalgesia by inhibiting NLRP3 inﬂammasome activation and NF-κB signaling pathway in DRG neurons in a rat model of lumbar disc herniation (LDH) [77].

These findings suggest the involvement of the NLRP3 inflammasome in development of vertebral disc degeneration and nerve root compression. Thus, inhibition of the NLRP3 inflammasome may be a potential therapeutic strategy to ameliorate disc degeneration and radiculopathy.

NLRP3 inflammasome in morphine analgesic tolerance

Morphine, an opioid agonist, has been used for the management of acute and chronic pain [78], such as neuropathic pain [79]. However, prolonged use of morphine can lead to the development of tolerance [80,81]. The mechanism underlying this condition is unknown; however, inflammatory responses mediated through microglial cell activation may be involved in the development of morphine tolerance [82-85]. Numerous studies have provided strong evidence supporting the causative role of microglial NLRP3 inflammasome in the development of tolerance [86,87]. Consistent with this finding, repeated exposure to morphine enhanced NLRP3 inflammasome activation in the dorsal spinal microglia in a rat model of CCI in the study by Grace et al. [88]. Notably, the activation of the NLRP3 inflammasome is correlated with persistent sensitization induced by morphine [88]. An inhibitory effect of miR-223 on NLRP3 inflammasome activation, which reduced tolerance to morphine analgesics, was observed in the same animal model in the study by Xie et al. [89]. The involvement of TLR4, a known initiator of the NLRP3 inflammasome priming step, has been implicated in the development of tolerance through the activation of the microglia [90]. Several studies have examined the role of the TLR4/NLRP3 axis in the etiology of morphine tolerance. For instance, tolerance led to an increased expression of spinal transcription factor 7-like 2 (TCF7L2), a transcription factor involved in neuropathic pain, in the study by Chen et al. [87]. Moreover, overexpression of TCF7L2 resulted in the activation of the TLR4/NF-κB/NLRP3 pathway in microglia, thereby contributing to the development of tolerance [87]. Similarly, the involvement of TLR4/TGF-β-activated kinase 1 (TAK1)/NLRP3 signaling in microglial activation and the progression of chronic morphine tolerance was observed in another study [91]. Consistent with the findings of this study, chronic morphine injections induced antinociceptive tolerance accompanied by increased spinal microglial activation and NLRP3 protein levels. The TLR4-and P2X7 receptor-mediated pathways are alternative mechanisms involved in the activation of the NLRP3 inflammasome during the development of tolerance [92]. Notably, repeated exposure to morphine promoted the release of neuronal heat shock protein 70 (HSP70), an endogenous TLR4 ligand, through the activation of ATP-sensitive potassium channels (K_ATP channels) in the study by Qu et al. [86]. This increase in the extracellular HSP70 levels can trigger inflammatory responses and microglial activation through the TLR4/NLRP3 inflammasome pathway. However, the administration of glibenclamide can significantly ameliorate analgesic tolerance by blocking the KATP channels and inhibiting NLRP3 inflammasome activation [86].

The capacity of opioids such as hydrocodone, remifentanil, oxycodone, and buprenorphine to activate the NLRP3 inflammasome and induce opioid analgesic tolerance remains unknown. Thus, further studies must be conducted in the future. However, repetitive administration of fentanyl induced analgesic tolerance and hyperalgesia through the activation of the NLRP3 inflammasome in astrocytes and serotonergic neurons, targeting TLR4 and opioid receptors, respectively, in the dorsal raphe nucleus in a previous study [93].

The findings of these studies indicate the involvement of the NLRP3 inflammasome in the development of morphine tolerance. Thus, NLRP3 inflammasome inhibitors may be potential therapeutic options for the prevention of the adverse consequences of long-term morphine therapy.

NLRP3 inflammasome and therapeutic approaches for the management of neuropathic pain

The NLRP3 inflammasome plays a significant role in the pathogenesis of neuropathic pain, representing a promising therapeutic target. Numerous sites for pharmacological intervention are present in the intricate pathways involved in the activation of NLRP3 inflammasome. Therapeutic strategies inhibit inflammasomes through their targeted effects on the activation, signaling, and effector pathways [94]. Various pharmacological agents with distinct inhibitory actions have been identified. Notably, the effects of some of these agents on inflammatory conditions such as Alzheimer’s disease (AD) [95], diabetes [96], and inflammatory bowel disease [97] have been evaluated. Table 1 summarizes the preclinical research on NLRP3 inhibitors in animal neuropathic pain models and details their pharmacological mechanisms.

Several Phase II clinical trials have evaluated the efficacy and safety of NLRP3 inflammasome inhibitors. For instance, GDC-2394, an NLRP3 inhibitor, exhibited appropriate pharmacokinetic and pharmacodynamic properties in the study conducted by Tang et al. [98]. Moreover, it effectively inhibited NLRP3 in healthy volunteers. However, these effect were associated with severe hepatic damage, precluding further research [98]. Dapansutrile, another NLRP3 inhibitor, exhibited cardioprotective effects in patients with heart failure and reduced the ejection fraction in the study conducted by Wohlford et al. [99] Furthermore, it exhibited a satisfactory safety profile and was well-tolerated. The administration of DFV890, an NLRP3 inhibitor, to patients with COVID-19 resulted in an improvement in the clinical status and SARS-CoV-2 clearance in the study conducted by Madurka et al. [100], indicating that NLRP3 inhibition may be a viable therapeutic approach. However, no phase II clinical trial has evaluated the safety and efficacy of NLRP3 inhibitors in the treatment of neuropathic pain. Thus, further studies must be conducted in this field to evaluate their potential.

The irreversible and nonspecific effects of the pharmacological options hamper their accuracy despite the advances in the field of pharmacology. Thus, future studies must aim to assess the putative side effects of NLRP3 inflammasome inhibition. This will aid in developing effective pharmacotherapies for neuropathic pain.

CONCLUSION

The NLRP3 inflammasome, a pivotal element of the innate immune system, plays a critical role in the pathophysiological processes underlying the development of central and peripheral neuropathic pain. The specific mechanisms underlying the activation of the NLRP3 inflammasome vary across various neuropathic pain-associated diseases. Thus, the strategic modulation of the NLRP3 inflammasome is a promising therapeutic avenue that can address the unmet clinical demand for novel and effective analgesics.

Notes

FUNDING

None.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

DATA AVAILABILITY STATEMENT

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

AUTHOR CONTRIBUTIONS

Writing - original draft: Zana Montazeri-Khosh, Ahmad Ebrahimpour, Mahyar Hossein-Zargari, Parsa Taghizadeh-Tabrizi, Mohammad Safari-Sahlabadi, MohammadHosein Sheybani-Arani. Writing - review & editing: Nahid Davoodian.

Fig. 1.

A schematic representation depicting the activation mechanism of the NLRP3 inflammasome. The initial priming phase involves the transcriptional upregulation of the pivotal components of the NLRP3 inflammasome, mediated by the TLR receptor, followed by NF-κB signaling. The NLRP3 inflammasome is activated by varioous inducers, including potassium efflux, ROS, and lysosomal disruption, during the activation phase. This culminates in the assembly of the NLRP3 inflammasome, leading to the activation of caspase-1. Caspase-1 facilitates the activation of pro-IL-1β and GSDMD. NLRP3: nucleotide-binding domain and leucine-rich repeat pyrin-containing protein-3, TLR: toll-like receptor, NF-κB: nuclear factor kappa B, ROS: reactive oxygen species, GSDMD: gasdermin D. Created in BioRender. Montazeri-Khosh Z (2025). Available from: https://BioRender.com/q1icnbb

Table 1.

Summary of the Preclinical Studies Assessing the Treatment of Neuropathic Pain by Targeting the NLRP3 Inflammasome

Agent	Neuropathic pain animal model	Proposed mechanism(s)	Dose/route and duration of administration	Study
Albiflorin	CCI in rats	Upregulation of the Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 signaling pathway and reduction of ROS production.	Albiflorin (50 mg/kg) in combination with MCC950 (10 mg/kg) administered intraperitoneally (i.p.) by daily injection, starting 15 days after CCI.	Liu et al., 2021 [101]
		Inhibitory effect on the activation of hippocampal NF-κB and NLRP3 inflammasome signaling pathway.
Aspirin-triggered Resolvin D1	SNL in rats	Impending NLRP3 inflammasome activation by increasing autophagy expression.	Different doses of aspirin-resolvin D1 (10 or 100 ng per rat per day) injected intrathecally for the first three consecutive days after surgery.	Wang et al., 2023 [102]
Bay11-7082	LDH in rats	Attenuation of NF-κB signaling pathway activation.	Bay11-7082 (5 mg/kg) injected for 4 wk. (i.p.).	Zhang et al., 2017 [77]
		Downregulation of NLRP3 inflammasome formation.
Berberine	Bortezomib-induced sciatic nerve and spinal cord damage in rats	Down-regulation of lipid peroxidation.	Berberine (100 mg/kg) administered orally through intragastric gavage.	Yardim et al., 2022 [103]
		Diminished NF-κB activation and TLR4 expression.
		Down-regulation of the NLRP3 inflammasome signaling pathway.
2-Bromopalmitate	Oxaliplatin-induced neuropathic pain in rats	Inhibition of NLRP3 inflammasome and its associated inflammatory response.	2-bromopalmitate (1 mg/kg) injected intrathecally.	Dong et al.,2022 [31]
		Stabilization of mitochondrial membrane integrity.
		Down-regulation of cyclooxygenase-2 (COX-2) expression and ROS production.
Carvacrol	CCI in rats	Potentiation of mitochondrial function and diminished oxidative events.	First group: 30 mg/kg orally.	Arruri et al., 2022 [48]
		Increase in Nrf-2 signaling pathway expression and autophagic process.	Second group: 60 mg/kg orally.
		Impeding NLRP3 inflammasome activation.	The drug was administered from 1st day to 14th after CCI in both groups.
D-β-hydroxybutyrate	SCI in mice	Promotion of mitochondrial function and reduction of oxidative events.	D-β-hydroxybutyrate (0.4, 0.8, and 1.6 mmol/kg) implants administered subcutaneously.	Qian et al.,2017 [60]
		Increase in the level of FOXO3a and down-regulation of histone deacetylases.
		Suppression of NLRP3 inflammasome formation and microglial and astroglial activation.
		Reduction of neutrophil and macrophage infiltration.
Dexmedetomidine	CCI in rats	Attenuation of NLRP3 inflammasome through the upregulation of Nrf-2 signaling pathway expression.	Different doses (1, 2, and 5 µg/kg) injected through i.p. in different groups for seven days.	Shan et al., 2021 [49]
Divanillyl sulfone	Diabetic neuropathic pain in rats.	Down-regulation of P2X4 receptor expression and NLRP3 inflammasome activation.	Dexmedetomidine (50 µg/kg, daily) injected through i.p. for 35 days.	Kang et al., 2019 [104]
	CCI in mice	Amelioration of ROS production and microglial apoptosis through the activation of mitophagy.	Divanillyl sulfone (1,3, and 10 mg/kg) administered intrathecally.	Shao et al., 2021 [105]
		Inhibition of NLRP3 inflammasome activation through the promotion of mitophagy and autophagy.
Jinmaitong	Diabetic neuropathic pain in rats	Diminished pyroptosis process through the suppression of NLRP3 inflammasome activation and GSDMD gene expression.	Jinmaitong (0.88 g/kg/day) administered orally for 12 weeks.	Sun et al., 2021 [106]
Hydrogen-rich Saline	SNL in rats	Attenuation of NLRP3 inflammasome activation through the upregulation of autophagy.	Hydrogen (10 ml/kg daily) administered through i.p. twice a day (each dose 5 ml/kg) 1-7 days after SNL.	Chen et al., 2019 [50]
Hydroxytyrosol	Chronic compression of the DRG in rats	Preserving homeostasis of mitochondria through the inhibition of the NF-κB signaling axis.	Intervertebral injection of hydroxytyrosol (100 µM).	Yu et al., 2022 [72]
		Alleviation of the PI3K/ AKT and extracellular signal-regulated kinase (ERK) signaling pathway.
Loganin	CCI in rats	Down-regulation of TXNIP by decreasing CXCL12 and CXCR4.	Loganin (5 mg/ kg, i.p.)	Cheng et al., 2019 [46]
		Diminishing NLRP3 inflammasome activation.	Loganin (5 mg/ kg, i.p.)	Cheng et al., 2019 [46]
Melatonin	CCI in rats	Down-regulation of gene expression of NLRP3 and NF-κB.	Melatonin (10 mg/kg, i.p.) injected for 14 days.	Mokhtari et al., 2023 [107]
		Diminished apoptosis process through the modulation of the level of B-Cell Lymphoma 2 (Bcl-2) and Bcl-2-associated X (Bax) proteins.	Melatonin (10 mg/kg, i.p.) injected for 14 days.	Mokhtari et al., 2023 [107]
	SNL in rats	Impeding the activation of NLRP3 inflammasome and hampering NF-κB axis.	Melatonin (20 mg/kg, i.p.) administered for the first 3 days after SNL operation.	Wang et al., 2021 [108]
miR-223	Hemorrhage-induced thalamic pain model in mice.	Inhibition of NLRP3 inflammasome activation via targeting 3'untranslated region (3′ UTR) of NLRP3 mRNA.	miR‑223 antagomir microinjection into the unilateral thalamus.	Huang et al., 2022 [57]
	CCI in mice	Avoiding apoptotic events through the inhibition of neuroinflammation-associated NLRP3.	Lenti-miR-223 administered intrathecally by a microinjection syringe 3 days before surgery.	Zhu et al., 2021 [40]
		Regulatory effect on decreasing M1-like macrophages.
		No effect on the NLRP3 gene was detected.
miR-185-5p	CCI in rats	Down-regulation of the expression of NLRP3 inflammasome by modulating myeloid differentiation primary response 88 (MYD88) and CXCR4.	Lentivirus-miR-185-5p (1 × 10⁸ PFU/ml, 10 µL) injected intrathecally.	Huang et al., 2022 [43]
miR-34c	CCI in mice	Inhibition of NLRP3 inflammasome and cell apoptosis.	1 µL of lentivirus particles with titers of 10⁸ TU/ml administered intrathecally daily for three consecutive days, 2 weeks before CCI.	Xu et al., 2019 [44]
miRNA-23a	Partial SNL (pSNL) in rats	Decrease in the expression of CXCR4 by binding to 3′ UTR of its mRNA.	Lentivirus with titers of 10⁸ TU/ml administered intrathecally for 7 days after pSNL.	Pan et al., 2018 [42]
	Partial SNL (pSNL) in rats	Inhibition of NLRP3 inflammasome and TXNIP through the downregulation of CXCR4.		Pan et al., 2018 [42]
MCC950	MS-induced central neuropathic pain in mice.	Inhibition of NLRP3 inflammasome activation.	MCC950 (50 mg/kg/day) administered orally by gavage.	Khan et al., 2018 [58]
Paeoniflorin	CCI of the sciatic nerve in rats	Impeding NLRP3 inflammasome expression.	Paeoniflorin (50 mg/kg) injected through i.p. daily for 11 consecutive days.	Liu et al., 2020 [109]
		Enhancement in Nrf-2 axis expression and boosting antioxidation.
		Down-regulation of NF-κB signaling pathway activation.
Probucol	CCI of sciatic nerve model in rats	Hampering NLRP3 and NF-κB associated neuroinflammatory response.	Probucol (8 mg/kg & 16 mg/kg) administered orally for 14 days.	Derangula et al., 2022 [47]
		Potentiation of antioxidant activity through the up-regulation of Nrf-2 pathway.		Derangula et al., 2022 [47]
Resolvin D1	SNL of spinal nerve in rats	Suppression of NLRP3 inflammasome activation by modulating the ERK phosphorylation associated with lipoxin A₄/formyl peptide receptor 2 (ALX/FPR2).	Resolvin D1 (10 ng or 100 ng, i.p.) administered from the first three consecutive days after SNL operation.	Wang et al., 2022 [110]
Salidroside	CCI of sciatic nerve in mice	Suppression of TXNIP-associated NLRP3 inflammasome activation.	Salidroside (200 mg/kg, i.p.) administered for 14 consecutive days.	Hu et al., 2022 [111]
	Diabetic neuropathic pain in rats	TXNIP/NLRP3 inflammasome activation suppression related to improvement of adenosine monophosphate-activated protein kinase (AMPK) activity.	Salidroside (100 mg/kg/day) administered for 6 weeks.	Zheng et al., 2021 [112]

ROS: reactive oxygen species, DRG: dorsal root ganglion, CCI: chronic constriction injury, SNL: spinal nerve ligation, SCI: spinal cord injury, MS: multiple sclerosis, NF-κB: nuclear factor kappa B, NRF2: Nuclear factor erythroid 2-related factor 2, TLR4: toll-like receptor 4, LDH: lumbar disc herniation, GSDMD: gasdermin D, TXNIP: thioredoxin-interacting protein, NLRP3: nucleotide-binding domain and leucine-rich repeat pyrin-containing protein-3.

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