Skip to main content

The NLRP3 inflammasome: an emerging therapeutic target for chronic pain

Abstract

Chronic pain affects the life quality of the suffering patients and posts heavy problems to the health care system. Conventional medications are usually insufficient for chronic pain management and oftentimes results in many adverse effects. The NLRP3 inflammasome controls the processing of proinflammatory cytokine interleukin 1β (IL-1β) and is implicated in a variety of disease conditions. Recently, growing number of evidence suggests that NLRP3 inflammasome is dysregulated under chronic pain condition and contributes to pathogenesis of chronic pain. This review provides an up-to-date summary of the recent findings of the involvement of NLRP3 inflammasome in chronic pain and discussed the expression and regulation of NLRP3 inflammasome-related signaling components in chronic pain conditions. This review also summarized the successful therapeutic approaches that target against NLRP3 inflammasome for chronic pain treatment.

Introduction

Pain accompanies with many chronic diseases. Chronic pain due to tissue inflammation, nerve lesion, tumor invasion, or chemotherapy represents a major health problem in the health care system [1]. Chronic pain is among the most common complaints in outpatient clinic [2]. It is estimated that 11–40% of adult population suffers from chronic pain [1]. Moreover, chronic pain is usually accompanied with emotional changes, including anxiety, depression, or even suicidal tendencies [2]. Therefore, chronic pain dramatically affects the life quality and posts heavy economic and social burdens to the suffering patients. However, conventional treatments for chronic pain are still limited to nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, corticosteroids, antidepressants, etc. These medications are usually insufficient for relieving chronic pain and often bring in many severe side effects [2, 3].

A large body of evidence indicates that inflammatory mediators (e.g., proinflammatory cytokines) in local inflamed tissues, peripheral nerves, and spinal cord make important contributions to the initiation and maintenance of chronic pain [3,4,5]. Among these proinflammatory cytokines, IL-1β is the most extensively studied cytokines. It exerts robust proinflammatory effects on many types of immune cells and tissues, whereas its excessive production is implicated in the pathophysiology of acute or chronic inflammation and pain. IL-1β may contribute to pain via direct and indirect mechanisms. On the one hand, IL-1β directly activates nociceptors to elicit action potentials and induce pain [6]. On the other hand, IL-1β contributes to peripheral or central sensitization by sensitizing nociceptors or promoting neuron-glia crosstalk [7,8,9]. Inhibition of IL-1β signaling has been shown to be effective for ameliorating pain in both animal models and human patients. Due to its important physiological function, the production of the active form of IL-1β is usually under tight regulation. One of the important mechanisms underlying such regulation is mediated via NLRP3 inflammasome.

NLRP3 inflammasome and its activation mechanism

The NLRP3 inflammasome consists of NLRP3, ASC adaptors, and caspase-1 enzymes [10, 11]. The NLRP3 inflammasome is present primarily in immune and inflammatory cells, including mast cells, neutrophils, and macrophages, following activation by inflammatory stimuli [12,13,14]. Recent studies also identified NLRP3 inflammasome in neurons of the sensory nerve system [15]. NLRP3 inflammasome can be activated by a variety of stimuli and ligands, including PAMPs (pathogen associated molecular patterns), such as exogenous microbial molecules and bacterial lipopolysaccharide (LPS), and DAMPs (damage associated molecular patterns), such as HMGB1, S100 proteins, ATP, IL-33, and monosodium urate (MSU) [16, 17]. The activation procedure of NLRP3 inflammasome usually involves two phases (Fig. 1). The first phase is the priming phase, mediated primarily by Toll-like receptors (TLRs) and cytokine receptors (e.g., tumor necrosis factor receptor (TNFR)), which recognize PAMPs, DAMPs, or endogenous cytokines. This process results in upregulation of inactive NLRP3 and pro-IL-1β transcription via nuclear factor kappa B (NF-κB)-mediated transcriptional regulation [25]. MyD88 and TRIF, two downstream adaptor molecules of TLRs, regulate the induction of NLRP3 and pro-IL-1β transcription in response to TLR ligands during priming phase. The second phase involves the assembly of NLRP3 with ASC into the inflammasome complex, initiated by the stimulation of NLRP3 by a plethora of stimuli, including Ca+ influx, K+ efflux, mitochondrial damage, and ATP, and subsequent activation of pro-caspase-1 with autocatalytic activity (Fig. 1) [25]. The active caspase-1 ultimately cleaves pro-IL-1β and pro-IL-18, leading to maturation and release of IL-1β and IL-18 with proinflammatory activities [25]. The dysregulation of NLRP3 inflammasome has been shown to be related with a variety of diseases, including multiple sclerosis, diabetes, atherosclerosis, Alzheimer’s disease, inflammatory bowel disease, and many other autoimmune diseases [26]. More recently, growing number of evidence suggests that NLRP3 inflammasome is dysregulated under chronic pain conditions and contributes to the pathogenesis of chronic pain [27].

Fig. 1
figure1

Schematic picture showing NLRP3 inflammasome activation and expression in the sensory nerve system and its surrounding microenvironment during chronic pain. The inset box depicts NLRP3 inflammasome activation procedure. The first phase (priming) involves Toll-like receptors (TLRs) and cytokine receptor recognition of the PAMPs/ DAMPs or endogenous cytokines, which results in activation of nuclear factor kappa B (NF-κB) signaling in the nucleus and upregulation of the transcription levels of inactive NLRP3 and pro-IL-1β. The second phase (assembly) involves the assembly of NLRP3 with ASC into inflammasome complex, initiated by the stimulation of NLRP3 by a plethora of stimuli, and subsequent activation of pro-caspase-1 with autocatalytic activity. The active caspase-1 ultimately cleaves pro-IL-1β and pro-IL-18, leading to maturation and release of IL-1β and IL-18. The expression of NLRP3 inflammasome has been identified in the following types of cells related with the sensory nerve system and surrounding microenvironment during chronic pain: peripheral inflamed tissues (including macrophages, neutrophils, mast cells) [14, 18, 19]; peripheral nerves and DRG (including DRG neurons and infiltrated macrophages) [20, 21]; spinal cord dorsal horn (including neurons, astrocytes and microglia) [15, 22]; brain regions (including neurons and astrocytes in DRN and microglia in PFC [23, 24]. This figure was created with BioRender.com

Here in this review, we provide an up-to-date review of the recent findings of NLRP3 inflammasome in chronic pain conditions, including inflammatory pain, neuropathic pain, migraine, bone cancer pain, and morphine-induced analgesic tolerance and hyperalgesia. We discussed the expression and regulation of NLRP3 inflammasome-related genes and proteins during chronic pain. Furthermore, we also discussed the mechanisms underlying NLRP3 inflammasome’s contribution to chronic pain. Finally, this review summarized the successful therapeutic approaches that target against NLRP3 inflammasome for chronic pain, including the specific NLRP3 inflammasome antagonist MCC950 (Fig. 2, Table 2) [28] and other approaches (e.g., specific gene knockdown/knockout, electroacupuncture treatment).

Fig. 2
figure2

The chemical structure of the specific NLRP3 inflammasome antagonist MCC950. MCC950, a sulfonylurea molecule, was first discovered by Matthew Cooper et al., with original name CRID3, and then renamed MCC950 for “Matthew Cooper compound 950” [28]. MCC950 is a potent, selective, and small-molecule inhibitor of NLRP3 working at nM concentration. It specifically inhibited NLRP3 activation but not other inflammasome activation, including NLRP1, NLRC4, or AIM. Recent evidence suggests that the mechanism of MCC950 involves the closing of the open conformation of active NLRP3 [29].

NLRP3 inflammasome in chronic pain

NLRP3 in neuropathic pain

Neuropathic pain is one of the most intractable pain conditions and usually caused by injuries, lesions, or dysfunctions of the peripheral or central nervous system [36]. Nerve injuries can result in neuron damage, apoptosis, or death that release an array of DAMPs (e.g., HMGB1, IL-33, and ATP) to initiate NLRP3 inflammasome activation [37, 38]. Neuropathic pain results in a great decline of the life quality of patients, both physically and mentally. Up to date, there are a number of studies showing that NLRP3 is involved in neuropathic pain conditions, which are listed as follows:

NLRP3 in nerve injury-induced neuropathic pain

A study using partial sciatic nerve ligation (pSNL) model showed that pSNL injury increased the protein expression of NLRP3 inflammasome components, including NLRP3, ASC, caspase-1, and increased IL-1β in the spinal cord [39]. The authors found that NLRP3 inflammasome was a direct downstream effector of chemokine receptor CXCR4 in spinal cord glial cells, which was implicated in neuropathic pain [39]. Similar studies using chronic constriction injury (CCI)-induced neuropathic pain model also found that the expression of NLRP3 and its downstream effectors were increased in neurons and glia cells of spinal cord dorsal horn (Table 1) [42, 43]. Blocking connexin 43 hemichannels results in a significant improvement in mechanical pain hypersensitivity, accompanied with reductions in NLRP3, ASC, and caspase-1 protein expression in spinal cord [43].

Table 1 Expression of NLRP3 inflammasome components under different pain conditions

Another study by Xu et al. found that overexpressing miR-34c improved CCI-induced neuropathic pain and spinal cord infarction and further alleviated cell apoptotic and inflammatory cytokine expression in CCI model mice [42]. The therapeutic effect of miR-34c is accompanied with decreased protein levels of NLRP3, ASC, caspase-1, IL-1β, and IL-18 in the spinal cord of CCI mice. Bioinformatic analyses and biochemical assays further revealed that miR-34c suppressed the expression of NLRP3 by directly binding to the 3'-untranslated region. Further experiments that specifically target against NLRP3 inflammasome will be needed to further verify its role in nerve injury-induced neuropathic pain [42]. Therefore, these studies suggest that NLRP3 inflammasome may be potentially involved in nerve injury-induced neuropathic pain and inflammation.

NLRP3 in chemotherapy-induced peripheral neuropathy (CIPN)

CIPN is one of the most serious complications caused by anticancer drugs [44]. Neuropathic pain is a major clinical symptom accompanying CIPN, which includes tingling, burning pain, and numbness in the feet and hands. The sensory abnormalities and pain can even become chronic and persist after chemotherapy is terminated, which severely affect the life quality of the patients [45]. Neoplastic cancer cells and chemotherapeutic drugs can lead to the release of DAMPs by cancer cells per se or by host cells [37]. In a paclitaxel-induced peripheral neuropathic pain rat model, paclitaxel treatment resulted in elevated expression of NLRP3, caspase-1, and IL-1β in dorsal root ganglion (DRG) and sciatic nerve [20]. The expression of NLRP3 was primarily expressed in macrophages that infiltrated in DRG and sciatic nerve (Table 1). Paclitaxel also caused mitochondrial damage and production of reactive oxygen species (ROS) in sciatic nerve, which triggered the activation of NLRP3 inflammasome [20]. Application of phenyl-N-tert-butylnitrone (a ROS scavenger) significantly reduced paclitaxel-induced mechanical allodynia and inhibited NLRP3 inflammasome activation in DRG and sciatic nerve [20].

In another CIPN animal model induced by bortezomib, the expression of NLRP3 was significantly increased in DRG. Further immunostaining results showed that NLRP3 expression was primarily located in DRG neurons and infiltrating macrophages, but not in satellite glial cells (Table 1) [21]. Knockdown of Nlrp3 gene expression via intrathecal siRNA injection significantly prevented bortezomib-induced mechanical allodynia. In contrast, the overexpression of Nlrp3 gene in DRG significantly reduced the paw withdrawal threshold in treated animals [21].

In addition, in oxaliplatin-induced CIPN animal model, the expression of NLRP3 and caspase-1 were increased in spinal cord. Blocking NLRP3 activation by daily intrathecal injection of MCC950 significantly alleviated oxaliplatin-induced neuropathic pain (Table 2) [30]. In all, these results indicate NLRP3 inflammasome plays an important role in CIPN-induced neuropathic pain.

Table 2 Application of MCC950 for treating different pain conditions

NLRP3 in complex regional pain syndrome type-I (CRPS-I)

CRPS-I is a progressive and devastating neuropathic pain condition that usually affects the limbs and is not accompanied with a clinically verifiable nerve injury [46]. CRPS-I usually develops after an initial injury, including ischemia, trauma, surgery, or fractures to the extremity. The pain is out of proportion to the severity of the initial injury and becomes chronic. CRPS patients usually suffer from excruciating and chronic pain in affected areas, leading even to disabilities. Unfortunately, no specific drugs haven been approved for CRPS-I treatment at present. Conventional medications, including NSAIDs, corticosteroids, and narcotics usually do not produce satisfactory relieving effects on CRPS-I, making it a challenging pain condition in clinic [47, 48]. To explore the mechanisms underlying CRPS-I, several preclinical animal models, including the rat chronic post-ischemic pain (CPIP) model, have been developed to recapitulate CRPS-I [49, 50].

To further explore the mechanisms underlying CRPS-I, our recent study performed transcriptome profiling of gene expression changes in ipsilateral DRG and spinal cord dorsal horn (SCDH) of CPIP model rats by means of RNA-Sequencing [31, 51, 52]. We identified Nlrp3 gene expression to be significantly upregulated in SCDH of the CPIP model rats. We further identified that the gene and protein expressions of NLRP3, caspase-1, and IL-1β were all significantly increased in ipsilateral SCDH of CPIP model rats. Pharmacological blockade of NLRP3 by intrathecal delivery of the specific NLRP3 antagonist MCC950 reduced IL-1β overproduction and glial activation in ipsilateral SCDH as well as mechanical allodynia of CPIP model rats (Table 2) [31]. It is known that spinal IL-1β and glia cell activation mediate pain mechanisms of CRPS-I (Table 1) [8, 53, 54]. Therefore, NLRP3 inflammasome is activated in SCDH of a rat model of CRPS-I and it contributes to the mechanical allodynia via promoting IL-1β overproduction and glia cell activation in SCDH. This study indicates that NLRP3 inflammasome may be a novel therapeutic target for CRPS-I management.

NLRP3 in central neuropathic pain (CNP)

CNP is common among patients with neurological complications of the central nervous system insult, such as spinal cord injury, stroke, or multiple sclerosis [55]. However, at present, the provision of effective pain alleviations to CNP can be difficult due to many unwanted side effects of conventional medications. Recently, Khan and colleagues established an optimized relapsing-remitting experimental encephalomyelitis (RR-EAE) mouse model to mimic human multiple sclerosis [32]. The RR-EAE model mice developed obvious mechanical allodynia in bilateral hind limbs. Daily oral administration of the NLRP3 antagonist MCC950 progressively and effectively alleviated the established mechanical allodynia in bilateral hind limbs of model mice (Table 2) [32]. Furthermore, MCC950 also improved the disease relapses in RR-EAE model mice, indicated by the improvement of hind limb weakness and tail limpness [32]. These results indicated that targeting NLRP3 inflammasome could be a potential method for alleviating multiple sclerosis-induced CNP and disease relapses.

In the mouse model of spinal cord injury (SCI), significant locomotor dysfunction and mechanical/thermal hyperalgesia were developed, accompanied with NLRP3 inflammasome activation and production of IL-1β and IL-18 in spinal cord. Treatment with D-β-hydroxybutyrate (DBHB), an endogenous ketone body NLRP3 inflammasome inhibitor, markedly improved locomotor function and relieved SCI-induced pain hypersensitivities, accompanied with attenuated NLRP3 inflammasome activation and protein expression of IL-1β and IL-18 in the spinal cord [56, 57], demonstrating a possible involvement of NLRP3 inflammasome in SCI-induced CNP.

NLRP3 in inflammatory pain

Inflammatory pain is usually triggered by infection, trauma, or tissue damage, which induces the release of an array of inflammatory mediators (e.g., bradykinin, prostaglandin, H+, ATP, nerve growth factor, endothelin), proinflammatory cytokines, chemokines, etc. [3, 58,59,60]. PAMPs (e.g., LPS) and DAMPs (e.g., MSU, S100 proteins) may be both involved in inflammatory pain, depending on specific inflammatory conditions [37, 61, 62]. The inflammatory mediators, cytokines, or chemokines can directly stimulate or sensitize the nociceptors in surrounding tissues and mediate inflammatory pain [3, 4].

NLRP3 in complete Freund’s adjuvant (CFA)-induced inflammatory pain

In CFA-induced animal inflammatory pain model, the expression of NLRP3 inflammasome components, including ASC, caspase-1, and IL-1β, are significantly increased in local inflamed hind paw tissues and spinal cord [40, 63, 64]. Immunostaining revealed that NLRP3 was colocalized with markers for keratinocytes, T cells, and macrophages (Table 1). Repetitive electroacupuncture (EA) treatment produced analgesic effects on CFA-induced pain model mice, accompanied with reduced NLRP3 inflammasome activation and IL-1β production in local inflamed tissues and especially in macrophages [40, 63]. Since IL-1β is known to be an important contributor to CFA-induced inflammatory pain, these results suggest that EA-induced analgesic effects may possibly be related with its inhibitory effects on NLRP3 inflammasome activation in local inflamed tissues [7]. Experiments that specifically target against NLRP3, e.g., using specific antagonist or gene knockdown approaches, will be further needed to elucidate the exact contributions of NLRP3 inflammasome in CFA-induced inflammatory pain condition.

Recently, another study by Huang et al. reported that the expression of TLR2 and TLR6 were significantly upregulated in plantar skin of CFA-induced inflammatory pain model. Selective activation of TLR2/TLR6 by agonist FSL1 triggered acute inflammatory pain, as well as a significant increase in Nlrp3 gene expression in hind paw tissues [33]. They found that the acute inflammatory pain was significantly reduced in Nlrp3 gene knockout animals or by MCC950 treatment (Table 2). Further evidence showed that the pain response was mediated via mechanisms involving NLRP3-dependent upregulation of IL-33, a pain-producing cytokine known to be involved in many pain conditions [65, 66]. Therefore, this study revealed an important role of NLRP3-dependent upregulation of IL-33 in mediating inflammatory pain.

NLRP3 in monosodium urate crystal-induced gout pain

Gout is evoked by monosodium urate (MSU) crystal deposition in joint and periarticular tissues. The deposition of MSU crystals triggers the activation of innate immune system, including neutrophil and macrophage influx, which induces intense inflammation and pain in local joint and periarticular tissues. Gout pain is the most common type of inflammatory arthritis and dramatically affects the life quality of patients [67]. Unfortunately, the incidence of gout is still constantly rising due to the aging population and dietary changes [68].

Mounting evidence indicates that MSU-induced inflammation and pain response depend on IL-1β release [69, 70]. Blocking IL-1 signaling with either recombinant IL-1 receptor antagonist or neutralizing antibodies of IL-1 or IL-1 receptor attenuates neutrophil infiltration in response to MSU challenge [71, 72]. In accordance, mice deficient in IL-1 receptor showed much reduced ankle edema and pain response after MSU injection into ankle joint [73]. MSU stimulates macrophages to release IL-1β via NLRP3 inflammasome activation. In a mouse model of MSU-induced peritonitis, macrophages from mice lacking the key components of NLRP3 inflammasome, e.g., NLRP3, caspase-1, or ASC, were incapable of producing the active form of IL-1β in response to MSU challenge [18]. Furthermore, in a mouse gout model by intraarticular MSU injection, mice deficient in NLRP3, caspase-1, or ASC showed much reduced pain response as well as reduced neutrophil infiltration and IL-1β in ankle joints [74]. In addition to macrophages, IL-1β production from other cellular sources should not be neglected. For example, IL-1β can be released from mast cells by activation of NLRP3 inflammasome [13]. Mast cell-derived IL-1β made important contributions to MSU-induced ankle inflammation, especially during early phase [19].

Despite much progress has been made in elucidating the importance of NLRP3 inflammasome in gout pathology, the precise mechanisms through which NLRP3 inflammasome is activated under gout condition remain elusive. Our recent work, together with others, demonstrated that the production of endogenous ROS are increased during gout condition and are critically involved in mediating gout pain and inflammation [66, 75,76,77]. It is known that the generation of ROS induces dissociation of ROS-sensitive NLRP3 ligand thioredoxin-interacting protein (TXNIP) from its inhibitor thioredoxin (TRX). TXNIP then binds to NLRP3 and leads to NLRP3 inflammasome activation [78, 79]. We further found that eliminating ROS productions by applying the natural product eucalyptol or classical antioxidants largely reduced NLRP3 inflammasome activation in vivo, which results in less caspase-1 and IL-1β expression in local inflamed ankle tissues and gout pain relief in a mouse MSU-induced gout model [75]. These results suggest that ROS are important triggers for NLRP3 inflammasome activation under gout condition and eliminating ROS overproduction may represent promising therapeutic options for gout arthritis.

At present, several clinical studies have proven that therapies targeting against IL-1β are successful strategies for relieving pain, inflammation, and recurrent attacks of gout, indicating that targeting IL-1β and its related pathways is effective for gout treatment [69]. Therefore, targeting ROS, NLRP3 inflammasome, and its downstream signaling may offer promising therapeutic options for gout.

NLRP3 in postoperative pain

The development of chronic postoperative pain after surgery constitutes a major clinical problem [80]. Postoperative pain possesses both inflammatory and neuropathic pain properties, which arise from tissue damage and incision of nerve endings at the surgery site. Studies have shown that IL-1β is significantly increased at the incision site [81, 82]. Inhibiting IL-1β signaling either by receptor antagonist or deletion of receptor IL-1R1 alleviated postoperative pain in both mouse model and human patients, suggesting IL-1β is a key contributor to postoperative pain [83,84,85,86]. Many endogenous activators of NLRP3 inflammasome, including ROS, ATP, and DAMPs, are released due to tissue damage after surgery, suggesting the possible activation of NLRP3 inflammasome during postoperative pain.

A recent study by Cowie et al. found that male mice deficient in NLRP3 showed less inflammation at the surgery site and recovered from surgery-induced pain faster than wild type controls. In contrast, female mice deficient in NLRP3 showed only modest attenuation of postoperative pain and no change in postoperative inflammation [82]. Further studies indicated that NLRP3 deletion reduced IL-1β expression only in males but not in females, suggesting that IL-1β production in females occurs via mechanisms independent of NLRP3 [82]. The authors continued to investigate this intriguing sex dimorphism by selectively deleting NLRP3 in peripheral sensory neurons. They found that NLRP3 expressed in non-neuronal cells and sensory neurons both contributed to the postoperative pain in male mice. In contrast, in female mice, the contribution of sensory neurons to postoperative pain is NLRP3 dependent, whereas the contribution of other non-neuronal cells is NLRP3 independent [82]. The exact immunological and neurological mechanisms underlying such drastic sex dimorphism of NLRP3’s contribution in postoperative pain is still unknown and awaiting further investigation [87]. But this study suggests targeting NLRP3 may be a novel strategy for alleviating postoperative pain and associated inflammation. More importantly, it also suggests that gender differences should be taken into consideration when evaluating therapeutic effects of NLRP3 antagonism on postoperative pain in preclinical animal models and further translational studies.

NLRP3 in muscle pain

Muscle pain is a very common type of pain condition and is usually induced by stress, tension, muscle overuse, or minor injuries [88]. Muscle pain can take place in a small area or even the whole body, ranging from mild to severe conditions [89]. Although most of muscle pains can recover on their own in a short period, it sometimes persists over months under certain pathological conditions (e.g., myofascial pain syndrome and fibromyalgia) and significantly affects life quality of the patients [90].

The role of NLRP3 inflammasome activation in a mouse model of muscle pain has recently been investigated by Yoshida et al. [41]. They established a mouse model of muscle pain using electrical stimulation to induce excessive muscle contraction in the mouse hind leg to mimic over exercise-induced muscle pain in humans. They observed that the stimulated hind leg developed obvious mechanical allodynia, accompanied with increased levels of uric acid, NLRP3, caspase-1 activity, IL-1β, and the number of macrophages, when compared with that of non-stimulated leg. Muscle overuse can trigger the increase of uric acid in the plasma [91]. When the level of uric acid in the plasma reaches its limit of solubility, MSU crystal formation then takes place and triggers NLRP3 inflammasome activation [18]. The authors continued to test the effects of caspase-1 inhibition, macrophage depletion, and blocking uric acid production using xanthine oxidase inhibitor. Administration of these reagents all reduced mechanical pain hypersensitivities in model mice, suggesting IL-1β released by NLRP3 inflammasome activation from macrophages contributed to mechanical pain hypersensitivity [91]. It should be noted that the electrical stimulation-induced muscle pain model may not completely recapitulate the pathophysiology underlying chronic muscle pain. This study suggests that pharmacological blocking NLRP3 inflammasome may be potentially utilized to alleviate muscle pain due to over-exercise in humans.

NLRP3 in migraine

Migraine is the most common type of disabling primary headache worldwide, which is characterized with moderate to severe throbbing or pulsing pain sensation [92]. Migraine usually lasts for hours or even days, which significantly affects the daily activities of the suffering patients [92, 93]. It is found that the serum level of IL-1β is significantly increased among migraine patients compared with healthy controls and correlated positively with the level of calcitonin gene-related peptide (CGRP), a well-established neuropeptide implicated in migraine pathology [94,95,96]. Recently, He et al. established a mouse migraine model by repeated nitroglycerin (NTG) administration [34]. Repeated NTG application triggered both acute and persistent mechanical pain hypersensitivity in periorbital area, an indication of migraine-like behavior in mouse [97]. Furthermore, the authors found that NLRP3 and IL-1β expression was significantly upregulated in the microglia of trigeminal nucleus caudalis (TNC) (Table 1), a place that receives and integrates pain signals from the trigeminal area and is considered as a central area relevant for migraine [98]. Pharmacological blocking NLRP3 (Table 2) or IL-1β with the NLRP3 antagonist MCC950 or IL-1ra not only improved NTG-induced hyperalgesia, but also inhibited the biomarkers related to central sensitization of migraine in TNC, such as p-ERK, c-Fos, and CGRP. These results indicate that the activation of NLRP3 in TNC contributes to nitroglycerin (NTG)-induced migraine-like behavior via promoting neuroinflammation and central sensitization [34]. Thus, inhibition of NLRP3 inflammasome may represent a potential therapeutic approach for alleviating migraine.

NLRP3 in visceral pain

Visceral pain mainly refers to pain originating from internal organs of the body (e.g., thoracic, abdominal, or pelvic organs). Stretching, inflammation, ischemia, pH, bacteria, immune mediators, and neurotransmitters can all evoke visceral pain. Therefore, PAMPs and DAMPs may both be involved in visceral pain. Among visceral pains, chronic pelvic pain syndrome (CPPS), also known as type III prostatitis [99], is the most prevalent urogenital disease among males with age < 50 years old. It causes pain and inflammation in the prostate, lower urinary tract, and pelvic area [100]. Recently, Zhang and colleagues explored the role of NLRP3 inflammasome in the pathogenesis of CPPS [35]. They established a mouse model of experimental autoimmune prostatitis (EAP) to mimic CPPS via intradermal injection of a mixture of prostate antigens and CFA. The EAP model mice developed obvious mechanical allodynia in the lower abdominal area nearby prostate. In addition, NLRP3, caspase-1, ASC, and IL-1β were all upregulated in prostate tissue of EAP model mice. Epidemiological studies reported an association between alcohol consumption and CPPS [101]. Then the authors found that treating EAP model mice with alcohol further exacerbated the pain response and promoted NLRP3 inflammasome activation in EAP model mice. The treatment with MCC950 inhibited NLRP3 inflammasome activation and reduced the mechanical allodynia of EAP model mice (Table 2). Furthermore, MCC950 attenuated the aggravated severity of alcohol-treated EAP model mice [35]. Therefore, NLRP3 inflammasome may be a promising therapeutic target for relieving pelvic pain and inflammation associated with CPPS and especially CPPS with alcohol consumption.

NLRP3 in cancer related pain

Pain is a common symptom among patients with cancer. It is reported that up to 75% of cancer patients suffer from severe bone pain induced by cancer [3]. Bone cancer pain (BCP) occurs in patients with primary bone cancer or with bone metastasis from other distal regions, such as prostate, lung, and breast cancer [102]. BCP can be debilitating and poses a heavy burden on patients’ daily activities and mental health [102, 103]. Mechanistically, BCP is considered as a specific type of pain condition with overlapping but distinct features of both inflammatory and neuropathic pain [102]. The tumor and surrounding microenvironment released a number of DMAPs (e.g., HMGB1, S100 proteins), which could trigger NLRP3 inflammasome activation [104]. Unfortunately, our current knowledge of the underlying mechanisms of BCP is still limited compared with the understandings of other inflammatory or neuropathic pain.

Recently, Chen and colleagues investigated the role of spinal NLRP3 inflammasome in the development of BCP [15]. A rat BCP model was established by inoculating Walker 256 carcinoma cells into the medullary cavity of the rat tibia. Mechanical allodynia and inflammasome activation were then evaluated, and it was found that BCP model rats developed mechanical allodynia, accompanied with increased expression of NLRP3 inflammasome, including NLRP3, ASC, caspase-1, and IL-1β, primarily in neurons of spinal cord dorsal horn (Table 1). MCC950 administration in BCP model rats reduced the upsurge of NLRP3 inflammasome and IL-1β protein expression in spinal cord dorsal horn and further relieved the mechanical allodynia (Table 2) [15]. These results suggest spinal NLRP3 inflammasome may be a novel target for BCP treatment.

NLRP3 in opioid analgesic tolerance and hyperalgesia

Morphine and fentanyl are opioids widely used for relieving pain, but prolonged usage in patients with chronic pain can end up in analgesic tolerance and hyperalgesia. These signs are two major adverse effects of prolonged morphine or fentanyl treatment, which severely reduced their clinical usages [105]. Prolonged morphine treatment can induce significant NLRP3 inflammasome activation in spinal cord of an animal model of morphine-induced analgesic tolerance and hyperalgesia [106, 107]. Further evidence demonstrates morphine treatment can induce a persistent release of DMAPs (including HMGB1, biglycan, heat shock protein 90) in spinal cord [108]. The contribution of NLRP3 inflammasome to morphine-induced analgesic tolerance and hyperalgesia is further supported by a study from Grace et al., who found that the knockdown of spinal Nlrp3 gene expression by siRNA resulted in alleviation of the prolongation of neuropathic pain induced by morphine treatment in a mouse CCI neuropathic pain model [22]. Mechanistically, they found that NLRP3 was primarily distributed in microglia of spinal cord dorsal horn (Table 1). Selective silencing spinal microglia via chemogenetic approaches prevented and persistently reversed morphine-induced prolongation of neuropathic pain [22].

In addition to spinal cord, recent studies identified significant activation of NLRP3 inflammasome in prefrontal cortex (PFC), dorsal raphe nucleus (DRN), and peripheral blood of morphine- or fentanyl-induced analgesic tolerance and hyperalgesia model animals [23, 24]. NLRP3 expression was primarily upregulated in astrocytes and serotonergic neurons in DRN following morphine or fentanyl treatment (Table 1). MCC950 delayed morphine and fentanyl analgesic tolerance and prevented fentanyl-induced hyperalgesia (Table 2) [24]. Besides, morphine-induced analgesic tolerance and hyperalgesia are abolished in Nlrp3 gene knockout mice. Mechanistic studies further revealed that prolonged morphine treatment induced the production of ROS, which triggers NLRP3 inflammasome activation in microglia in PFC (Table 1) [23], suggesting a critical contribution of ROS-mediated NLRP3 inflammasome activation in microglia to the maintenance of morphine-induced analgesic tolerance and hyperalgesia. Therefore, counteracting ROS by antioxidants or with NLRP3 antagonist may provide novel targets for preventing the development of opioid analgesic tolerance and hyperalgesia.

Conclusions

In this review, we summarized the recent advances in our understanding of the involvement of NLRP3 inflammasome in chronic pain. Recently, mounting evidence suggest that NLRP3 inflammasome is activated in local tissues, peripheral sensory nerves and neurons, spinal cord, and brain regions of a variety of animal models of chronic pain. These regions are all related with pain signal initiation, transduction, integration, and perception (Fig. 1). Pharmacological studies using NLRP3 inflammasome antagonist or genetic approaches further confirmed the participation of NLRP3 inflammasome and its downstream signaling components in mediating chronic pain. Therefore, it has become more and more accepted that NLRP3 inflammasome plays an important role in the pathogenesis of chronic pain. Further preclinical and translational studies will be needed to evaluate the safety and effectiveness of drugs or approaches that specifically target against NLRP3 inflammasome in chronic pain treatment.

Availability of data and materials

Not applicable.

Abbreviations

IL-1β:

Interleukin 1β

LPS:

Lipopolysaccharide

NSAIDs:

Nonsteroidal anti-inflammatory drugs

PAMPs:

Pathogen associated molecular patterns

DAMPs:

Damage-associated molecular patterns

DRG:

Dorsal root ganglion

MSU:

Monosodium urate

TLRs:

Toll-like receptors

MyD88:

Myeloid differentiation primary response 88

TNFR:

Tumor necrosis factor receptor

NF-κB:

Nuclear factor kappa B

pSNL:

Partial sciatic nerve ligation

CCI:

Chronic constriction injury

CIPN:

Chemotherapy-induced peripheral neuropathy

CRPS-I:

Complex regional pain syndrome type-I

CPIP:

Chronic post-ischemic pain

SCDH:

Spinal cord dorsal horn

CNP:

Central neuropathic pain

SCI:

Spinal cord injury

RR-EAE:

Relapsing-remitting experimental encephalomyelitis

DBHB:

D-β-hydroxybutyrate

CFA:

Complete Freund’s adjuvant

EA:

Electroacupuncture

ROS:

Reactive oxygen species

TXNIP:

Thioredoxin-interacting protein

TRX:

Thioredoxin

CGRP:

Calcitonin gene-related peptide

NTG:

Nitroglycerin

TNC:

Trigeminal nucleus caudalis

CPPS:

Chronic pelvic pain syndrome

EAP:

Experimental autoimmune prostatitis

BCP:

Bone cancer pain

DRN:

Dorsal raphe nucleus

PFC:

Prefrontal cortex

References

  1. 1.

    Dahlhamer J, Lucas J, Zelaya C, Nahin R, Mackey S, DeBar L, et al. Prevalence of chronic pain and high-impact chronic pain among adults - United States, 2016. MMWR Morb Mortal Wkly Rep. 2018;67(36):1001–6. https://doi.org/10.15585/mmwr.mm6736a2.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Dydyk AM, Conermann T. Chronic pain. Treasure Island (FL): In StatPearls; 2020.

    Google Scholar 

  3. 3.

    Jiang BC, Liu T, Gao YJ. Chemokines in chronic pain: cellular and molecular mechanisms and therapeutic potential. Pharmacol Ther. 2020;212:107581. https://doi.org/10.1016/j.pharmthera.2020.107581.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Ji RR, Xu ZZ, Gao YJ. Emerging targets in neuroinflammation-driven chronic pain. Nat Rev Drug Discov. 2014;13(7):533–48. https://doi.org/10.1038/nrd4334.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Ji RR, Chamessian A, Zhang YQ. Pain regulation by non-neuronal cells and inflammation. Science. 2016;354(6312):572–7. https://doi.org/10.1126/science.aaf8924.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Binshtok AM, Wang H, Zimmermann K, Amaya F, Vardeh D, Shi L, et al. Nociceptors are interleukin-1beta sensors. J Neurosci. 2008;28(52):14062–73. https://doi.org/10.1523/JNEUROSCI.3795-08.2008.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Safieh-Garabedian B, Poole S, Allchorne A, Winter J, Woolf CJ. Contribution of interleukin-1 beta to the inflammation-induced increase in nerve growth factor levels and inflammatory hyperalgesia. Br J Pharmacol. 1995;115(7):1265–75. https://doi.org/10.1111/j.1476-5381.1995.tb15035.x.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Helyes Z, Tekus V, Szentes N, Pohoczky K, Botz B, Kiss T, et al. Transfer of complex regional pain syndrome to mice via human autoantibodies is mediated by interleukin-1-induced mechanisms. Proc Natl Acad Sci U S A. 2019;116(26):13067–76. https://doi.org/10.1073/pnas.1820168116.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Li T, Chen X, Zhang C, Zhang Y, Yao W. An update on reactive astrocytes in chronic pain. J Neuroinflammation. 2019;16(1):140. https://doi.org/10.1186/s12974-019-1524-2.

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Alexander SPH, Kelly E, Mathie A, Peters JA, Veale EL, Armstrong JF, et al. THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Introduction and Other Protein Targets. Br J Pharmacol. 2019;176(Suppl 1):S1–S20.

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    O'Brien WT, Pham L, Symons GF, Monif M, Shultz SR, McDonald SJ. The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target. J Neuroinflammation. 2020;17(1):104. https://doi.org/10.1186/s12974-020-01778-5.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Zhang T, Fang Z, Linghu KG, Liu J, Gan L, Lin L. Small molecule-driven SIRT3-autophagy-mediated NLRP3 inflammasome inhibition ameliorates inflammatory crosstalk between macrophages and adipocytes. Br J Pharmacol. 2020;177(20):4645–65. https://doi.org/10.1111/bph.15215.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Nakamura Y, Kambe N, Saito M, Nishikomori R, Kim YG, Murakami M, et al. Mast cells mediate neutrophil recruitment and vascular leakage through the NLRP3 inflammasome in histamine-independent urticaria. J Exp Med. 2009;206(5):1037–46. https://doi.org/10.1084/jem.20082179.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Goldberg EL, Asher JL, Molony RD, Shaw AC, Zeiss CJ, Wang C, et al. Dixit VD: beta-hydroxybutyrate deactivates neutrophil NLRP3 inflammasome to relieve gout flares. Cell Rep. 2017;18(9):2077–87. https://doi.org/10.1016/j.celrep.2017.02.004.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Chen SP, Zhou YQ, Wang XM, Sun J, Cao F, HaiSam S, et al. Pharmacological inhibition of the NLRP3 inflammasome as a potential target for cancer-induced bone pain. Pharmacol Res. 2019;147:104339. https://doi.org/10.1016/j.phrs.2019.104339.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Roh JS, Sohn DH. Damage-associated molecular patterns in inflammatory diseases. Immune Netw. 2018;18(4):e27. https://doi.org/10.4110/in.2018.18.e27.

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Gong T, Yang Y, Jin T, Jiang W, Zhou R. Orchestration of NLRP3 inflammasome activation by ion fluxes. Trends Immunol. 2018;39(5):393–406. https://doi.org/10.1016/j.it.2018.01.009.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440(7081):237–41. https://doi.org/10.1038/nature04516.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Reber LL, Marichal T, Sokolove J, Starkl P, Gaudenzio N, Iwakura Y, et al. Contribution of mast cell-derived interleukin-1beta to uric acid crystal-induced acute arthritis in mice. Arthritis Rheumatol. 2014;66(10):2881–91. https://doi.org/10.1002/art.38747.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Jia M, Wu C, Gao F, Xiang H, Sun N, Peng P, et al. Activation of NLRP3 inflammasome in peripheral nerve contributes to paclitaxel-induced neuropathic pain. Mol Pain. 2017;13:1744806917719804.

    CAS  Article  Google Scholar 

  21. 21.

    Liu CC, Huang ZX, Li X, Shen KF, Liu M, Ouyang HD, et al. Upregulation of NLRP3 via STAT3-dependent histone acetylation contributes to painful neuropathy induced by bortezomib. Exp Neurol. 2018;302:104–11. https://doi.org/10.1016/j.expneurol.2018.01.011.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Grace PM, Strand KA, Galer EL, Urban DJ, Wang X, Baratta MV, et al. Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation. Proc Natl Acad Sci U S A. 2016;113(24):E3441–50. https://doi.org/10.1073/pnas.1602070113.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Liu Q, Su LY, Sun C, Jiao L, Miao Y, Xu M, et al. Melatonin alleviates morphine analgesic tolerance in mice by decreasing NLRP3 inflammasome activation. Redox Biol. 2020;34:101560. https://doi.org/10.1016/j.redox.2020.101560.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Carranza-Aguilar CJ, Hernandez-Mendoza A, Mejias-Aponte C, Rice KC, Morales M, Gonzalez-Espinosa C, et al. Morphine and fentanyl repeated administration induces different levels of NLRP3-dependent pyroptosis in the dorsal raphe nucleus of male rats via cell-specific activation of TLR4 and opioid receptors. Cell Mol Neurobiol. 2020. https://doi.org/10.1007/s10571-020-00957-5.

  25. 25.

    He Y, Hara H, Nunez G. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem Sci. 2016;41(12):1012–21. https://doi.org/10.1016/j.tibs.2016.09.002.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Shao BZ, Xu ZQ, Han BZ, Su DF, Liu C. NLRP3 inflammasome and its inhibitors: a review. Front Pharmacol. 2015;6:262.

    Article  Google Scholar 

  27. 27.

    Zhang H, Li F, Li WW, Stary C, Clark JD, Xu S, et al. The inflammasome as a target for pain therapy. Br J Anaesth. 2016;117(6):693–707. https://doi.org/10.1093/bja/aew376.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Coll RC, Robertson AA, Chae JJ, Higgins SC, Munoz-Planillo R, Inserra MC, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015;21(3):248–55. https://doi.org/10.1038/nm.3806.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Tapia-Abellan A, Angosto-Bazarra D, Martinez-Banaclocha H, de Torre-Minguela C, Ceron-Carrasco JP, Perez-Sanchez H, et al. MCC950 closes the active conformation of NLRP3 to an inactive state. Nat Chem Biol. 2019;15(6):560–4. https://doi.org/10.1038/s41589-019-0278-6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Wahlman C, Doyle TM, Little JW, Luongo L, Janes K, Chen Z, et al. Chemotherapy-induced pain is promoted by enhanced spinal adenosine kinase levels through astrocyte-dependent mechanisms. Pain. 2018;159(6):1025–34. https://doi.org/10.1097/j.pain.0000000000001177.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Chen R, Yin C, Hu Q, Liu B, Tai Y, Zheng X, et al. Expression profiling of spinal cord dorsal horn in a rat model of complex regional pain syndrome type-I uncovers potential mechanisms mediating pain and neuroinflammation responses. J Neuroinflammation. 2020;17(1):162. https://doi.org/10.1186/s12974-020-01834-0.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Khan N, Kuo A, Brockman DA, Cooper MA, Smith MT. Pharmacological inhibition of the NLRP3 inflammasome as a potential target for multiple sclerosis induced central neuropathic pain. Inflammopharmacology. 2018;26(1):77–86. https://doi.org/10.1007/s10787-017-0401-9.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Huang J, Gandini MA, Chen L, M'Dahoma S, Stemkowski PL, Chung H, et al. Hyperactivity of innate immunity triggers pain via TLR2-IL-33-mediated neuroimmune crosstalk. Cell Rep. 2020;33(1):108233. https://doi.org/10.1016/j.celrep.2020.108233.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    He W, Long T, Pan Q, Zhang S, Zhang Y, Zhang D, et al. Microglial NLRP3 inflammasome activation mediates IL-1β release and contributes to central sensitization in a recurrent nitroglycerin-induced migraine model. J Neuroinflammation. 2019;16(1):78. https://doi.org/10.1186/s12974-019-1459-7.

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Zhang LG, Chen J, Meng JL, Zhang Y, Liu Y, Zhan CS, et al. Effect of alcohol on chronic pelvic pain and prostatic inflammation in a mouse model of experimental autoimmune prostatitis. Prostate. 2019;79(12):1439–49. https://doi.org/10.1002/pros.23866.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Widerström-Noga E. Neuropathic pain and spinal cord injury: phenotypes and pharmacological management. Drugs. 2017;77(9):967–84. https://doi.org/10.1007/s40265-017-0747-8.

    Article  PubMed  Google Scholar 

  37. 37.

    Donnelly CR, Chen O, Ji RR. How do sensory neurons sense danger signals? Trends Neurosci. 2020;43(10):822–38. https://doi.org/10.1016/j.tins.2020.07.008.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Liu S, Mi WL, Li Q, Zhang MT, Han P, Hu S, et al. Spinal IL-33/ST2 signaling contributes to neuropathic pain via neuronal CaMKII-CREB and astroglial JAK2-STAT3 cascades in mice. Anesthesiology. 2015;123(5):1154–69. https://doi.org/10.1097/ALN.0000000000000850.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Pan Z, Shan Q, Gu P, Wang XM, Tai LW, Sun M, et al. Cheung CW: miRNA-23a/CXCR4 regulates neuropathic pain via directly targeting TXNIP/NLRP3 inflammasome axis. Journal of neuroinflammation. 2018;15(1):29. https://doi.org/10.1186/s12974-018-1073-0.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Gao F, Xiang HC, Li HP, Jia M, Pan XL, Pan HL, et al. Electroacupuncture inhibits NLRP3 inflammasome activation through CB2 receptors in inflammatory pain. Brain Behav Immun. 2018;67:91–100. https://doi.org/10.1016/j.bbi.2017.08.004.

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Yoshida S, Hagiwara Y, Tsuchiya M, Shinoda M, Koide M, Hatakeyama H, et al. Involvement of inflammasome activation via elevation of uric acid level in nociception in a mouse model of muscle pain. Mol Pain. 2019;15:1744806919858797.

    CAS  Article  Google Scholar 

  42. 42.

    Xu L, Wang Q, Jiang W, Yu S, Zhang S. MiR-34c ameliorates neuropathic pain by targeting NLRP3 in a mouse model of chronic constriction injury. Neuroscience. 2019;399:125–34. https://doi.org/10.1016/j.neuroscience.2018.12.030.

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Tonkin RS, Bowles C, Perera CJ, Keating BA, Makker PGS, Duffy SS, et al. Attenuation of mechanical pain hypersensitivity by treatment with Peptide5, a connexin-43 mimetic peptide, involves inhibition of NLRP3 inflammasome in nerve-injured mice. Experimental neurology. 2018;300:1–12. https://doi.org/10.1016/j.expneurol.2017.10.016.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Banach M, Juranek JK, Zygulska AL. Chemotherapy-induced neuropathies-a growing problem for patients and health care providers. Brain Behav. 2017;7(1):e00558. https://doi.org/10.1002/brb3.558.

    Article  PubMed  Google Scholar 

  45. 45.

    Flatters SJL, Dougherty PM, Colvin LA. Clinical and preclinical perspectives on chemotherapy-induced peripheral neuropathy (CIPN): a narrative review. Br J Anaesth. 2017;119(4):737–49. https://doi.org/10.1093/bja/aex229.

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Urits I, Shen AH, Jones MR, Viswanath O, Kaye AD. Complex regional pain syndrome, current concepts and treatment options. Curr Pain Headache Rep. 2018;22(2):10. https://doi.org/10.1007/s11916-018-0667-7.

    Article  PubMed  Google Scholar 

  47. 47.

    Bruehl S. An update on the pathophysiology of complex regional pain syndrome. Anesthesiology. 2010;113(3):713–25. https://doi.org/10.1097/ALN.0b013e3181e3db38.

    Article  PubMed  Google Scholar 

  48. 48.

    Hu Q, Zheng X, Li X, Liu B, Yin C, Li Y, et al. Electroacupuncture alleviates mechanical allodynia in a rat model of complex regional pain syndrome type-I via suppressing spinal CXCL12/CXCR4 signaling. J Pain. 2020;21(9-10):1060–74. https://doi.org/10.1016/j.jpain.2020.01.007.

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Coderre TJ, Xanthos DN, Francis L, Bennett GJ. Chronic post-ischemia pain (CPIP): a novel animal model of complex regional pain syndrome-type I (CRPS-I; reflex sympathetic dystrophy) produced by prolonged hindpaw ischemia and reperfusion in the rat. Pain. 2004;112(1):94–105. https://doi.org/10.1016/j.pain.2004.08.001.

    Article  PubMed  Google Scholar 

  50. 50.

    Hu Q, Zheng X, Chen R, Liu B, Tai Y, Shao X, et al. Chronic post-ischemia pain model for complex regional pain syndrome type-I in rats. J Vis Exp. 2020;(155). https://doi.org/10.3791/60562.

  51. 51.

    Wang J, Zheng X, Liu B, Yin C, Chen R, Li X, et al. Electroacupuncture alleviates mechanical allodynia of a rat model of CRPS-I and modulates gene expression profiles in dorsal root ganglia. Front Neurol. 2020;11:580997. https://doi.org/10.3389/fneur.2020.580997.

    Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Yin C, Hu Q, Liu B, Tai Y, Zheng X, Li Y, et al. Transcriptome profiling of dorsal root ganglia in a rat model of complex regional pain syndrome type-I reveals potential mechanisms involved in pain. J Pain Res. 2019;12:1201–16. https://doi.org/10.2147/JPR.S188758.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Tang Y, Liu L, Xu D, Zhang W, Zhang Y, Zhou J, et al. Interaction between astrocytic colony stimulating factor and its receptor on microglia mediates central sensitization and behavioral hypersensitivity in chronic post ischemic pain model. Brain Behav Immun. 2018;68:248–60. https://doi.org/10.1016/j.bbi.2017.10.023.

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Hu Q, Wang Q, Wang C, Tai Y, Liu B, Shao X, et al. TRPV1 Channel contributes to the behavioral hypersensitivity in a rat model of complex regional pain syndrome type 1. Front Pharmacol. 2019;10:453. https://doi.org/10.3389/fphar.2019.00453.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Watson JC, Sandroni P. Central neuropathic pain syndromes. Mayo Clin Proc. 2016;91(3):372–85. https://doi.org/10.1016/j.mayocp.2016.01.017.

    Article  PubMed  Google Scholar 

  56. 56.

    Qian J, Zhu W, Lu M, Ni B, Yang J. D-beta-hydroxybutyrate promotes functional recovery and relieves pain hypersensitivity in mice with spinal cord injury. Br J Pharmacol. 2017;174(13):1961–71. https://doi.org/10.1111/bph.13788.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015;21(3):263–9. https://doi.org/10.1038/nm.3804.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Liu BY. Zhang HL: [Bradykinin modulates ion channel in inflammatory pain]. Yao Xue Xue Bao. 2009;44(10):1066–71.

    CAS  PubMed  Google Scholar 

  59. 59.

    Liu B, Linley JE, Du X, Zhang X, Ooi L, Zhang H, et al. The acute nociceptive signals induced by bradykinin in rat sensory neurons are mediated by inhibition of M-type K+ channels and activation of Ca2 + -activated Cl- channels. J Clin Invest. 2010;120(4):1240–52. https://doi.org/10.1172/JCI41084.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Zheng X, Tai Y, He D, Liu B, Wang C, Shao X, et al. ETAR and protein kinase A pathway mediate ET-1 sensitization of TRPA1 channel: a molecular mechanism of ET-1-induced mechanical hyperalgesia. Mol Pain. 2019;15:1744806919842473.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Calil IL, Zarpelon AC, Guerrero AT, Alves-Filho JC, Ferreira SH, Cunha FQ, et al. Lipopolysaccharide induces inflammatory hyperalgesia triggering a TLR4/MyD88-dependent cytokine cascade in the mice paw. PLoS One. 2014;9(3):e90013. https://doi.org/10.1371/journal.pone.0090013.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Lieberthal J, Sambamurthy N, Scanzello CR. Inflammation in joint injury and post-traumatic osteoarthritis. Osteoarthritis Cartilage. 2015;23(11):1825–34. https://doi.org/10.1016/j.joca.2015.08.015.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Yu ML, Wei RD, Zhang T, Wang JM, Cheng Y, Qin FF, et al. Electroacupuncture relieves pain and attenuates inflammation progression through inducing IL-10 production in CFA-induced mice. Inflammation. 2020;43(4):1233–45. https://doi.org/10.1007/s10753-020-01203-2.

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Yu S, Zhao G, Han F, Liang W, Jiao Y, Li Z, et al. Muscone relieves inflammatory pain by inhibiting microglial activation-mediated inflammatory response via abrogation of the NOX4/JAK2-STAT3 pathway and NLRP3 inflammasome. Int Immunopharmacol. 2020;82:106355. https://doi.org/10.1016/j.intimp.2020.106355.

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Fattori V, Hohmann MSN, Rossaneis AC, Manchope MF, Alves-Filho JC, Cunha TM, et al. Targeting IL-33/ST2 signaling: regulation of immune function and analgesia. Expert Opin Ther Targets. 2017;21(12):1141–52. https://doi.org/10.1080/14728222.2017.1398734.

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Yin C, Liu B, Li Y, Li X, Wang J, Chen R, et al. IL-33/ST2 induces neutrophil-dependent reactive oxygen species production and mediates gout pain. Theranostics. 2020;10(26):12189–203. https://doi.org/10.7150/thno.48028.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Rees F, Hui M, Doherty M. Optimizing current treatment of gout. Nat Rev Rheumatol. 2014;10(5):271–83. https://doi.org/10.1038/nrrheum.2014.32.

    CAS  Article  PubMed  Google Scholar 

  68. 68.

    Safiri S, Kolahi AA, Cross M, Carson-Chahhoud K, Hoy D, Almasi-Hashiani A, et al. Prevalence, incidence, and years lived with disability due to gout and its attributable risk factors for 195 countries and territories 1990-2017: a systematic analysis of the global burden of disease study 2017. Arthritis Rheumatol. 2020. Online ahead of print.

  69. 69.

    Szekanecz Z, Szamosi S, Kovacs GE, Kocsis E, Benko S. The NLRP3 inflammasome - interleukin 1 pathway as a therapeutic target in gout. Arch Biochem Biophys. 2019;670:82–93. https://doi.org/10.1016/j.abb.2019.01.031.

    CAS  Article  PubMed  Google Scholar 

  70. 70.

    Mariotte A, De Cauwer A, Po C, Abou-Faycal C, Pichot A, Paul N, et al. A mouse model of MSU-induced acute inflammation in vivo suggests imiquimod-dependent targeting of Il-1beta as relevant therapy for gout patients. Theranostics. 2020;10(5):2158–71. https://doi.org/10.7150/thno.40650.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Chen CJ, Shi Y, Hearn A, Fitzgerald K, Golenbock D, Reed G, et al. MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals. J Clin Invest. 2006;116(8):2262–71. https://doi.org/10.1172/JCI28075.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72.

    So A, De Smedt T, Revaz S, Tschopp J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther. 2007;9(2):R28. https://doi.org/10.1186/ar2143.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Torres R, Macdonald L, Croll SD, Reinhardt J, Dore A, Stevens S, et al. Hyperalgesia, synovitis and multiple biomarkers of inflammation are suppressed by interleukin 1 inhibition in a novel animal model of gouty arthritis. Ann Rheum Dis. 2009;68(10):1602–8. https://doi.org/10.1136/ard.2009.109355.

    CAS  Article  PubMed  Google Scholar 

  74. 74.

    Amaral FA, Costa VV, Tavares LD, Sachs D, Coelho FM, Fagundes CT, et al. NLRP3 inflammasome-mediated neutrophil recruitment and hypernociception depend on leukotriene B(4) in a murine model of gout. Arthritis Rheum. 2012;64(2):474–84. https://doi.org/10.1002/art.33355.

    CAS  Article  PubMed  Google Scholar 

  75. 75.

    Yin C, Liu B, Wang P, Li X, Li Y, Zheng X, et al. Eucalyptol alleviates inflammation and pain responses in a mouse model of gout arthritis. Br J Pharmacol. 2020;177(9):2042–57. https://doi.org/10.1111/bph.14967.

  76. 76.

    Trevisan G, Hoffmeister C, Rossato MF, Oliveira SM, Silva MA, Silva CR, et al. TRPA1 receptor stimulation by hydrogen peroxide is critical to trigger hyperalgesia and inflammation in a model of acute gout. Free Radic Biol Med. 2014;72:200–9. https://doi.org/10.1016/j.freeradbiomed.2014.04.021.

    CAS  Article  PubMed  Google Scholar 

  77. 77.

    Trevisan G, Hoffmeister C, Rossato MF, Oliveira SM, Silva MA, Ineu RP, et al. Transient receptor potential ankyrin 1 receptor stimulation by hydrogen peroxide is critical to trigger pain during monosodium urate-induced inflammation in rodents. Arthritis Rheum. 2013;65(11):2984–95. https://doi.org/10.1002/art.38112.

    CAS  Article  PubMed  Google Scholar 

  78. 78.

    Tschopp J, Schroder K. NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production? Nat Rev Immunol. 2010;10(3):210–5. https://doi.org/10.1038/nri2725.

    CAS  Article  PubMed  Google Scholar 

  79. 79.

    Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol. 2010;11(2):136–40. https://doi.org/10.1038/ni.1831.

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Chapman CR, Vierck CJ. The transition of acute postoperative pain to chronic pain: an integrative overview of research on mechanisms. J Pain. 2017;18(359):e351–9 e338.

    Google Scholar 

  81. 81.

    Ghasemlou N, Chiu IM, Julien JP, Woolf CJ. CD11b + Ly6G- myeloid cells mediate mechanical inflammatory pain hypersensitivity. Proc Natl Acad Sci U S A. 2015;112(49):E6808–17. https://doi.org/10.1073/pnas.1501372112.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Cowie AM, Menzel AD, O'Hara C, Lawlor MW, Stucky CL. NOD-like receptor protein 3 inflammasome drives postoperative mechanical pain in a sex-dependent manner. Pain. 2019;160(8):1794–816. https://doi.org/10.1097/j.pain.0000000000001555.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Wolf G, Livshits D, Beilin B, Yirmiya R, Shavit Y. Interleukin-1 signaling is required for induction and maintenance of postoperative incisional pain: genetic and pharmacological studies in mice. Brain Behav Immun. 2008;22(7):1072–7. https://doi.org/10.1016/j.bbi.2008.03.005.

    CAS  Article  PubMed  Google Scholar 

  84. 84.

    Hu Y, Liang D, Li X, Liu HH, Zhang X, Zheng M, et al. The role of interleukin-1 in wound biology. Part I: Murine in silico and in vitro experimental analysis. Anesth Analg. 2010;111(6):1525–33. https://doi.org/10.1213/ANE.0b013e3181f5ef5a.

    CAS  Article  PubMed  Google Scholar 

  85. 85.

    Hu Y, Liang D, Li X, Liu HH, Zhang X, Zheng M, et al. The role of interleukin-1 in wound biology. Part II: In vivo and human translational studies. Anesth Analg. 2010;111(6):1534–42. https://doi.org/10.1213/ANE.0b013e3181f691eb.

    CAS  Article  PubMed  Google Scholar 

  86. 86.

    Rohde C, Chiang A, Adipoju O, Casper D, Pilla AA. Effects of pulsed electromagnetic fields on interleukin-1 beta and postoperative pain: a double-blind, placebo-controlled, pilot study in breast reduction patients. Plast Reconstr Surg. 2010;125(6):1620–9. https://doi.org/10.1097/PRS.0b013e3181c9f6d3.

    CAS  Article  PubMed  Google Scholar 

  87. 87.

    Cowie AM, Dittel BN, Stucky CL. A novel sex-dependent target for the treatment of postoperative pain: the NLRP3 inflammasome. Front Neurol. 2019;10:622. https://doi.org/10.3389/fneur.2019.00622.

    Article  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Yoshida S, Hagiwara Y, Tsuchiya M, Shinoda M, Koide M, Hatakeyama H, et al. Involvement of neutrophils and interleukin-18 in nociception in a mouse model of muscle pain. Mol Pain. 2018;14:1744806918757286.

    CAS  Article  Google Scholar 

  89. 89.

    Sarzi-Puttini P, Giorgi V, Marotto D, Atzeni F. Fibromyalgia: an update on clinical characteristics, aetiopathogenesis and treatment. Nat Rev Rheumatol. 2020;16(11):645–60. https://doi.org/10.1038/s41584-020-00506-w.

    Article  PubMed  Google Scholar 

  90. 90.

    Littlejohn G. Neurogenic neuroinflammation in fibromyalgia and complex regional pain syndrome. Nat Rev Rheumatol. 2015;11(11):639–48. https://doi.org/10.1038/nrrheum.2015.100.

    CAS  Article  PubMed  Google Scholar 

  91. 91.

    Balsom PD, Seger JY, Sjodin B, Ekblom B. Physiological responses to maximal intensity intermittent exercise. Eur J Appl Physiol Occup Physiol. 1992;65(2):144–9. https://doi.org/10.1007/BF00705072.

    CAS  Article  PubMed  Google Scholar 

  92. 92.

    Goadsby PJ, Holland PR. An update: pathophysiology of migraine. Neurol Clin. 2019;37(4):651–71. https://doi.org/10.1016/j.ncl.2019.07.008.

    Article  PubMed  Google Scholar 

  93. 93.

    May A, Schulte LH. Chronic migraine: risk factors, mechanisms and treatment. Nat Rev Neurol. 2016;12(8):455–64. https://doi.org/10.1038/nrneurol.2016.93.

    CAS  Article  PubMed  Google Scholar 

  94. 94.

    Yucel M, Kotan D, Gurol Ciftci G, Ciftci IH, Cikriklar HI. Serum levels of endocan, claudin-5 and cytokines in migraine. Eur Rev Med Pharmacol Sci. 2016;20(5):930–6.

    CAS  PubMed  Google Scholar 

  95. 95.

    Han D. Association of serum levels of calcitonin gene-related peptide and cytokines during migraine attacks. Ann Indian Acad Neurol. 2019;22(3):277–81. https://doi.org/10.4103/aian.AIAN_371_18.

    Article  PubMed  PubMed Central  Google Scholar 

  96. 96.

    de Vries T, Villalon CM, MaassenVanDenBrink A. Pharmacological treatment of migraine: CGRP and 5-HT beyond the triptans. Pharmacol Ther. 2020;211:107528. https://doi.org/10.1016/j.pharmthera.2020.107528.

    CAS  Article  PubMed  Google Scholar 

  97. 97.

    Marone IM, De Logu F, Nassini R, De Carvalho GM, Benemei S, Ferreira J, et al. TRPA1/NOX in the soma of trigeminal ganglion neurons mediates migraine-related pain of glyceryl trinitrate in mice. Brain. 2018;141(8):2312–28. https://doi.org/10.1093/brain/awy177.

    Article  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Haanes KA, Edvinsson L. Pathophysiological mechanisms in migraine and the identification of new therapeutic targets. CNS Drugs. 2019;33(6):525–37. https://doi.org/10.1007/s40263-019-00630-6.

    CAS  Article  PubMed  Google Scholar 

  99. 99.

    Liu Y, Mikrani R, Xie D, Wazir J, Shrestha S, Ullah R, et al. Chronic prostatitis/chronic pelvic pain syndrome and prostate cancer: study of immune cells and cytokines. Fundam Clin Pharmacol. 2020;34(2):160–72. https://doi.org/10.1111/fcp.12517.

    CAS  Article  PubMed  Google Scholar 

  100. 100.

    Polackwich AS, Shoskes DA. Chronic prostatitis/chronic pelvic pain syndrome: a review of evaluation and therapy. Prostate Cancer Prostatic Dis. 2016;19(2):132–8. https://doi.org/10.1038/pcan.2016.8.

    CAS  Article  PubMed  Google Scholar 

  101. 101.

    Zhang Z, Li Z, Yu Q, Wu C, Lu Z, Zhu F, et al. The prevalence of and risk factors for prostatitis-like symptoms and its relation to erectile dysfunction in Chinese men. Andrology. 2015;3(6):1119–24. https://doi.org/10.1111/andr.12104.

    CAS  Article  PubMed  Google Scholar 

  102. 102.

    Falk S, Dickenson AH. Pain and nociception: mechanisms of cancer-induced bone pain. J Clin Oncol. 2014;32(16):1647–54. https://doi.org/10.1200/JCO.2013.51.7219.

    CAS  Article  Google Scholar 

  103. 103.

    Kane CM, Hoskin P, Bennett MI. Cancer induced bone pain. BMJ. 2015;350(jan29 7):h315. https://doi.org/10.1136/bmj.h315.

    Article  PubMed  Google Scholar 

  104. 104.

    Srikrishna G, Freeze HH. Endogenous damage-associated molecular pattern molecules at the crossroads of inflammation and cancer. Neoplasia. 2009;11(7):615–28. https://doi.org/10.1593/neo.09284.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Volkow ND, McLellan AT. Opioid abuse in chronic pain--misconceptions and mitigation strategies. N Engl J Med. 2016;374(13):1253–63. https://doi.org/10.1056/NEJMra1507771.

    CAS  Article  PubMed  Google Scholar 

  106. 106.

    Cai Y, Kong H, Pan YB, Jiang L, Pan XX, Hu L, et al. Procyanidins alleviates morphine tolerance by inhibiting activation of NLRP3 inflammasome in microglia. J Neuroinflammation. 2016;13(1):53. https://doi.org/10.1186/s12974-016-0520-z.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Wang H, Zhang Y, Ma X, Wang W, Xu X, Huang M, et al. Spinal TLR4/P2X7 receptor-dependent NLRP3 inflammasome activation contributes to the development of tolerance to morphine-induced antinociception. J Inflamm Res. 2020;13:571–82. https://doi.org/10.2147/JIR.S266995.

    Article  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Grace PM, Strand KA, Galer EL, Rice KC, Maier SF, Watkins LR. Protraction of neuropathic pain by morphine is mediated by spinal damage associated molecular patterns (DAMPs) in male rats. Brain Behav Immun. 2018;72:45–50. https://doi.org/10.1016/j.bbi.2017.08.018.

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This project was supported by National Natural Science Foundation of China (81873365), Zhejiang Provincial Natural Science Funds for Distinguished Young Scholars (LR17H270001), National Natural Science Foundation of China (81603676), and research funds from Zhejiang Chinese Medical University (Q2019J01) to B.L.

Author information

Affiliations

Authors

Contributions

B.L. and J.F. defined the research topic. R.C. performed document retrieval and wrote the first draft of the manuscript. C.Y. aided in figure design and document retrieval. B.L. and R.C. prepared the final draft of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jianqiao Fang or Boyi Liu.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chen, R., Yin, C., Fang, J. et al. The NLRP3 inflammasome: an emerging therapeutic target for chronic pain. J Neuroinflammation 18, 84 (2021). https://doi.org/10.1186/s12974-021-02131-0

Download citation

Keywords

  • NLRP3
  • Caspase-1
  • Inflammasome
  • Inflammation
  • Interleukins
  • Pain
\