The Emerging Role of Quercetin in the Treatment of Chronic Pain

Abstract

Despite much research efforts being devoted to designing alternative pharmacological interventions, chronic pain remains to be an unresolved clinical problem. Quercetin, a compound that belongs to the flavonoids family, is abundantly found in fruits and vegetables. Emerging evidence indicates that quercetin possesses anti-nociceptive effects in different rodent models of chronic pain, including inflammatory pain, neuropathic pain and cancer pain. In this review, we summarize the mechanisms underlying the analgesic effect of quercetin in preclinical studies. These studies showed that quercetin exerts potent analgesic effects against chronic pain via suppressing neuroinflammation and oxidative stress as well as modulation of synaptic plasticity, GABAergic system, and opioidergic system. Considering that the safety of quercetin is well established, it has great potential for clinical use in pain treatment.

1. INTRODUCTION

Chronic pain is pain that lasts more than several months, which significantly affects an individual’s quality of life [1, 2]. Currently, non-steroidal anti-inflammatory drugs (NSAIDs) and opioids remain to be the first-line analgesics for the management of chronic pain in the clinic [3, 4]. However, long-term use of NSAIDs and opioids inevitably causes unacceptable side effects. Despite much research efforts being devoted to designing alternative pharmacological interventions, chronic pain remains to be an unresolved clinical problem [5-7]. Therefore, novel therapeutic targets and strategies are urgently needed for the management of chronic pain.

Quercetin, a compound that belongs to the flavonoids family, is abundantly found in fruits and vegetables [8, 9]. It has been reported that quercetin may play a critical role in the prevention or treatment of various diseases, such as neurological diseases and cancers [10, 11]. Emerging evidence indicates that quercetin possesses anti-nociceptive effects in different rodent models of chronic pain, including inflammatory pain, neuropathic pain, and cancer pain [12-14]. Anjaneyulu et al. provided the first evidence that chronic treatment with quercetin significantly attenuated streptozotocin-induced thermal hyperalgesia and cold allodynia [15]. In a rat model of chronic constriction injury (CCI)-induced neuropathic pain, Civi et al. showed that the analgesic effect of quercetin was significantly superior to gabapentin and morphine [13]. Moreover, administration of quercetin dose-dependently alleviated thermal hyperalgesia and mechanical allodynia in paclitaxel-induced neuropathic pain mice via inhibiting the expression of protein kinase C epsilon isoform and transient receptor potential vanilloid 1cation channel in the spinal cords and DRG [16]. In another study, Li et al. demonstrated that chronic treatment with quercetin considerably ameliorated bone cancer pain via suppressing peripheral and central sensitization [12]. It has been reported that the sigma-1 receptor plays a critical role in the generation and maintenance of chronic pain [17, 18]. Recently, Espinosa-Juarez et al. demonstrated that the sigma-1 receptor antagonist potentiated the anti-nociceptive effect of quercetin in neuropathic pain induced by CCI [19]. As its safety is well established, quercetin has great potential for clinical use in pain treatment. In this review, we summarized and discussed the preclinical evidence demonstrating the therapeutic potential of quercetin in chronic pain.

2. EFFECT OF QUERCETIN ON NEUROINFLAMMATION IN CHRONIC PAIN

Neuroinflammation is characterized by activation of glial cells such as microglia and astrocytes, overproduction of proinflammatory cytokines and chemokines, and infiltration of immune cells in the peripheral and central nervous system (CNS) [20-22]. A great deal of evidence from our laboratory and others has demonstrated that neuroinflammation plays a vital role in chronic pain [22-24]. Recent evidence indicates that quercetin exerts neuroprotective effects via suppression of neuroinflammation in the CNS [25-27]. In a rat model of spared nerve injury (SNI)-induced neuropathic pain, Muto et al. demonstrated that oral administration of quercetin attenuated mechanical allodynia via inhibiting the activation of satellite glial cells in the ipsilateral L5 dorsal root ganglions (DRG) [28]. In another study, Yang et al. showed that chronic treatment with quercetin significantly ameliorated mechanical allodynia and thermal hyperalgesia in a rat model of diabetic neuropathic pain [29]. Moreover, they found that quercetin suppressed the upregulation of the P2X4 receptor and activation of satellite glial cells as well as the upregulation of phosphorylated p38 mitogen-activated protein kinase (MAPK) in the DRG of diabetic neuropathic pain rats. Recently, Ye et al. reported that administration of quercetin considerably attenuated CCI-induced neuropathic pain via suppressing the activation of microglia in the spinal cord [30]. Taken together, these results demonstrate that quercetin exerts analgesic effects against chronic pain via inhibiting the activation of glial cells in DRG and spinal cord.

It is well-established that glial cell activation releases proinflammatory cytokines and chemokines, which play a critical role in the development of chronic pain [31-33]. Valerio et al. reported that intraperitoneal and oral treatment with quercetin dose-dependently ameliorated formalin- and carrageenan-induced inflammatory pain by suppressing the production of interleukin 1beta (IL-1β) in the paw skin [34]. Moreover, they also found that quercetin inhibited the hyper-nociception induced by intra-plantar injection of tumor necrosis factor α (TNF-α) and CXCL1. In a mice model of cancer pain, Calixto-Campos et al. showed that quercetin significantly reduced Ehrlich tumor-induced mechanical allodynia and thermal hyperalgesia via inhibiting the production of TNF-α and IL-1β as well as neutrophil recruitment [35]. In another study, Ji et al. showed that single or continuous oral administration of quercetin significantly attenuated thermal and cold hyperalgesia in spinal nerve ligation (SNL)-induced neuropathic pain [36]. Moreover, they found that quercetin administration inhibited the upregulation of TNF-α and IL-1β in the DRG from SNL rats. Furthermore, quercetin decreased the phosphorylation of transforming growth factor-β-activated kinase, inhibitor of nuclear factor-κB-kinase, and c-Jun N-terminal kinase 2 in cultured astrocytes. Palmitoylethanolamide (PEA), a naturally-occurring fatty acid amide, is well-known for its analgesic and anti-inflammatory properties [37, 38]. Britti et al. investigated the analgesic effect of PEA co-ultramicronized with the quercetin (PEA-Q) on carrageenan-induced inflammatory pain and sodium monoiodoacetate (MIA)-induced osteoarthritis pain [14]. They found that intragastrical (i.g.) administration of PEA-Q 30 minutes before carrageenan injection significantly improved thermal hyperalgesia and reduced activity of myeloperoxidase (MPO), a marker of inflammatory cell infiltration. Moreover, PEA-Q treatment also considerably alleviated mechanical allodynia and thermal hyperalgesia in MIA-treated rats by counteracting the increased serum levels of TNF-α, IL-1β, and nerve growth factor. These findings confirmed the analgesic and anti-inflammatory effects of the new composite PEA-Q in rodent inflammatory pain models. Moreover, Ruiz-Miyazawa et al. demonstrated that subcutaneous (s.c.) injection of quercetin markedly suppressed monosodium urate crystals (MSU)-induced mechanical hyperalgesia, leukocyte recruitment, activation of nuclear factor kappa B (NF-κB), and release of TNF-α and IL-1β [39]. Considering the pivotal role of the NLR family pyrin domain containing 3 (NLRP3) inflammasome-mediated neuroinflammation in chronic pain [40-42], they further determined the effect of quercetin on the activation of NLRP3 inflammasome. They found that quercetin treatment dramatically suppressed the upregulation of NLRP3, C-terminal caspase recruitment domain, and pro-caspase-1 in the knee joints after MSU injection. Their further study verified the analgesic effect of quercetin on titanium dioxide (TiO2)-induced arthritis pain [43]. In a rat model of CCI-induced neuropathic pain, Ye et al. reported that administration of quercetin for 21 days starting from 7 days after CCI surgery significantly improved the paw withdrawal threshold and paw withdrawal latency in response to von Frey filament stimuli in CCI rats, which was reversed by AMP-activated protein kinase (AMPK) inhibitor Compound C [30]. Moreover, they found that chronic treatment with quercetin not only reduced the inflammatory cells at the ligation site of the sciatic nerve, but also reduced the levels of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6. Furthermore, quercetin treatment inhibited the activation of mitogen-activated protein kinase (MAPK), which was reversed by AMPK inhibitor Compound C. These results demonstrated that quercetin may attenuate neuropathic pain via activation of AMPK and inhibition of MAPK signaling pathways. Taken together, these studies indicate that quercetin exerts analgesic effects against chronic pain via suppressing the release of proinflammatory cytokines and chemokines in DRG and spinal cord.

3. EFFECT OF QUERCETIN ON OXIDATIVE STRESS IN CHRONIC PAIN

Quercetin is widely used in traditional Chinese medicine due to its potent antioxidant activity [45, 45]. Valerio et al. reported that quercetin dose-dependently reversed the downregulation of glutathione (GSH) in the paw skin of formalin- and carrageenan-induced inflammatory pain mice [34]. Moreover, Raygude et al. demonstrated that chronic treatment with quercetin for 10 weeks significantly ameliorated mechanical allodynia and thermal hyperalgesia in ethanol-induced neuropathic pain rats [46]. Additionally, quercetin treatment considerably decreased elevated levels of malondialdehyde (MDA), a biomarker of oxidative stress, and oxidative stress-induced DNA fragmentation and upregulation of nitric oxide (NO) in ethanol-treated rats. It is important to note that physiological amounts of NO are neuroprotective, while higher concentrations are obviously neurotoxic [47]. Furthermore, the preconditioning signal leading to cellular protection through hormesis is an important redox-dependent aging-associated with free radicals species accumulation, and inflammatory responses involved in cellular survival mechanisms [48, 49]. Interestingly, bilirubin, a final product of heme metabolism, can serve as an endogenous scavenger of both NO and reactive nitrogen species [50, 51]. In a mouse model of oxaliplatin-induced neuropathic pain, Azevedo et al. showed that quercetin significantly attenuated mechanical allodynia and thermal hyperalgesia via suppressing lipid peroxidation and protein nitrosylation in the spinal cord [52]. In another study, Calixto-Campos et al. showed that quercetin attenuated Ehrlich tumor-induced cancer pain by improving the antioxidant defense system as evidenced by restoration of GSH levels, free-radical scavenging ability, and ferric-reducing ability potential (FRAP) [35]. Similarly, Ruiz-Miyazawa et al. demonstrated that administration of quercetin remarkably ameliorated MSU-induced mechanical hyperalgesia and improved the antioxidant defense system [39]. Moreover, quercetin inhibited the production of superoxide anions and upregulation of gp91phox after MSU injection. Their further study showed that chronic treatment with quercetin also significantly attenuated TiO2-induced mechanical hyperalgesia via similar mechanisms [43]. Previously, our laboratory has demonstrated that activation of nuclear factor erythroid-2-related factor 2 (Nrf2), a critical regulator of endogenous antioxidant defense, exerts potent analgesic effects on chronic pain [53-56]. Borghi et al. reported that quercetin treatment showed an analgesic effect via activation of the nuclear Nrf2/heme oxygenase-1 (HO-1) signaling pathway [43]. Taken together, quercetin may attenuate chronic pain by suppressing oxidative stress due to an improved antioxidant defense system.

4. EFFECT OF QUERCETIN ON SYNAPTIC PLASTICITY IN CHRONIC PAIN

A great deal of evidence indicates that synaptic plasticity is a key cellular mechanism for the development and maintenance of chronic pain [57, 58]. Wang et al. reported that administration of quercetin once daily for 8 weeks significantly alleviated thermal hyperalgesia in diabetic neuropathic pain mice [59]. Moreover, chronic quercetin treatment reduced the total dendritic length, the number of dendritic branches, and the dendritic spine density in the spinal cord dorsal horn neurons of diabetic neuropathic pain mice. Furthermore, they found that quercetin treatment inhibited the upregulation of synaptic plasticity associated proteins and the phosphorylated levels of mammalian target of rapamycin and p70 ribosomal S6 kinase in the spinal cord of diabetic neuropathic pain mice. These results indicate that quercetin alleviates diabetic neuropathic pain by inhibiting mTOR/p70S6K -mediated changes in synaptic morphology and synaptic plasticity-associated proteins in the spinal cord.

5. EFFECT OF QUERCETIN ON GABAERGIC SYSTEM IN CHRONIC PAIN

γ-aminobutyric acid (GABA) is a well-known inhibitory neurotransmitter in the CNS. Emerging evidence from our laboratory and others has demonstrated that loss of GABAergic inhibition contributes to the development and maintenance of chronic pain [33, 60-62]. Filho et al. demonstrated that quercetin dose-dependently ameliorated formalin- and capsaicin-induced inflammatory pain, which was significantly reversed by GABAA receptor antagonist or GABAB receptor antagonist [63]. However, the underlying mechanisms remain unclear. Nevertheless, a recent study showed that quercetin displayed good binding affinities with GABA receptor subunits such as A5, B1, and B2 [64]. Overall, these results indicate that quercetin may exert analgesic effects via restoring GABAergic inhibition.

6. EFFECT OF QUERCETIN ON THE OPIOIDERGIC SYSTEM IN CHRONIC PAIN

It is well-established that the endogenous opioid system has been implicated in chronic pain [65, 66]. In a mice model of diabetic neuropathic pain, Anjaneyulu et al. provided the first evidence that quercetin significantly attenuated thermal hyperalgesia, which was reversed by naloxone, an opioid receptor antagonist [67]. In another study, Calixto-Campos et al. reported that the analgesic effect of quercetin on Ehrlich tumor-induced cancer pain was reversed by naloxone [35]. Notably, co-administration of morphine and quercetin at doses that were ineffective as a single treatment attenuated Ehrlich tumor-induced cancer pain. Furthermore, Ruiz-Miyazawa et al. demonstrated that quercetin substantially attenuated MSU-induced mechanical hyperalgesia, which was blocked by pre-treatment with naloxone [39]. Moreover, the inhibitory effects of quercetin on both neuroinflammation and oxidative stress in MSU-injected mice were abolished by pre-treatment with naloxone. Taken together, these results demonstrated that quercetin possesses anti-nociceptive property, probably through modulation of the opioidergic mechanism.

CONCLUSION AND FUTURE PERSPECTIVE

In this review, we summarized and discussed the therapeutic potential of quercetin against chronic pain in preclinical studies (Table 1). These studies showed that quercetin exerts potent analgesic effects against chronic pain via suppressing neuroinflammation and oxidative stress as well as modulation of synaptic plasticity, GABAergic system, and opioidergic system (Fig. 1). However, these findings raise further questions.

Table 1.

Summary of therapeutic potential of quercetin in chronic pain.

Model	Treatment Strategy	Effects	Mechanisms	References
Carrageenan-induced inflammatory pain rats	PEA-Q (10 and 20 mg/kg, i.g.) was administered 30 min before carrageenan injection.	PWL↑	MPO↓	[8]
Formalin-induced inflammatory pain mice Capsaicin-induced inflammatory pain mice	Quercetin (10-60 mg/kg, i.p. or 100-500 mg/kg, i.g.) was administered on 30 minutes before formalin or capsaicin injection	PWL↑	Activation of GABAergic system Activation of 5-HT receptors	[21]
Formalin-induced inflammatory pain mice Carrageenan-induced inflammatory pain mice	Quercetin (3, 10, 30 and 100 mg/kg, i.p. or 30, 100 and 300 mg/kg, i.g.) was administered on 30 minutes before formalin or capsaicin injection	PWL↑	IL-1β↓ GSH↓	[60]
MSU-induced gout arthritis pain mice	Quercetin (10, 30 and 100 mg/kg, s.c.) was administered on 30 minutes before MSU injection.	PWT↑	Activation of opioidergic system Leukocyte recruitment↓ NF-κB, TNF-α, IL-1β↓ NLRP3, ASC, pro-caspase-1↓ GSH, FRAP, ABTS↑ Superoxide anion, gp91phox↓	[53]
TiO2-induced arthritis pain mice	Quercetin (10, 30 and 100 mg/kg, i.p.) was administered once daily for 30 days starting from the first day after TiO2 injection.	PWT↑	Leukocyte recruitment↓ Neutrophil recruitment↓ TNF-α, IL-1β, IL-6, COX2↓ GSH, FRAP, ABTS↑ Superoxide anion, gp91phox↓ Nrf2, HO-1↑	[7]
MIA-induced osteoarthritis pain rats	PEA-Q (10 and 20 mg/kg, i.g.) was administered three times per week for 21 days starting from the third day after MIA injection.	PWT↑ PWL↑	TNF-α, IL-1β, NGF↓ MMP1, MMP3, MMP9↓	[8]
CCI-induced neuropathic pain rats	Quercetin (100 mg/kg, i.p.) was administered at 21 days after CCI surgery. Quercetin (100 mg/kg, i.p.) was administered for 4 consecutive days before CCI surgery. Quercetin (100 mg/kg, i.p.) was administered for 4 consecutive days after CCI surgery.	PWT↑ PWL↑	/	[16]
CCI-induced neuropathic pain rats	Quercetin (30, 60 and 120 mg/kg, i.g.) was administered for 21 days starting from 7 days after CCI surgery.	PWT↑ PWL↑	Microglial activation↓ p-JNK, p-p38, p-ERK↓ TNF-α, IL-6, IL-1β↓	[65]
CCI-induced neuropathic pain rats	Quercetin (5.6, 17.8, 56.2, 177.8 and 316 mg/kg, s.c.) was administered on 10 days after CCI surgery.	PWT↑ PWL↑	/	[20]
SNL-induced neuropathic pain rats	A single administration of quercetin (100 mg/kg, i.g.) was performed on 14 days after SNL surgery. Quercetin (100 mg/kg, i.g.) was administered for 14 days starting from 0 day after SNL surgery. Quercetin (100 mg/kg, i.g.) was administered for 14 days before SNL surgery.	PWL↑	TNF-α, IL-1β↓ MMP-9, MMP-2, CCL2↓ NF-κB, TAK1, JNK2↓	[33]
SNI-induced neuropathic pain rats	MF diet containing 1% or 0.1% quercetin was given from 4 days before SNI surgery until sacrifice. MF diet containing 1% quercetin was given from 7 days after SNI surgery.	PWT↑	Activation of satellite glial cells↓ p-STAT3↓	[48]
STZ-induced diabetic neuropathic pain rats	Quercetin (10 mg/kg, i.g.) was administered for 4 weeks starting from 21 days after STZ-injection.	PWL↑	/	[2]
STZ-induced diabetic neuropathic pain rats	Quercetin (50 mg/kg, i.p.) was administered for 14 days starting from 7 days after STZ-injection.	PWT↑ PWL↑	Activation of satellite glial cells↓ P2X4 receptor↓ p38 MAPK↓	[64]
STZ-induced diabetic neuropathic pain mice	A single administration of quercetin (50 and 100 mg/kg, i.p.) was performed on 4 weeks after STZ injection.	PWL↑	Activation of opioidergic system	[1]
Diabetic neuropathic pain in db/db mice	Quercetin (50 and 100 mg/kg, i.g.) was administered once daily for 8 weeks.	PWL↑	Changes of synaptic morphology↓ PSD-95, synaptophysin↓ mTOR, p70S6K↓	[62]
Oxaliplatin-induced neuropathic pain mice	Quercetin (25, 50 and 100 mg/kg) was administered 30 minutes before every oxaliplatin injection.	PWT↑ PWL↑	MDA↓ Fos, nitrotyrosine, iNOS↓	[3]
Paclitaxel-induced neuropathic pain mice	Quercetin (20, and 60 mg/kg) was administered once daily starting from the first day after the first injection of paclitaxel for 40 days in rats. Quercetin (20, and 60 mg/kg) was administered once daily starting from the first day after the first injection of paclitaxel for 12 days in mice.	PWT↑ PWL↑	PKCε, TRPV1↓	[23]
Ethanol-induced neuropathic pain rats	Quercetin (10, 20 and 40 mg/kg, i.g.) was administered for 10 week starting from 1 hour before ethanol administration.	PWT↑ PWL↑	MDA, MPO, NO↓ DNA fragmentation↓	[51]
TCI-induced bone cancer pain mice	Quercetin (5, 10 and 20 mg/kg, i.g.) was administered once daily for 21 days starting from the first day after TCI.	PWT↑	TNF-α, IL-1β↓ RANKL, RANK, OPG↓ PAR2, TRPV1↓	[38]
Ehrlich tumor-induced cancer pain mice	Quercetin (10, 30 and 100 mg/kg, i.p.) was administered on 8 days after injection of tumor cells. Quercetin (10, 30 and 100 mg/kg, i.p.) was administered once daily for 12 days after injection of tumor cells.	PWT↑ PWL↑	Activation of opioidergic system Neutrophil recruitment↓ TNF-α, IL-1β↓ GSH, FRAP, ABTS↑	[12]

Abbreviations: ABTS: free radical scavenging ability; ASC: C-terminal caspase recruitment domain; CCI: chronic constriction injury; CCL2: C-C Motif chemokine ligand 2; COX-2: cyclooxygenase 2; DNA: deoxyribonucleic acid; ERK: extracellular regulated protein kinases; 5-HT: 5-hydroxytryptamine; FRAP: ferric reducing ability potential; GSH: glutathione; HO-1: heme oxygenase-1; IL-1β: interleukin 1beta; IL-6: interleukin 6; i.g.: intragastrically; iNOS: inducible nitric oxide synthase; i.p.: intraperitoneally; i.t.: intrathecally; JNK: c-Jun N-terminal kinase; MAPK: mitogen-activated protein kinase; MDA: malondialdehyde; MIA: monoiodoacetate; MPO: myeloperoxidase; MMP: matrix metallopeptidase; MSU: monosodium urate crystals; mTOR: mammalian target of rapamycin; NF-κB: nuclear factor kappa B; NGF: nerve growth factor; NO: nitric oxide; NLRP3: NLR family pyrin domain containing 3; Nrf2: nuclear factor erythroid-2-related factor 2; OPG: osteoprotegerin; PAR2: protease-activated receptor 2; PEA-Q: palmitoylethanolamide-quercetin; PI3K: phosphoinositide 3-kinase; PSD-95: postsynaptic density protein-95; p70S6K: 70 kDa ribosomal protein S6 kinase; PWL: paw withdrawal latency; PWT: paw withdrawal threshold; RANKL: receptor activator of nuclear factor-kappa B ligand; RANK: receptor activator of nuclear factor-kappa B; SNI: spared nerve injury; SNL: spinal nerve ligation; s.c.: subcutaneously; STAT3: signal transducer and activator of transcription 3; STZ: streptozotocin; TAK1: TGF-β activated kinase 1; TCI: tumor cell implantation; TiO₂: titanium dioxide; TNF-α: tumor necrosis factor α; TRPV1: transient receptor potential vanilloid 1; ↑: upregulated; ↓: downregulated.

Fig. (1).

The mechanisms underlying the analgesic effect of quercetin in preclinical studies. Abbreviations: GSH: glutathione; HO-1: heme oxygenase-1; IL-1β: interleukin 1β; IL-6: interleukin 6; MDA: malondialdehyde; NF-κB: nuclear factor kappa B; NLRP3: NLR family pyrin domain containing 3; Nrf2: nuclear factor erythroid-2-related factor 2; SGCs: satellite glial cells. TNF-α: tumor necrosis factor-α;

First of all, current studies indicate that the analgesic effects of quercetin rely on mechanisms in the peripheral nervous system and spinal cord. It has been reported that quercetin showed medium permeability across the blood-brain barrier [68]. Moreover, supraspinal mechanisms are of great importance to chronic pain [69, 70]. Therefore, whether quercetin exerts analgesic effects via supraspinal mechanisms needs further exploration.

Secondly, the evidence mentioned above is based on studies mostly using male rodents, although most patients with chronic pain are women. It is becoming increasingly clear that sex difference exists in pain processing [71, 72], highlighting the necessity of including subjects of both sexes in preclinical pain research. It would be interesting to investigate whether quercetin possesses a similar analgesic effect on chronic pain in female rodents.

Additionally, it is well-established that hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels play a critical role in chronic pain [73, 74]. Interestingly, Liang et al. demonstrated that quercetin remarkably left-shifted the voltage-dependent activation curves of HCN channels and decelerated the deactivation process [75]. These results indicate that quercetin might be a potent HCN channels blocker, which sheds light on the mechanism of the analgesic effects of quercetin.

Finally, despite the promising future of quercetin in chronic pain, few clinical trials are available. Nevertheless, it should be noted that supplementation with a mango leaf extract (Zynamite^®) in combination with quercetin attenuated muscle pain caused by exercise-induced muscle damage and accelerated the recovery of muscle performance in humans. Moreover, a randomized controlled trial reported that quercetin supplementation significantly improved the clinical symptoms in women with rheumatoid arthritis, including morning pain and after-activity pain. Overall, considering that the safety of quercetin is well established, it has great potential for clinical use in pain treatment.

LIST OF ABBREVIATIONS

AMPK

AMP-activated protein kinase

CCI

Chronic constriction injury

CNS

Central nervous system

DRG

Dorsal root ganglions

FRAP

Ferric-reducing ability potential

GABA

γ-aminobutyric acid

GSH

Glutathione

HCN

Hyperpolarization-activated cyclic-nucleotide-gated

HO-1

Heme oxygenase-1

IL-1β

Interleukin 1beta

MAPK

Mitogen-activated protein kinase

MDA

Malondialdehyde

MPO

Myeloperoxidase

MSU

Monosodium urate crystals

NF-κB

Nuclear factor kappa B

NLRP3

NLR family pyrin domain containing 3

NO

Nitric oxide

Nrf2

Nuclear factor erythroid-2-related factor 2

NSAIDs

Nonsteroidal anti-inflammatory drugs

PEA

Palmitoylethanolamide

SNI

Spared nerve injury

SNL

Spinal nerve ligation

TNF-α

Tumor necrosis factor α

TiO2

Titanium dioxide

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

This work was supported by grants from the National Natural Science Foundation of China 82001198, 82101310, 82071556, 81974170.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.