Compounds of Traditional Chinese Medicine and Neuropathic Pain

Available online at www.sciencedirect.com

Chinese Journal of Natural Medicines 2020, 18(1): 28–35 doi: 10.1016/S1875-5364(20)30002-9

Compounds of traditional Chinese medicine and neuropathic pain

LI Shun-Hua2Δ, LI Lin1,3Δ, YANG Ru-Nan1,3, LIANG Shang-Dong1,3, *

1 Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang 330006, China; 2 Undergraduate Student of Class 155 of Nanchang University Queen Marry University of London Joint Programme, Nanchang 330006, China; 3 Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang 330006, China Available online 20 Jan., 2020

[ABSTRACT] Neuropathic pain (NP) has become a serious global health issue and a huge clinical challenge without available effective treatment. P2 receptors family is involved in pain transmission and represents a promising target for pharmacological intervention. Traditional Chinese medicine (TCM) contains multiple components which are effective in targeting different pathological mechanisms involved in NP. Different from traditional analgesics, which target a single pathway, TCMs take the advantage of multiple components and multiple targets, and can significantly improve the efficacy of treatment and contribute to the prediction of the risks of NP. Compounds of TCM acting at nucleotide P2 receptors in neurons and glial cells could be considered as a potential research direction for moderating neuropathic pain. This review summarized the recently published data and highlighted several TCMs that relieved NP by acting at P2 receptors. [KEY WORDS] Traditional Chinese medicine; Diabetic neuropathic pain; HIV-gp120-associated neuropathic pain; Chronic constriction injury; Nucleotide receptors [CLC Number] R284, R965 [Document code] A [Article ID] 2095-6975(2020)01-0028-08

Introduction For all types of drugs, 20% to 40% of patients either experi- ence a less than 30% pain relief or have intolerable side ef- Neuropathic pain (NP) is defined as pain caused by a le- fects [5-7]. Therefore, developing novel compounds for the ef- sion or disease of the somatosensory system, belongs to fective management of NP with little influence on other nor- chronic pain. The typical symptoms of NP include spontan- mal physiological functions is necessary. eous pain, allodynia (pain response to normally innocuous Nucleotides of purinergic signaling were proposed as ex- stimuli), hyperpathia (abnormal pins-and-needles or electric- tracellular signaling molecules in 1972 [8]. Purinergic recep- shock-like sensations), and hyperalgesia (aggravated pain evoked by non-noxious stimuli) [1-3]. NP has become a seri- tors include P1 receptors and P2 receptors, which bind to ad- ous global health issue, with estimated prevalence rates ran- enosine-5′-triphosphate (ATP) and its analogues [adenosine- [9] ging from 1% to 8.9% of the total population [4]. Its long dur- 5′-diphosphate (ADP) and adenosine] respectively . Purino- ation reduces the quality of patients’ life and places a heavy ceptors are widely distributed in both the peripheral and burden on society. Although various drugs, including antide- central nervous systems (CNS), being present in neurons and [9-10] pressants, anti-epileptics, opioids, and topical anesthetics, are glia . To date, seven homomeric (P2X1, P2X2, P2X3, used for clinical treatment of NP, their side effects are marked, P2X4, P2X5, P2X6, and P2X7), and six heteromeric P2X re- and their therapeutic effects are generally limited [5-6]. Com- ceptors (P2X1/2, P2X1/4, P2X1/5, P2X2/3, P2X2/6, and [10] plete freedom from NP often cannot be achieved by drugs. P2X4/6) have been identified . P2Y receptors consist of P2Y1-12. Purinergic signaling was proposed and hypothes- ized for the initiator and modulator of pain [11]. Since then, [Received on] 27-Jul.-2019 [Research funding] This work was supported by the National Natur- many subsequent research studies have expanded this al Science Foundation of China (Nos. 81570735, 8181101216, concept. P2X and P2Y receptors are involved in the modula- 31560276, 81970749, and 81870574). tion of pain transmission. After nerve injury, ATP is released [*Corresponding author] Tel/Fax: 86-791-86360552, E-mail: liangsd @hotmail.com from the nerve endings of primary sensory neurons. Extracel- ∆These authors contributed equally to this work. lular ATP triggers the activation of different P2 receptors,

These authors have no conflict of interest to declare. which induce the production and release of bioactive factors

– 28 – LI Shun-Hua, et al. / Chin J Nat Med, 2020, 18(1): 28–35 including cytokines and neurotrophic factors, which in turn convulsants (e.g., gabapentin, pregabalin, and topical lido- lead to the hyperexcitability of sensory neurons and, con- caine). Opioid analgesics and tramadol are recommended as sequently, NP developed [10-11]. second-line therapies. However, they are sometimes used as Ligand-gated ion channel P2X receptor has seven sub- first-choice drugs [25]. But those therapies only offer marginal types, among which the P2X3, P2X4, and P2X7 subtypes are relief because of either a lack of efficacy or the risk of unac- most related to pain transmission [11-12]. It has been reported ceptable side effects (e.g., sedation, dizziness, edema, and that P2X antagonists were successful in relieving NP [13-14]. ataxia) [23]. Patients with NP continue to have moderately P2X3 receptor antagonists (A-317491, RO3 and RO4) have severe pain on average, despite taking prescribed medica- exhibited their potent ability to relieve NP [15-17]. An effective tions for their condition [26]. Furthermore, the development of P2X4 receptor antagonist named paroxetine has been sugges- tolerance, and the risks of addiction and abuse, significantly ted to successfully relieve NP [18]. P2X7 receptor antagonists limit the clinical application of NP pharmacotherapy. No (A-740003, KN-62 and KN-04) produced antinociceptive ef- treatment option has been shown to reverse NP. Therefore, fects in NP [19]. Among the G protein coupled P2Y receptor the discovery of novel therapeutic alternatives with superior family, only the P2Y12 receptor subtype is clearly known to effectiveness and minimal adverse effects would be beneficial. be involved in NP onset. Several genetic deletions of P2Y12 Currently, more attention has been focused on herbal for- receptors produce analgesic effect [20-22]. These observations mulations in the field of drug discovery, especially on medi- indicate that drugs selectively targeting specific P2 receptors cinal plants and herbal extracts from traditional Chinese can exert their analgesic activity at the site of receptor, thus medicine (TCM) (Fig. 1), which are increasingly used world- limiting the occurrence of unwanted side effects [9-11]. wide. TCM has unique advantages in the clinical prevention The advantage of traditional Chinese medicine in NP and treatment of NP because of its fewer complications and treatment side effects compared with synthetic drugs. Moreover, the NP, a kind of chronic pain, is the focus of many research multiple components and targets of TCM avoid the shortcom- studies due to the high incidence, complex pathogenesis, and ings of clinical drugs targeting a single pathway [27]. Several lack of efficient treatments. Trauma (surgery, amputation), studies have indicated that natural products could be a good metabolic disorders (diabetes, uremia), infection (herpes source of the new specific molecules needed for the treat- zoster, HIV), poisoning (chemotherapy), vascular disease (ar- ment of pain-related diseases through the regulation of P2 re- teritis nodosa), and malnutrition are considered to be incent- ceptors [28-29]. For example, the TCM compound Emodin acts ives for the initiation of NP [23]. NP is an area of largely un- at tumor cells to inhibit their migratory ability via P2X7 met therapeutic need due to its complex underlying patho- blockade [30]. Recently, the antagonistic effect of bioflavon- physiology and heterogeneous etiology [5, 7]. The presently oids from the methanolic extract fractions of Rheedia logifo- available treatment for NP contains non-pharmacological ap- lia on the P2X7 receptor has been found to promote analges- proaches, such as electroacupuncture [24], and drugs. On the ic action on inflammatory pain [31]. In addition, it has been re- basis of randomized clinical trials, medications are recom- ported that bioactive molecules contained in analgesic prepa- mended as first-line treatments for NP include certain antide- rations from TCM (e.g., tetramethylpyrazine, sodium ferulate, pressants [e.g., tricyclic antidepressants (TCAs), serotonin and puerarin) can inhibit P2X3-mediated pain transmission in norepinephrine reuptake inhibitors (SNRIs)] and certain anti- primary afferent neurons [28]. Thus, TCM may be an alterna-

CH OH H 3 OH OH O OH OH O O H3C HO O HO O H H O OH H3C OH CH 3 OH O OH O O Emodin Resveratrol Artemisinin Quercetin

O O HO O

HO OH HO N O O H OO O CH3 O OH CH3 O HO O H HO

Curcumin Andrographolide Osthole Sinomenine Fig. 1 Chemical structures of different TCMs

– 29 – LI Shun-Hua, et al. / Chin J Nat Med, 2020, 18(1): 28–35 tive option to relieve and manage NP by acting at P2 receptors. odeficiency virus (HIV), and herpes infections, the resultant Classical drug research focuses mainly on a single active NP is often modifiable with prevention strategies. Therefore, compound. Systemic administration can reduce local drug after precise prediction of the disease risk, TCM can provide concentration and at the same time cause adverse reactions preventive treatment of diseases [45]. Compared with targeted and complications [32]. Conversely, natural compounds are at- therapy, TCM has the merit of a dispersed application point, tracting increasing attention and should be taken into account slow effect, and relative safety, but a complex mechanism of as they are safe and have fewer side effects. For example, action [45]. The difficulty in TCM-based drug development TCMs, characterized by multiple components, multiple tar- is to decrypt the scientific mechanisms responsible for the gets, and holistic regulations, have been widely used in clin- clinical effects. Several studies found that TCM inhibited ics for centuries [33]. TCM transdermal penetration enhancers spinal glial activation and the following proinflammatory cy- can increase local drug concentration and alleviate local tokine production, or that eliciting anti-inflammatory effect pain [32]. Pharmacological mixtures also have the advantage of might contribute to its capability of anti-nociception [48-50]. potentiating the action of their multiple bioactive compon- P2 receptors and TCM ents and the option of an individualized therapy [34]. TCMs Inhibitory effects of TCM in diabetic neuropathic pain medi- can modify the imbalanced disease-associated network ated by the P2 receptors in dorsal root ganglia through the interactions of their active components and cor- Diabetes mellitus (DM) is one of the major causes of responding targets, so as to achieve their particular therapeut- peripheral neuropathy. Diabetic neuropathic pain (DNP) is a ic effect [33]. While NP has multiple possible mechanisms, a common complication of DM with limited treatment [51]. The growing body of literature shows that the combination of P2X3 receptor mediated hyperalgesia in DNP rats [52-53]. Sino- TCM natural compounds focusing on multiple targets may menine is the main active compound extracted from TCM present therapeutic candidates for the development of new Sinomenium acutum, which has anti-inflammatory and neuro- drugs to alleviate NP. For instance, levo-tetrahydropalmatine protective effects [54]. Sinomenine attenuated DNP induced by (l-THP) and levo-Corydalmine (l-CDL) are extracted from upregulated P2X3 [55]. Sinomenine reduced the thermal and Corydalis yanhusuo W. T. Wang, which is a Chinese herb mechanical hyperalgesia of DM rats, and decreased the asso- that has long been used in TCM. Recent studies indicate that ciated overexpression of P2X3 in the dorsal root ganglia these compounds relieve chemotherapy-induced NP (CIPN), (DRG) of the DM group [55]. Phosphorylation of P38MAPK nervous system injured NP, and cancer pain through the (mitogen-activated protein kinase) and the following release primary dopamine D1 receptor, dopamine D2 receptor, and of pro-inflammatory cytokines are involved in inflammatory the co-inhibition of NMDA and mGlu1/5 receptors, respect- pain [29]. Sinomenine lessened pain behaviors by decreasing ively [35-37]. the activation of the DRG P38MAPK in DM rats. Further- Some chemotherapeutic drugs, such as oxaliplatin and more, sinomenine showed a similar inhibition effect with morphine, are known to be neurotoxic and can lead to CIPN. P2X3-specific antagonist A317491 to inhibit P2X3 agonist These adverse effects decrease the patient ’s quality of life, ATP-activated currents in the transfected human embryonic hinder anticancer therapy with the drug, and may cause pre- kidney (HEK) 293 cells [55]. mature discontinuation of therapy. TCM can overcome these Emodin is an anthraquinone isolated from the traditional shortcomings as an alternative therapeutic measure for treat- Chinese herb of Rheum. It has exhibited excellent biological ing cancer pain. Some compounds in TCM, such as aurapten- activities in inflammatory diseases [56]. The targeting and ol, Xiao-Ai-Tong, Danshen, (+)-borneol, Processed aconite bioavailability of drugs were improved by encapsula- (PA) root, and Corydalis yanhusuo, are suggested to allevi- tion of nanoparticles, which also lower toxic side effects. ate CIPN [27, 37-41]. Moreover, (+)-borneol can prevent Nanoparticle-encapsulated emodin (nano emodin) can re- nociceptive behaviors induced by acetic-acid or formalin and lieve DNP in diabetic rats by reducing P2X3 receptor-medi- mechanical hyperalgesia, as well as chronic inflammation and ated excitatory conduction in DRG [56]. Nano emodin treat- NP [42-43]. PA also played an anti-allodynic role in the rat spin- ment weakened the enhanced mechanical withdrawal al nerve ligation (SNL) model [33-44]. Notably, repeated treat- threshold (MWT) and thermal withdrawal latency (TWL) of ment with TCM showed no evidence of the development of untreated DM rats by inhibiting exaggerated P2X3 expres- tolerance and did not affect weight or locomotor activity. sion. The α, β-meATP-activated currents in HEK293 cells Considering the need for long-term treatment of NP, this lack transfected with the human P2X3 receptor were restrained in of addictive or resistant development is significant and nano emodin treatment. ATP released by the injured nerve clearly shows TCM’s advantage as a potential analgesic. acts via the facilitated P2X3 receptor to cause the phos- Clinical trials have illuminated that the TCM formula phorylation of extracellular regulated protein kinases (ERK), shows promise in relieving NP and deserves further investig- inducing the release of tumor necrosis factor (TNF)-α and ex- ation [45-46]. Moreover, given that TCM is potentially effective acerbating NP. The attenuating effects of nano emodin on in the prevention of relapse, it has been suggested that TCM DNP were related to the blocked ERK pathway and the inhib- may be the ideal choice in the future for the treatment of opi- ition of TNF-α release [56]. ate addiction [47]. In diseases such as diabetes, human immun- The overexpressed P2X4 receptor in DRG is implicated

– 30 – LI Shun-Hua, et al. / Chin J Nat Med, 2020, 18(1): 28–35 in the initiation and maintenance of NP [57-58]. Quercetin, an injection increased the downregulated expression of anti-in- abundant dietary flavonoid, possesses remarkable analgesic, flammatory cytokine IL-10 in the DRG of DM rats. There- antioxidative, and anti-inflammatory properties [59]. Quercet- fore, osthole treatment alleviated DNP through decreasing the in can decrease the sensitization of P2X4 receptor-involved upregulation of P2X4 receptor and the activation of SGC, fol- hyperalgesia induced by DM in rats [60]. Following nerve in- lowed by the downregulation of IL-1β, TNF-α, BDNF, and p- jury, glial cells undergo activation and exclusively increase p38MAPK and the upregulation of IL-10 in DM rats [64]. their expression of P2X4 receptors. Quercetin could markedly P2Y12 receptors are expressed on SGCs of DRG. The reduce the co-expression of P2X4 receptor and glial fibril- upregulation of P2Y12 receptor was found in HIV-gp120 ad- lary acidic protein [GFAP, a satellite glial cell (SGC) marker] ded to combination antiretroviral therapy-induced neuro- in diabetic rats. Quercetin reduced P2X4 overexpression in pathology, and the reduction of P2Y12 receptor by short hair- the DRG of DM rats, increasing the threshold values of pin RNA (shRNA) showed resistance to HIV-associated mechanical and thermal hyperalgesia. Quercetin decreased NP [66-67]. Moreover, it has been reported that P2Y12 shRNA the amplitudes of currents in HEK293 cells transfected with treatment decreased SGC activation and relieved DNP [68]. P2X4 receptor. Those results support the notion that P2X4 re- Those studies suggested that P2Y12 participated in NP can ceptor is the pharmacological target of Quercetin for the serve as a potential therapeutic target. Curcuminis extracted therapeutic treatment of DPN [60]. from turmeric rhizome, a natural medicine with anti-inflam- Osthole, an active coumarin isolated from the anti-in- matory and antioxidant activities, as well as the effect of re- flammatory TCM Cnidium monnieri (L.) Cusson, has been lieving DNP [69]. The nanoparticle-encapsulated curcumin reported to exert analgesic effect [61-63]. Osthole treatment ac- (nano-curcumin) treatment inhibited mechanical and thermal ted on the P2X4 receptor and alleviated the mechanical and hyperalgesia and reduced the expression of P2Y12 receptor in thermal hyperalgesia in DM rats [64]. The increased expres- the SGCs of DRG in DM rat model [70]. The activation of sion of P2X4 mRNA and protein and enhanced co-expres- SGCs and the following production of IL-1β were also sup- sion staining of P2X4 receptor and GFAP in the SGCs of pressed by nano-curcumin. Gap junctions between SGCs are DRG were reversed in DM + osthole treated rats, as well as involved in neuronal excitability and contribute to the induc- the activated P2X4 receptor-p38 MAPK pathway (Fig. 2). tion and/or maintenance of pain. Connexin 43 (Cx43) is a gap The link between glial cells and dorsal horn neurons is estab- junction subunit, whose dramatic expression level was de- lished by brain-derived neurotrophic factor (BDNF) and pro- creased in the nano-curcumin-treated group. Protein kinase B inflammatory cytokines interleukin (IL)-1β and TNF-α, (PKB/Akt) phosphorylation is related to the upregulation of through the P38 MAPK pathway [65], which was inhibited by the P2Y12 receptor and NP mechanisms. Nano-curcumin osthole. In addition, osthole administered by intraperitoneal blocked this pathway and relived DNP. Thus, the nociceptive

Osthole

ATP Damaged nerve P2X4R expression

SGC Neuropathic activation pain P p38 Anti-inflammatory Satellite glial MAPK P cytokines cell (SGC)

Injury

Pro-inflammatory cytokines Neuron Fig. 2 Multitargeted TCM inhibit NP (Take the osthole’s inhibition effect of DNP as an example). Damaged nerve triggers the release of increased extracellular ATP, which causes exaggerated expression of P2X4 receptors on DRG SCGs. The following glial cells activation induces the over-production of pro-inflammatory cytokine and decline of anti-inflammatory cytokine through p38 MAPK phosphorylation. Accordingly neuropathic pain developed, osthole decreased P2X4 expression and reversed abnormal conditions of cytokine, then relieved neuropathic pain.

– 31 – LI Shun-Hua, et al. / Chin J Nat Med, 2020, 18(1): 28–35 signaling of DRG under the condition of DNP could be inhib- Inhibitory effect of TCM on NP transmission mediated by ited by blocking the function of P2Y12 receptor in the P2X receptors in DRG SGCs of DRG using curcumin [70]. NP has a long duration, and treatments for NP have been Inhibitory effects of TCMs on HIV-gp120-associated NP me- less effective [10]. The upregulated expression of P2X4 receptor- diated by the P2X receptors in the DRG in the SGCs of the DRG is a key process in NP. Artemisinin, HIV-1 infection contributes to various neurological dis- a sesquiterpene endoperoxide lactone found in the TCM plant orders. Glycoprotein 120 (gp120) is a HIV envelope gly- Artemisia annua L., has been used clinically as an anti- mal- coprotein, which has neurotoxic properties and can directly arial and an anti-tumor drug [83]. Artemisinin inhibits the stimulate the primary sensory afferent neurons, causing hy- nociceptive transmission, which mediated by the P2X4 re- peralgesia [71]. The P2X3 receptor in the DRG has been recog- ceptor in the SGCs of DRG, thus, relieves pain behaviors in nized to play an important role in the pathogenesis of rats with chronic constriction injury (CCI) [84]. Consistent gp120-induced pain [72]. Curcumin is a major bioactive com- with the time course of NP, a dramatic increase in the expres- ponent of TCM turmeric, which has the effects of alleviating sion of P2X4 in the SGCs of DRG was detected in the hyper- NP induced by streptozotocin, sciatic nerve injury, and cis- algesic CCI rats. Artemisinin administration reversed abnor- platin [73-75]. Nano-curcumin showed a treatment effect on mal hyperalgesia response to heat and mechanical stimula- gp120-induced NP mediated by the P2X3 receptor in rat tion by reducing the expression of P2X4 in the SGCs of primary afferent neurons [76]. The significantly decreasing DRG. The SGCs were activated under the condition of nerve MWT and TWL in the gp120 model were increased by nano injury, whereas the increased co-expression staining of P2X4 curcumin treatment. Upregulated P2X3 expression in gp120 and GFAP in the DRG was decreased in artemisinin-treated rat DRGs resulted in the phosphorylation of the ERK path- rats. The results also confirmed that the effects of artemisinin way and the following pain behaviors. Nano curcumin de- on attenuating chronic NP were related to decreased the ex- creased the abnormal expression levels of P2X3 mRNA and pression of P2X4 in the SGCs of DRG and reduced SGC ac- protein in a rat model to reverse the activated ERK pathway tivation [84]. and HIV-associated NP. The exaggerated amplitudes of P2X3 P2X7 receptors are localized in the SGCs of DRG and agonist α, β-meATP-activated currents in DRG neurons activated by extracellular ATP, promoting to the release of treated with gp120 were decreased in nano-curcumin-treat- inflammatory cytokines and thus resulting in NP. P2X7 levels ment. Therefore, nano curcuminmay inhibit P2X3 activation, are increased in the CCI rat model [85-86]. RES can moderate decrease the sensitizing primary afferents in DRG, and re- the hyperalgesia after nerve injury [87]. RES suppressed the lieve mechanical and thermal hyperalgesia in gp120-treated transmission of P2X7 receptor activation in CCI rats to in- rats [76]. crease the threshold of thermal or mechanical hypersensitiv- The combination of gp120 and the antiretroviral drug za- ity. RES blocked the activation of P2X7 receptor in SGCs to lcitabine (ddC) (gp120 + ddC) results in NP characterized by diminish the following pro-inflammatory cytokine (e.g., mechanical allodynia and upregulates TNF-α [77-78]. The anti- TNF-α and IL-6) production. Moreover, RES may alleviate inflammatory molecule IL-10 can reduce HIV-related NP [79]. NP through the ERK1/2 and p38 MAPK pathways. RES ant- The upregulated P2X7 receptor expression level in DRG is agonizes the P2X7 receptor as the P2X7 receptor agonist Bz- closely related to NP induced by HIV [80]. Resveratrol (RES) ATP-activated current was inhibited in RES-treated rats. and andrographolide (Andro) are a natural polyphenol and an Thus, RES could inhibit the transmission of pain in rats with active ingredient extracted from grapes and Andrographis NP by suppressing P2X7 expression and preventing the elev- (Andrographis paniculata), respectively. Both of them have ation of the pain threshold after CCI [87]. In addition, it has anti-inflammatory and anti-nociceptive effects. RES or An- been reported that the stimulating P2X7 receptor triggers the dro relieved the hyperalgesia in the gp120 + ddC rats relating P2X3-mediated pain response in DRG neurons [88], suggest- to inhibition of the P2X7 receptor in the SGCs of DRG [81-82]. ing the TCM acting on P2X7 receptors may be the potent tar- In gp120 + ddC rats, the MWL and TWL were reduced, get to relieve NP through further regulating the neural P2X3 which accompanied by the overexpressed P2X7 receptor in receptor. DRG. After treatment with TCM, the hyperalgesia and the Conclusion expression level of P2X7 receptor were relieved and decreased. Activating SGCs of model rats released cytokines NP is a complex and heterogeneous group of disease and thus augmented NP. In RES or Andro-treated rats, the en- states with limited treatment protocols. The current existing hanced co-localization intensity of the P2X7 receptor and painkillers are generally accompanied by harmful side ef- GFAP, and the protein levels of TNF-α receptor and IL-1β fects. Furthermore, under the lack of effective alternatives, were significantly decreased. Meanwhile, the decreased IL-10 the major abuse of opioids has become an ongoing crisis. Re- protein was increased by inhibiting the evoked P2X7-ERK cently, natural products and their constitutive compounds, pathway. Moreover, RES decreased the ATP-activated cur- mainly TCMs, have been considered as a new direction for rents in the HEK293 cells that were transfected with P2X7 the development of analgesics to resolve NP. Different from plasmid [81-82]. traditional analgesics, which target a single pathway, TCMs

– 32 – LI Shun-Hua, et al. / Chin J Nat Med, 2020, 18(1): 28–35

take the advantage of multiple components and targets, and [15] Jarvis MF, Burgard EC, McGaraughty S, et al. A-317491, a can significantly improve the efficacy of treatment and con- novel potent and selective non-nucleotide antagonist of P2X3 and P2X receptors, reduces chronic inflammatory and neuro- tribute to the prediction of the risks of NP. 2/3 pathic pain in the rat [J]. Proc Natl Acad Sci USA, 2002, P2 receptors are promising potential targets for NP thera- 99(26): 17179–17184.

peutics, especially for P2X3, P2X4, P2X7, and P2Y12 recept- [16] Gever JR, Cockayne DA, Dillon MP, et al. Pharmacology of ors, which play a particularly crucial role in the initiation and P2X channels [J]. Pflugers Arch-Eur J Phy, 2006, 452(5): maintenance of NP. Therefore, studies on the P2 receptor and 513–537.

associated pharmacology may provide new tools and insights [17] Carter DS, Alam M, Cai H, et al. Identification and SAR of novel diaminopyrimidines. Part 1: The discovery of RO-4, a into the pathological process of NP and reduction of adverse dual P2X3/P2X2/3 antagonist for the treatment of pain [J]. effects. Based on the recent studies, this review highlight sev- Bioorg Med Chem Lett, 2009, 19(6): 1628–1631.

eral TCMs that relieve NP by acting at P2 receptors. The [18] Nagata K, Imai T, Yamashita T, et al. Antidepressants inhibit characteristics and widely application of TCMs inspire that P2X4 receptor function: a possible involvement in neuropathic the combination of TCM and western medicines may im- pain relief [J]. Mol Pain, 2009, 5: 20.

[19] Burnstock G. Purinergic receptors and pain [J]. Current Phar- prove the curative effect of many diseases. Secondly, dis- maceutical Design, 2009, 15(15): 1717–1735. eases prevention provides a potential focus in the further [20] Maeda M, Tsuda M, Tozaki-Saitoh H, et al. Nerve injury-activ- study of TCM. Still, more investigation of the detailed mech- ated microglia engulf myelinated axons in a P2Y12 signaling- anism of NP is needed for the advanced theoretical support of dependent manner in the dorsal horn [J]. Glia, 2010, 58(15): pharmaceutical development. In future work, it is necessary 1838–1846. not only to describe the mechanism of action of a single herb [21] Moore C, Ase A, Kinsara A, et al. Identification of P2Y12 as a mediator of migration and inflammation in human and a single component, but also to conduct in-depth re- microglia [J]. J Neuroimmunol, 2014, 275(1-2): 90. search and analysis of the interaction of the combination of [22] Horvath G, Goloncser F, Csolle C, et al. Central P2Y12 recept- substances and the interaction with chemotherapy. or blockade alleviates inflammatory and neuropathic pain and cytokine production in rodents [J]. Neurobiol Dis, 2014, 70: References 162–178.

[23] Yan YY, Li CY, Zhou L, et al. Research progress of mechan-

[1] Leung L, Cahill CM. TNF-α and neuropathic pain-a review [J]. J Neuroinflamm, 2010, 7(1): 27. isms and drug therapy for neuropathic pain [J]. Life Sci, 2017, 190: 68–77.

[2] Singh R, Kishore L, Kaur N. Diabetic peripheral neuropathy: current perspective and future directions [J]. Pharmacol Res, [24] Choi J, Kang S, Choi J, et al. Analgesic effect of electroacu- 2014, 80: 21–35. puncture on paclitaxel-induced neuropathic pain via spinal opioidergic and adrenergic mechanisms in mice [J]. Am J [3] Yoo M, Sharma N, Pasnoor M, et al. Painful diabetic peripheral neuropathy: Presentations, mechanisms, and exercise ther- Chinese Med, 2015, 43(1): 57–70.

apy [J]. J Diabetes Metab, 2013, S10: 005. [25] Lim EY, Kim YT. Food-derived natural compounds for pain relief in neuropathic pain [J]. Biomed Res Int, 2016, 2016: [4] Smith BH, Torrance N. Epidemiology of neuropathic pain and its impact on quality of life [J]. Curr Pain Headache Rep, 2012, 7917528.

16(3): 191–198. [26] O ’Connor AB. Neuropathic pain quality-of-life impact, costs and cost effectiveness of therapy [J]. Pharmacoeconomics, [5] Binder A, Baron R. The pharmacological therapy of chronic neuropathic pain [J]. Dtsch Arztebl Int, 2016, 113(37): 2009, 27(2): 95–112.

616–625. [27] Wang ZY, Zhang PX, Han N, et al. Effect of modified formula Radix Hedysari on the amplification effect during peripheral [6] Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain [J]. Pain, 2010, nerve eegeneration [J]. Evid Based Complement Alternat Med, 150(3): 573–581. 2013, 2013: 647982.

[28] Liang SD, Xu CS, Li GL, et al. P2X receptors and modulation [7] Finnerup NB, Haroutounian S, Kamerman P, et al. Neuro-pathic pain: an updated grading system for research and clinical of pain transmission: focus on effects of drugs and compounds practice [J]. Pain, 2016, 157(8): 1599–1606. used in traditional Chinese medicine [J]. Neurochem Int, 2010,

[8] Burnstock G. Purinergic signalling: from discovery to current 57(7): 705–712.

developments [J]. Exp Physiol, 2014, 99(1): 16–34. [29] Soares-Bezerra RJ, Calheiros AS, da Silva Ferreira NC, et al.

[9] Burnstock G. Purinergic signalling: Therapeutic develop- Natural products as a source for new anti-inflammatory and an- ments [J]. Front Pharmacol, 2017, 8: 661. algesic compounds through the inhibition of purinergic P2X re-

[10] Magni G, Ceruti S. The purinergic system and glial cells: emer- ceptors [J]. Pharmaceuticals (Basel), 2013, 6(5): 650–658.

ging costars in nociception [J]. Biomed Res Int, 2014, 2014: [30] Jelassi B, Anchelin M, Chamouton J, et al. Anthraquinone 495789. emodin inhibits human cancer cell invasiveness by antagoniz-

[11] Burnstock G. Purinergic mechanisms and pain [J]. Adv Phar- ing P2X7 receptors [J]. Carcinogenesis, 2013, 34(7): macol, 2016, 75: 91–137. 1487–1496.

[12] Burnstock G. Purines and sensory nerves [J]. Sensory Nerves, [31] Santos JA, Fidalgo-Neto AA, Faria RX, et al. Effect of Rhee- 2009,(194): 333–392. dia longifolia leaf extract and fractions on the P2X7 receptor in

[13] Zeiser R, Robson SC, Vaikunthanathan T, et al. Unlocking the vitro: novel antagonists? [J]. J Med Food, 2011, 14(9): potential of purinergic signaling in transplantation [J]. Am J 920–929.

Transplant, 2016, 16(10): 2781–2794. [32] Deng B, Jia L, Pan L, et al. Wen-Luo-Tong prevents glial ac-

[14] Volonté C, Apolloni S, Skaper SD, et al. P2X7 receptors: chan- tivation and nociceptive sensitization in a rat model of oxali- nels, pores and more [J]. CNS Neurol Disord-Dr, 2012, 11: platin-induced neuropathic pain [J]. Evid Based Complement 705–721. Alternat Med, 2016, 2016: 3629489.

– 33 – LI Shun-Hua, et al. / Chin J Nat Med, 2020, 18(1): 28–35

[33] Zhang YQ, Wang C, Guo QY, et al. Molecular mechanisms of 53(10): 6835–6848.

the analgesic action of Wu-tou Decoction on neuropathic pain [51] Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy in mice revealed using microarray and network analysis [J]. for neuropathic pain in adults: a systematic review and meta- Acta Pharmacol Sin, 2018, 39(6): 988–997. analysis [J]. Lancet Neurol, 2015, 14(2): 162–173.

[34] Schroder S, Beckmann K, Franconi G, et al. Can medical herbs [52] Xu GY, Li GW, Liu NG, et al. Mechanisms underlying pur- stimulate regeneration or neuroprotection and treat neuropathic inergic P2X3 receptor-mediated mechanical allodynia induced pain in chemotherapy-induced peripheral neuropathy? [J]. Evid in diabetic rats [J]. Mol Pain, 2011, 7: 60.

Based Complement Alternat Med, 2013, 2013: 423713. [53] Burnstock G, Novak I. Purinergic signalling and diabetes [J].

[35] Guo ZG, Man Y, Wang XY, et al. Levo-tetrahydropalmatine Purinergic Signal, 2013, 9(3): 307–324.

attenuates oxaliplatin-induced mechanical hyperalgesia in [54] Zhao XX, Peng C, Zhang H, et al. Sinomenium acutum: a re- mice [J]. Sci Rep, 2014, 4: 3905. view of chemistry, pharmacology, pharmacokinetics, and clin-

[36] Wang L, Zhang Y, Wang ZW, et al. The antinociceptive prop- ical use [J]. Pharm Biol, 2012, 50(8): 1053–1061.

erties of the Corydalis yanhusuo extract [J]. PLoS ONE, 2016, [55] Rao SQ, Liu SM, Zou LF, et al. The effect of sinomenine in 11(9): e0162875. diabetic neuropathic pain mediated by the P2X3 receptor in

[37] Dai WL, Yan B, Jiang N, et al. Simultaneous inhibition of NM- dorsal root ganglia [J]. Purinergic Signal, 2017, 13(2): DA and mGlu1/5 receptors by levo-corydalmine in rat spinal 227–235.

cord attenuates bone cancer pain [J]. Int J Cancer, 2017, [56] Li L, Sheng X, Zhao SH, et al. Nanoparticle-encapsulated 141(4): 805–815. emodin decreases diabetic neuropathic pain probably via a

[38] Cong Y, Sun K, He XM, et al. A traditional Chinese medicine mechanism involving P2X3 receptor in the dorsal root Xiao-Ai-Tong suppresses pain through modulation of cy- ganglia [J]. Purinergic Signal, 2017, 13(4): 559–568.

tokines and prevents adverse reactions of morphine treatment in [57] Tsuda M, Masuda T, Tozaki-Saitoh H, et al. P2X4 receptors bone cancer pain patients [J]. Mediators Inflamm, 2015, 2015: and neuropathic pain [J]. Front Cell Neurosci, 2013, 7: 191.

961635. [58] Suurvali J, Boudinot P, Kanellopoulos J, et al. P2X4: A fast

[39] Di Cesare Mannelli L, Piccolo M, Maione F, et al. Tan- and sensitive purinergic receptor [J]. Biomed J, 2017, 40(5): shinones from Salvia miltiorrhiza Bunge revert chemotherapy- 245–256.

induced neuropathic pain and reduce glioblastoma cells malig- [59] Russo M, Spagnuolo C, Tedesco I, et al. The flavonoid quercet- nancy [J]. Biomed Pharmacother, 2018, 105: 1042–1049. in in disease prevention and therapy: facts and fancies [J]. Bio-

[40] Zhou HH, Zhang L, Zhou QG, et al. (+)-Borneol attenuates ox- chem Pharmacol, 2012, 83(1): 6–15.

aliplatin-induced neuropathic hyperalgesia in mice [J]. [60] Yang RN, Li L, Yuan HL, et al. Quercetin relieved diabetic Neuroreport, 2016, 27(3): 160–165. neuropathic pain by inhibiting upregulated P2X4 receptor in

[41] Suzuki T, Miyamoto K, Yokoyama N, et al. Processed aconite dorsal root ganglia [J]. J Cell Physiol, 2018, 234(3): root and its active ingredient neoline may alleviate oxaliplatin- 2756–2764.

induced peripheral neuropathic pain [J]. J Ethnopharmacol, [61] Zhang ZR, Leung WN, Cheung HY, et al. Osthole: A review 2016, 186: 44–52. on its bioactivities, pharmacological properties, and potential as

[42] Almeida, Souza GR, Silva JC, et al. Borneol, a bicyclic alternative medicine [J]. Evid Based Complement Alternat Med, monoterpene alcohol, reduces nociceptive behavior and inflam- 2015, 2015: 919616.

matory response in mice [J]. The Scientific World J, 2013, [62] Wu HX, Wang YM, Xu H, et al. Osthole, a coumadin analog 2013: 1–5. from Cnidium monnieri (L.) Cusson, ameliorates nucleus

[43] Jiang J, Shen YY, Li J, et al. (+)-Borneol alleviates mechanical pulposus-induced radicular inflammatory pain by inhibiting the hyperalgesia in models of chronic inflammatory and neuropath- sctivation of extracellular signal-regulated kinase in rats [J]. ic pain in mice [J]. Eur J Pharmacol, 2015, 757: 53–58. Pharmacology, 2017, 100(1-2): 74–82.

[44] Yang J, Park KS, Yoon JJ, et al. Anti-allodynic effect of in- [63] Singh G, Bhatti R, Mannan R, et al. Osthole ameliorates neuro- trathecal processed Aconitum jaluense is associated with the in- genic and inflammatory hyperalgesia by modulation of iNOS, hibition of microglial activation and P2X7 receptor expression COX-2, and inflammatory cytokines in mice [J]. Inflammo- in spinal cord [J]. BMC Complement Altern Med, 2016, 16: pharmacology, 2018, 27(5): 949–960.

214. [64] Yuan HL, Ouyang S, Yang RN, et al. Osthole alleviated diabet-

[45] Wang S, Zhang D, Hu JS, et al. A clinical and mechanistic ic neuropathic pain mediated by the P2X4 receptor in dorsal study of topical borneol-induced analgesia [J]. EMBO Mol root ganglia [J]. Brain Res Bull, 2018, 142: 289–296.

Med, 2017, 9(6): 802–815. [65] Popiolek-Barczyk K, Mika J. Targeting the microglial signal-

[46] Tsai CI, Li TC, Chang MH, et al. Chinese medicinal formula ing pathways: new insights in the modulation of neuropathic (MHGWT) for relieving diabetic neuropathic pain: A random- pain [J]. Curr Med Chem, 2016, 23: 2908–2928.

ized, double-blind, placebo-controlled trial [J]. Evid Based [66] Shi LR, Wu B, Yi ZH, et al. P2Y12 shRNA treatment relieved Complement Alternat Med, 2013, 2013: 767498. HIV gp120-induced neuropathic pain in rats [J]. Neurochem

[47] Xiao LJ, Tao R. Traditional Chinese medicine (TCM) Int, 2018, 112: 259–266.

therapy [J]. Adv Exp Med Biol, 2017, 1010: 261. [67] Yi ZH, Xie LH, Zhou CF, et al. P2Y12 receptor upregulation in

[48] Cao FL, Xu M, Wang Y, et al. Tanshinone IIA attenuates satellite glial cells is involved in neuropathic pain induced by neuropathic pain via inhibiting glial activation and immune re- HIV glycoprotein 120 and 2′, 3′-dideoxycytidine [J]. Puriner- sponse [J]. Pharmacol Biochem Behav, 2015, 128: 1–7. gic Signal, 2018, 14(1): 47–58.

[49] Chen FF, Huo FQ, Xiong H, et al. Analgesic effect of total [68] Wang SY, Wang ZL, Li L, et al. P2Y12 shRNA treatment de- flavonoids from Sanguis draxonis on spared nerve injury rat creases SGC activation to relieve diabetic neuropathic pain in model of neuropathic pain [J]. Phytomedicine, 2015, 22(12): type 2 diabetes mellitus rats [J]. J Cell Physiol, 2018, 233(12): 1125–1132. 9620–9628.

[50] Yin JB, Zhou KC, Wu HH, et al. Analgesic effects of Danggui- [69] Guo CL, Li MS, Qi X, et al. Intranasal delivery of nanomicelle Shaoyao-San on various “Phenotypes” of nociception and in- curcumin promotes corneal epithelial wound healing in strepto- flammation in a Formalin Pain model [J]. Mol Neurobiol, 2016, zotocin-induced diabetic mice [J]. Sci Rep, 2016, 6: 29753.

– 34 – LI Shun-Hua, et al. / Chin J Nat Med, 2020, 18(1): 28–35

[70] Jia TY, Rao JA, Zou LF, et al. Nanoparticle-encapsulated simplex virus vector reduces neuropathic pain induced by HIV curcumin inhibits diabetic neuropathic pain involving the gp120 combined with ddC in rats [J]. Mol Pain, 2014, 10(1): P2Y12 receptor in the dorsal root ganglia [J]. Front Neurosci, 49.

2017, 11: 755. [80] Wu B, Peng LC, Xie JY, et al. The P2X7 receptor in dorsal

[71] Hao SL. The molecular and pharmacological mechanisms of root ganglia is involved in HIV gp120-associated neuropathic HIV-related neuropathic pain [J]. Curr Neuropharmacol, 2013, pain [J]. Brain Res Bull, 2017, 135: 25–32.

11: 499–512. [81] Wu B, Ma YC, Yi ZH, et al. Resveratrol-decreased hyperal-

[72] Yi ZH, Rao SQ, Ouyang S, et al. A317491 relieved HIV gesia mediated by the P2X7 receptor in gp120-treated rats [J]. gp120-associated neuropathic pain involved in P2X3 receptor Mol Pain, 2017, 13: 1–9.

in dorsal root ganglia [J]. Brain Res Bull, 2017, 130: 81–89. [82] Yi ZH, Ouyang S, Zhou CF, et al. Andrographolide inhibits

[73] Sharma S, Kulkarni SK, Agrewala JN, et al. Curcumin attenu- mechanical and thermal hyperalgesia in a rat model of HIV-in- ates thermal hyperalgesia in a diabetic mouse model of neuro- duced neuropathic pain [J]. Front Pharmacol, 2018, 9: 593.

pathic pain [J]. Eur J Pharmacol, 2006, 536(3): 256–261. [83] Thomas E. Cancer combination therapies with artemisinin-type

[74] Jeon Y, Kim CE, Jung D, et al. Curcumin could prevent the de- drugs [J]. Biochem Pharmacol, 2017, 139: 56–70.

velopment of chronic neuropathic pain in rats with peripheral [84] Ying MF, Liu H, Zhang TL, et al. Effect of artemisinin on nerve injury [J]. Curr Ther Res Clin Exp, 2013, 74: 1–4. neuropathic pain mediated by P2X4 receptor in dorsal root

[75] Al Moundhri MS, Al-Salam S, Al Mahrouqee A, et al. The ef- ganglia [J]. Neurochem Int, 2017, 108: 27–33.

fect of curcumin on oxaliplatin and cisplatin neurotoxicity in [85] He WJ, Cui J, Du L, et al. Spinal P2X7 receptor mediates mi- rats: some behavioral, biochemical, and histopathological stud- croglia activation-induced neuropathic pain in the sciatic nerve ies [J]. J Med Toxicol, 2013, 9(1): 25–33. injury rat model [J]. Behav Brain Res, 2012, 226(1): 163–170.

[76] Zhao SH, Yang JP, Han XY, et al. Effects of nanoparticle-en- [86] Xu J, Chen XM, Zheng BJ, et al. Electroacupuncture relieves capsulated curcumin on HIV-gp120-associated neuropathic nerve injury-induced pain hypersensitivity via the inhibition of pain induced by the P2X3 receptor in dorsal root ganglia [J]. spinal P2X7 receptor-positive microglia [J]. Anesth Analg, Brain Res Bull, 2017, 135: 53–61. 2016, 122(3): 882–892.

[77] Zheng WW, Ouyang HD, Zheng XX, et al. Glial TNFα in the [87] Xie JY, Liu SM, Wu B, et al. The protective effect of res- spinal cord regulates neuropathic pain induced by HIV gp120 veratrol in the transmission of neuropathic pain mediated by the application in rats [J]. Mol Pain, 2011, 7: 40. P2X7 receptor in the dorsal root ganglia [J]. Neurochem Int,

[78] Herzberg U, Sagen J. Peripheral nerve exposure to HIV viral 2017, 103: 24–35.

envelope protein gp120 induces neuropathic pain and spinal [88] Burnstock G, Krugel U, Abbracchio MP, et al. Purinergic sig- gliosis [J]. J Neuroimmunol, 2001, 116: 29–39. nalling: from normal behaviour to pathological brain

[79] Zheng WW, Huang W, Liu S, et al. IL-10 mediated by herpes function [J]. Prog Neurobiol, 2011, 95(2): 229–274.

Cite this article as: LI Shun-Hua, LI Lin, YANG Ru-Nan, LIANG Shang-Dong. Compounds of traditional Chinese medicine and neuropathic pain [J]. Chin J Nat Med, 2020, 18(1): 28-35.

– 35 –