Iranian Journal of Basic Medical Sciences ijbms.mums.ac.ir

Medicinal herbs in the treatment of neuropathic pain: a review Fatemeh Forouzanfar 1, Hossein Hosseinzadeh 2, 3* 1 Department of Neuroscience, Mashhad University of Medical Sciences, Mashhad, Iran 2 Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran 3 Department of Pharmacodynamy and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

A R T I C L E I N F O A B S T R A C T Article type: Review article challenge to health-care. Despite the large number of available drugs, there are no curative conventional treatmentsChronic neuropathic for neuropathic pain ispain. a commonNowadays, significant more attention and debilitating has been focused problem on thatthe herbal presents formulation a major Article history: Received: Jun 2, 2017 Accepted: Jan 7, 2018 in thedifferent field ofneuropathic drug discovery. pain Therefore,model, either we inperformed animals oran inextensive patients review are reported. about herbal Moreover, drugs the and possible plants Keywords: involvedthat exhibited mechanisms protective for effectsthe protective on neuropathic effects are pain. discussed. In this review,The more the common beneficial plants effects which of each are plantused for the treatment of neuropathic pain are included as: Acorus calamus, Artemisia dracunculus, Butea Antinociceptive monosperma, Citrullus colocynthis, Curcuma longa, Crocus sativus, Elaeagnus angustifolia, Ginkgo biloba, Chronic pain Mitragyna speciosa, Momordica charantia, Nigella sativa, Ocimum sanctum, Phyllanthus amarus, Pterodon Herbal medicine Neuropathic pain apoptotic,pubescens neuroprotective Benth, Rubia cordifolia and calcium and Salvia inhibitory officinalis. actions. Furthermore, the most pathways which are known Into beconclusion, involved thisin pain review relief suggests by means that of some herbal herbal remedies plants are can anti-oxidant be suitable activity, candidates anti-inflammatory, for the treatment anti- of neuropathic pain.

►Please cite this article as: Forouzanfar F, Hosseinzadeh H. Medicinal herbs in the treatment of neuropathic pain: a review. Iran J Basic Med Sci 2018; 21:347-358. doi: 10.22038/ IJBMS.2018.24026.6021

Introduction Pain, an unpleasant sensation and emotional experience that in our daily life, is an alert of tissue thisdisease state lead resolves to persist as healing nociception, occurs then and the inflammation changes in subsides.primary afferent But, stimulation neurons may from continue ongoing (11). injury Central or (1). Acute pain is a useful biologic purpose and self- changes can result from peripheral nerve lesions, which injury to prevent further or impending tissue damage have been investigated in animals mainly at the spinal cord or sometimes at supraspinal levels (12, 13). limitingas a disease in nature state. that It may arises outlast in response the usual to aduration specific Several types of alterations can induce pathologic injury. Chronic pain, in contrast, may be considered activation of central nociceptive neurons: such as neuroplasticity, microglial activation and hyper- ofthat recovery, comes iffrom accompanied direct consequence with a disease of ora lesioninjury (1,or excitability (central sensitization) of nociceptive 2).disease The definitionwhich affect of thechronic somatosensory neuropathic system” pain is (3).“pain It neurons. Central sensitization possibly depends critically on intracellular changing that induced by on the site of the lesion. The most causes of chronic the activation of N-methyl-D-aspartate (NMDA) and mayneuropathic be classified pain are as centralmetabolic or peripheral,disease, viral, depending trauma, glutamate metabotropic receptors (12, 13). The severe ischemic insults, and autoimmune diseases (4-6). stimulation of non-neuronal cells, microglia in central Neuropathic pain usually does not have effective and macrophages in periphery, leads to production of a treatment, because of heterogeneous etiology and complex underlying pathophysiology, moreover, the play critical roles in neuropathic pain condition (14, 15). variety inflammatory cytokines and chemokines which drugs (7-9). Neuropathic pain and herbal medicinal products unwanted side effect profiles limit the use of available The usage of natural products, principally herbal Neuropathic pain and underlying mechanisms medicines is one of the ancient therapies used by Neuropathic pain humanity (16). During the recent years, people are in response to physical stimuli, that may manifest as eager to use herbal medicines due to their lower increased sensitivity mayto pain be spontaneous(hyperalgesia) or or evoked as a complications and fewer side effects than synthetic drugs (17). Regarding to the increasing demand 10). for medicinal plants and related compounds the pain evoked by a nonpainful stimuli (allodynia) (5, phytopharmaceutical studies and the use of these as peripheralOnce injury sensitization. occurs, inflammation Many types and of reparatoryperipheral remedies for the management of painful neuropathy processesmechanisms ensue, have leads been to described,a hyperexcitable in most state patients, known have been growing throughout the world (18).

*Corresponding author: Hossein Hosseinzadeh. Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran. Tel: +98-51-38819042; Fax: +98-51-38823251; Email: [email protected] Forouzanfar and Hosseinzadeh Neuropathic pain and herbal medicine

thalidomide. These drugs exert direct and indirect Animal models and/or pharmacological mechanisms effects on sensory nerves to diminish the amplitude of neuropathic pain of action potential, slow conduction velocity and Animal models of neuropathic pain have been induce pain in patients, mainly those who experience essential in the exploration of molecular mechanisms nociceptive sensory loss through their cancer treatment of pain also for the analysis of novel in the (28, 29). treatment of chronic pain (19). The animal models for studying neuropathic pain and a brief description of Research methodology each model are as follows: The current search was done in databases of Google Scholar, Medline and Scopus, using the following The streptozotocin (STZ)-induced diabetes The STZ-induced diabetic neuropathic pain model phytotherapy and natural products. The search included mimics the diabetic neuropathy. This neuropathy is keywords:literatures published neuropathic as late as pain, 31 April medicinal 2017. plants, one of the most frequent peripheral neuropathies In the present review, plants and some constituents associated with hyperalgesia, cold or hot allodynia of herbal medicine which have the potential to cure and hyperesthesia, the high blood glucose level neuropathic pain have been discussed alphabetically. induced oxidative and nitrosative stress which have For a summary of the selected experimental and been proposed to be an essential mechanism of human studies see Table 1 and Table 2.

Reactive oxygen species (ROS) enhanced nociceptors Acorus calamus neuronalsensitization injury so related that theyto diabetic not onlyneuropathy respond (20-22). more A. calamus, belongs to Araceae family, it has been used vigorously towards noxious stimuli, but also start to respond towards normally subthreshold stimuli. This in Indian traditional medicine (30). The hydroalcoholic peripheral sensitization not only induces pain directly forextract the managementof A. calamus of several(HAE-AC) inflammatory has been showndisorders to but furthermore induces central sensitization in the spinal cord, which also indirectly contributes to pain (7, allodynia and mechanical hyperalgesia on neuropathic 23). In high concentrations superoxide combine with significantlypain induced by attenuate tibial and thermal sural nerve hyperalgesia, transection thermal(TST) in nitric oxide to form peroxynitrite, which is implicated in diabetes accompanied by motor and sensory nerve anion, total calcium levels and myeloperoxidase (MPO) rats.activity Moreover, were also a significant observed decrement (31). Furthermore, in the superoxide HAE-AC decreased superoxide anion, total calcium levels and conduction deficits, in addition to peripheral nerve energyHigh-fat deficiency diet (7, 24). (CCI). It also attenuated CCI induced development of MPOpainful activity behavioral in sciatic changes nerve including: chronic constriction thermal, radiant, injury mechanical hyperalgesia and thermal, chemical, tactile neuropathyHigh-fat with diet isalimentary an important obesity, risk hyperinsulinemia, factor for nerve allodynia in rats (32). In other study, HAE-AC attenuated conductionand impaired velocityglucose tolerance deficit anddevelops small neuronal sensory damage fiber the development of painful behavioral (thermal and resulting from oxidative stress of lipid metabolism and mechanical hyperalgesia and mechanical allodynia), indicate increased sorbitol pathway activity, oxidative- biochemical (rises in the levels of superoxide anion, total calcium and myeloperoxidase activity) and peripheral nervous system (PNS) (25, 26). This model histological changes in vincristine-induced neuropathy nitrosativehas been used stress, in studies and on pro-inflammatory pathophysiology changesof impaired in in rats (33). In a further study saponin rich extract of A. glucose tolerance (IGT) and type 2 diabetes and for calamus improved CCI- development of new treatments (27). induced nociceptive pain threshold, sciatic functional and electrophysiological(20 and 40 changesmg/kg) significantlyin rats (34). These effects Neuropathy produced by sciatic nerve injury may have been exerted probably by multiple mechanisms The experimental model of neuropathy produced by inhibitory activity and neuroprotective actions (31-33). sciaticwidely nerve used injuryin behavioral in animals examination. mimic symptoms In this observed model, containing antioxidative, anti-inflammatory, calcium inprolonged human beingschanges with in nerveneurotransmitter injury, and thisand modelreceptor is Alstonia scholaris expression, lead to produce central sensitization in A. scholaris belongs to Apocyanaceae family, it has been used for treating diarrhea, dysentery, malaria, and pain mediators observed, which in turn enhances fever and cardiac diseases as well as rheumatic pains in responsethe sensitivity towards of peripheral the release sensory of numerous afferents inflammatory at the site traditional medicine (35). (7). Singh et al. in 2017, showed that methanol extract of A. scholaris ofChemotherapy injury and also‐induced in the peripheral CNS neuropathy mechanical hyperalgesia and cold allodynia as well as Peripheral neuropathy is a common side effect of significantly attenuated heat hyperalgesia, activity in CCI rats (36). They have suggested that the of chemotherapy drugs that induce peripheral protectiontherapeutic againsteffect of oxidative this extract stress may and be inflammatory due to the manyneuropathy classes (CIPN) of anti-cancer including the drugs, antitubulins the major (paclitaxel, classes docetaxel, ixabepilone, and vincristine), platinum analogs (oxaliplatin, carboplatin, and cisplatin), and presence of kaempferol and attributed to inhibit the the proteasome inhibitors such as bortezomib and Artemisiainflammatory dracunculus cytokines and ROS production (36).

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Artemisia mechanical allodynia and thermal hyperalgesia in A. dracunculus,species belongs are to beneficial Asteraceae herbal family, remedies display inflammatoryCCI mice along activities with increasing (43, 44). spinal Curcumin monoamine improved (or with antioxidant and anti-inflammatory effects (25, 37). metabolite) contents. 6-Hydroxydopamine (6-OHDA) PMI-5011, is an ethanolic extract of A. dracunculus. PMI- totally abolished the effects of curcumin on mechanical anti-inflammatory5011 normalized glycemia, and antinociceptive improved nerve effects conduction (25, 35). allodynia and p-chlorophenylalanine (PCPA) completely slowing and sensory neuropathy, and diminished 12/15-lipoxygenase upregulation and nitrated protein on thermal hyperalgesia. Chronic co-treatment with expression in peripheral nervous system in rats with blocked the antinociceptive influence of curcumin high-fat diet-induced neuropathy of prediabetes and acute co-treatment with the delta-opioid receptor obesity, potentially, by multiple mechanisms that the β2-adrenoceptor antagonist ICI 118,551, or by are including the inhibition of oxidative nitrosative action of curcumin on mechanical stimuli. However, stress and lipoxygenase activation (25). Another study antagonistco-treatment naltrindolewith the irreversible blocked mu-opioid the anti-allodynic receptor demonstrated that A. dracunculus leaf aqueous extract 1A diminished the acute and chronic pain on fructose fed WAY-100635 chronically completely male rats (38). abrogatedantangonist theβ-funaltrexamine anti-hyperalgesic acutely effect or with of thecurcumin 5-HT on thermal stimuli. According to these results, the descending monoamine system (coupl - Butea monosperma 2 adrenoceptor and 5-HT receptor) for antinociceptive B. monosperma is distributed in deciduous forest and 1A in open areas. It has been used in traditional medicine for properties of curcumin in neuropathiced pain with isspinal crucial. β various therapeutic effects such as diuretic, anti-diabetic, anthelmintic, antimicrobial, arthritis, wound healing in downstream targets (44). In another study, curcumin addition to treating burning sensation of the body (39, Delta-reduced and mechanical mu-opioid and receptors cold allodynia are likely and rendered attenuated as the serum concentration of cyclooxygenase 2 (COX-2) 40). Pretreatment with B. monosperma significantly increased the behavioral (i.e. hyperalgesia and allodynic in CCI model of neuropathic pain in rats, that may be pain sensation) changes and decreased thiobarbituric acid reactive substances (TBARS), total calcium levels effects of COX-2 enzyme activity (45). besides increased the glutathione (GSH) levels in the mediated, at least partially, by reducing the inflammatory Crocus sativus sciatic nerve tissue when compared with the normal C. sativus control group on vincristine-induced neuropathic the Iridaceae family and extensively cultivated in Iran pain model in rats, that may be due to its potential of and other countries commonly such known as India as and saffron, Greece belongs (46, 47). to neuroprotective, antioxidant and calcium channel It is used traditionally as food and remedy for several inactivation (39). Another study investigated the disorders including bronchospasm, insomnia, asthma, ameliorative effect of ethanolic extract from leaves menstruation problems, pain relief and cardiovascular of B. monosperma in CCI model. Pretreatment of B. disorders (48). Chemical studies have shown that monosperma attenuated CCI induced development of histopathological, biochemical and behavioral most important bioactive constituents of C. sativus alterations dose dependently, which is comparable to are crocin, crocetin, safranal and picrocrocin (49, 50). that of pregabalin pretreated group. This may be due to The ethanolic and aqueous extracts of saffron as well its potential anti-oxidative, neuroprotective and calcium as safranal attenuated the behavioural symptones of channel modulatory effects of B. monosperma (40). neuropathic pain in CCI model in rats (48). Besides, the ethanolic and aqueous extracts of C. sativus attenuated Citrullus colocynthis malondialdehyde (MDA) and increased GSH levels in CCI C. colocynthis (cucurbitaceae), endemic in Southern animals (51). Safranal showed an anti-nociceptive effect in chemical (formalin and acid acetic tests) methods of nociception in mice (52). Stigma extracts of C. sativus Tunisia,in acetic inacid folk writhing medicinal test used in mice as an and analgesic the carrageenan- and anti- inflammatoryinduced paw edema agents assay (41). inAqueous rats had extracts analgesic of theand plant anti- exertedthermal anti-inflammatoryhyperalgesia and effectsmechanical (53). Aallodynia, recent study but double-blind randomized placebo-controlled clinical showedcrocin at that lower saffron dose and crocin (30 mg/kg) reduced inflammatorytrial using a effectsparallel (41). design, More sixtyrecently, painful in a two-armdiabetic produce protective effects (54). Ethanolic and aqueous polyneuropathy (PDPN) patients were randomly extracts of C. sativus (15as well mg/kg) as safranal was ineffective diminished to allocated to treat either with a topical formulation allodynia and hyperalgesia induced by (CCI) of the of C. colocynthis or placebo, after 3 months the results sciatic nerve, besides C. sativus showed that administration of a topical formulation decreased the lumbar spinal cord contents of MDA of C. colocynthis fruit extract diminished pain in patients extracts significantly with PDPN (42). (55). A more recent study showed that, saffron as an and proinflammatory cytokines (TNFα, IL-1β, IL-6) Curcuma longa lead to improvement of the therapeutic outcome in the C. longa, a perennial herb of the ginger family, is adjunctivemanagement therapy of neuropathic in combination pain (56). with amitriptyline cultivated widely in south and southeast tropical Asia. It has been used medically for thousands of years (43). As Elaeagnus angustifolia a main constituent of C. longa, curcumin has a variety of E. angustifolia (Elaeagnaceae) is cultivated from pharmacological properties such as antioxidant and anti- the northern areas of Asia to the Himalayas and

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Europe because of its ability to grow in a wide range M. charantia (Cucurbitaceae) grows in Asia, Africa, of environmental conditions (57, 58). In Iranian traditional medicines, E. angustifolia fruit has been and remedy for several disorders such as asthma used as an analgesic agent for decreasing of pain in and Latinanaemia America (71). andAdministration is used traditionally of M. charantia as food rheumatoid arthritis (59). E. angustifolia showed muscle alterations including cold, mechanical, and heat Administration of different doses of this fruit showed significantlyhyperalgesia, attenuateddynamic mechanical TST induced allodynia, behavioral and relaxant (60) and anti-inflammatory (61) activity. cold allodynia in rats. Furthermore, treatment of M. plate test (57). Flavonoids have been considered the charantia also prevents TST-induced rise in nerve tissue significantmost essential analgesic components effect on in nerve E. angustifolia ligated mice that in have hot TNF-alpha and TBARS contents. It is speculated that activities (62). Recently in a randomized controlled trial antioxidative potential is critical for antinociceptive beenstudy relatedE. angustifolia to antinociceptive extract reduced and anti-inflammatory the symptoms of PPAR-gammaeffect of M. charantia agonistic in neuropathic effect, anti-inflammatory, pain (72). and ibuprofen. It was also safe and well tolerated during the Nigella sativa osteoarthritiscourse of trial and with no an adverse efficacy effect comparable was seen to(63). that of N. sativa is an annual flowering plant belonging to the Ranunculaceae family (73, 74). It consists of more Ginkgo biloba G. biloba is the popular herb that has shown some volatile oil have 18.4%–24% thymoquinone (TQ) (75, neuroprotective effects such as protective activity than76). N. 30% sativa fixed oil and 0.4%-0.45% volatile oil. The against transient and permanent focal cerebral ischemia in elevated serum glucose and increased the lowered (64) and dementia (65). The most unique constituents serum insulin andconcentration. TQ caused They a significant also increased reduction the of the G. biloba extracts are the terpene trilactones, that evaluation of the tissues in diabetic animals treated with Kim, et al. , administration of G. biloba extract, EGb 761, levelTQ and of especially insulin immunoreactive N. sativa exhibited β-cells. fewer The morphologic histologic are,lead ginkgolidesto reduction and of bilobalide.the paw withdrawal In a study, thresholdsconducted byto alterations. The results are attributed to its direct and mechanical stimuli and withdrawal frequencies to cold indirect antioxidant actions of TQ and especially N. stimuli in the rat model of neuropathic pain induced by sativa (76). Another study showed that administration G. biloba apoptotic factors also oxidative effects of neuropathic spinal nerve ligation (SNL). The beneficial effect of ofpain TQin CCI significantly rats (77). improvedIn a study behavioralconducted signsby Tewari and a platelet extract activating on neuropathic factor antagonist pain was and likely a protective due to a et al. , N. sativa combinationeffect against of anNMDA anti-inflammatory, induced neurotoxicity antioxidant effect,(66). cisplatin induced neuropathic pain in rats (78). Administration of EGb 761, a standardized extract of showed significant analgesic effects on G. biloba, Ocimum sanctum O. sanctum is an indigenous plant commonly found and mechanicalafter the allodynia third week on STZ-inducedof STZ administration neuropathic for in India and is recommended in the Ayurveda to treat 14 dayspain in rats reversed by inhibiting diabetes oxidative induced andthermal nitrosative hyperalgesia stress various diseases such as arthritis and painful eye (67). diseases (79). Treatment with O. sanctum attenuated sciatic nerve transection-induced axonal degeneration, Mitragyna speciosa decrement of nociceptive threshold and motor M. speciosa (Korth.) belongs to Rubiaceae family, in-coordination. Furthermore, it also attenuated is endemic to tropical Southeast Asia (68). The leaves axotomy-induced increase in TBARS, total calcium of M. speciosa have been used for medicinal purposes and diminution in GSH levels (80). In another study such as relieve muscle pain and fever (69), and has long treatment with O. sanctum and its saponin rich fraction

the withdrawal duration of the hind paw in response beenfound usedto possess in Thailand the most for potent its opioid-like opioid agonistic effects effects (70). significantlyto non-noxious attenuated cold stimuli vincristine-induced and noxious mechanicalincrease in 7-Hydroxymitragynineamong the components is isolated an indole from the traditional and was herbal medicine M. speciose (70). Matsumoto et al. stimulicalcium levels and significantlyin vincristine-induced decreased neuropathic the vincristine- pain in 15 and MGM-16 from 7-hydroxymitragynine for the inducedrats, which increase may be in attribute oxidatived to stress diminution markers in andoxidative total developedtreatment of dual-acting acute and µ-chronic and ∆-opioidpain. MGM-16 agonists exhibited MGM- stress and calcium levels (79). A recent study showed a higher potency than that of 7-hydroxymitragynine that O. sanctum has potential effects in attenuating and MGM-15 in in vitro and in vivo assays. Also MGM- painful neuropathic state in CCI-induced peripheral both in vitro and in vivo tests. Systemic administration of responsible for its useful effect in neuropathic pain. MGM-1616 exhibited caused a high antinociceptive affinity for µ- effects and ∆-opioid in a mouse receptors acute neuropathy,Besides, the andauthors saponins suggested may be that the keythe chemicalpain relieving class pain model and antiallodynic effects in a neuropathic effects of O. sanctum and its saponin rich fraction may be pain model in mice (70). A recent study demonstrated that M. speciosa produced antinociceptive effects similar increased contents of calcium and free radicals (81). to the reference opioid agonists (69). via to attenuation of nerve injury inciting agent-induced Phyllanthus amarus Momordica charantia The plants belonging to the genus Phyllanthus

350 Iran J Basic Med Sci, Vol. 21, No. 4, Apr 2018 Neuropathic pain and herbal medicine Forouzanfar and Hosseinzadeh

(Euphorbiaceae) have more than 600 species, which are extensively distributed in most tropical and subtropical countries (82). Several species from the genus Commonof Himalayas names in ofthe this North plant and are Western Indian madder, Ghats in majit the Phyllanthus are extensively used in traditional medicine, andPeninsula, manjishtha. Ceylon, It isSouth distributed India, allJapan, over Indonesia, the lower hillsJava in several countries, to treat of numerous diseases and in tropical Africa moist temperate and tropical forests (89). Generally root, leaves, fruits, stem etc. of calculus (82). The hexanic extract of P. amarus inhibited the plant R. cordifolia are used for their therapeutic theincluding mechanical flu, dropsy, allodynia diabetes, in mice jaundice after andthe bladderpartial activities (89). Patel et al. investigated the analgesic and to that obtained with gabapentin. Administration of properties such as analgesic and anti-inflammatory ligationhexanic ofextract the sciatic inhibited nerve, the with increase a quite of similar MPO activity,efficacy that methanolic extract of the root of R. cordifolia anti-inflammatory activities of this plant. They showed the carrageenan and increased the reaction time in either following intraplantar injection of complete significantly reduced in the paw edema produced by Freund’s(82). It has adjuvant been suggested (CFA) or afterthat the partial antihyperalgesic sciatic nerve alcoholic extract of roots and rhizomes of R. cordifolia ligation (PSNL) partly via the anti-inflammatoryP. amarus actions in a tail flick test (89). In a further study, administration of allodynia method and withdrawal latency in the hot andare mediated anti-inflammatory through spinal properties or supraspinal of neuronal significantlyplate method decreasedin paclitaxel-induced withdrawal neuropathic latency inpain cold in modelmechanisms, of chronic principally musculoskeletal by inhibition inflammatory of PGE2 (73). pain rats. The results may be because of the involvement of GABA or antioxidant mechanism (90). Pterodon pubescens Benth. P. pubescens Salvia officinalis S. officinalis (sage, also called garden sage, or common Benth. (Leguminosae) is a tree native sage) (family: can be found worldwide. This toactivities central (83). Brazil that has been used in folk medicine plant is suitable to relive of unilateral headaches and forThe its anti-inflammatory,hexane fraction of anti-rheumatic the ethanolic extractand analgesic of the headaches withLamiaceae) neurological origin (91). The different fruits of P. pubescens extracts of S. officinalis in enzyme dependent and effects in two animal models including: carrageenan- enzyme-independent lipid peroxidation systems showed Benth induced anti-inflammatory properties (28). Qnais and colleagues demonstrated inducedAdministration inflammatory of ethanolic reaction extract in thefrom pleural P. pubescens cavity anthat antioxidantthe aqueous activity and butanol (92) andextracts anti-inflammatory of S. officinalis and complete Freund’s adjuvant-induced arthritis (84). increased the latency on hot-plate assay and showed and thermal (heat and cold) hyperalgesia induced by antinociceptive response in both phases of formalin and fruits (EEPp) causes significant inhibition of mechanical the carrageenan-induced paw oedema in rats (93). The diminished nociceptive behavior induced by intrathecal hydroalcoholic extract of S. officinalis leaves presents PSNL in mice (83). Also, oral administration of EEPp significant anti-inflammatory as well as antinociceptive (capsaicin and cinnamaldehyde, respectively). The effects on chemical behavioral models of nociception injectiontreatment ofwith TRPV1 EEPp inhibited and TRPA1channels the nociceptive activators behavior that involves an opioid mechanism. Furthermore, responses induced by the following intrathecal carnosol and ursolic acid/oleanolic acid contained in this plant appears to contribute for the antinociceptive ACPD. In addition, EEPp also inhibited the nociceptive effect of the extract, probably via a modulatory effect injections with glutamate, kainate, NMDA and trans- on TRPA1-receptors (94). In another in vivo study the hydroalcoholic extract of S. officinalis elicited anti- behavioreffects may responses be mediated induced at least by inintrathecal part, by the injection inhibition of proinflammatory cytokines (TNF-α andIL-1β). These vincristine-induced peripheral neuropathic pain in mice inflammatory effects and decreased pain response on of proinflammatory cytokines, glutamatergic receptors asRosmarinus well as TRPV1 officinalis and TRPA1 channels (83). (95).Salvigenin Salvigenin in a dose (5-Hydroxy-6,7,4′-trimethoxy dependent manner demonstrated flavones) a R. officinalis , belongs is one of the active flavonoids found in ). this plant. medicine for severalcommonly disorders known such as rosemaryas dysmenorrhea significantConstituents analgesic of herbal effect likemedicine with (91 protective toand Labiatae rheumatic family. pain This (85). plant Rosemary has been is richused in in caffeic traditional acid, rosmarinic acid, ursolic acid, carnosic acid and carnosol effect against neuropathy A9-Tetrahydrocannabinol/Cannabidiol (THC/CBD) compounds (86). Administration of rosmarinic acid and Cannabis sativa has a long history of use as a medicinal ethanolic extract of R. officinalis decreased contents agent (96). THC/CBD is derived from strains of C. sativa plant developed to produce high and reproducible yields of THC and CBD, with trace quantities of other ofCCI spinalrats (87). inflammatory The ethanolic markers extract comprisingof aerial parts matrix of R. cannabinoids and terpenes in a solution having ethanol, officinalismetallopeptidase 2 (MMP2), COX2, IL-1b and PGE- 2 in in CCI rats (88). significantly diminished the amounts of glial propylenethe extracts glycol, (97). THC/CBDand peppermint display oil many flavoring. pharmacologic THC and activity, inflammation, and apoptosis markers Rubia cordifolia CBD contain ≥ 90% of the total cannabinoid content of R. cordifolia (Rubiaceae) is an ayurvedic herb. antiemetic effects (96). THC/CBD has been approved in effects such as anti-inflammatory, appetite stimulant and

Canada as adjunctive treatment for the symptomatic Iran J Basic Med Sci, Vol. 21, No. 4, Apr 2018 351 Forouzanfar and Hosseinzadeh Neuropathic pain and herbal medicine improve of neuropathic pain in multiple sclerosis (MS) DRG level (107). in adults (97). The standardized extract of C. sativa DA-9801 DA-9801 is a botanical drug, extracted from Dioscorea model in rat, that was mediated by vanilloid receptors species including: D. rhizoma and D. nipponica evoked a total. A phase relief II of randomized thermal hyperalgesia, clinical trial in study CCI (108). Many species of Dioscorea have traditionally been showed that administration of active cannabis ranging used clinically in Asia to treat numerous syndromesMakino TRPV1in potency (96) between 1 and 8% D-9-tetrahydrocannabinol associated with metabolic disorders. Besides, the extracts of the Dioscorea species had antidiabetic and associated distal sensory predominant polyneuropathy antiobesity effects (108-110). significantly(DSPN). These reduced results neuropathic showed that pain cannabinoid intensity therapy in HIV- Administration of DA-9801 improved damage may be an effective choice for pain relief in patients produced by diabetic neuropathy by increasing the levels of NGF in plasma and the sciatic nerve and DSPN with mild and self-limited side effects (98). showed improvement on nerve conduction velocity withMoreover, medically in randomized intractable controlled pain due to trials HIV-associated THC/CBD and recovery from neuronal degeneration in STZ rat/ was effective in patients with central neuropathic mouse diabetic models and in db/db mouse model pain and MS who completed -2 years of treatment (111). Another study demonstrated that oral treatment with no evidence of tolerance (97). Also Johnson et with DA-9801 decreased the blood glucose contents al. in a double-blind, randomized, placebo-controlled, and increased the withdrawal latencies in hot plate parallel-group trial study showed that THC/CBD is a procedures. Furthermore, it prevented ner based on increased nerve conduction velocity and with intractable cancer-related pain who experience ultrastructural changes (108). ve injury usefulinadequate adjunctive analgesia treatment despite for chronicrelief of painopioid in patientstherapy (99). Same authors in an open-label extension study showed that long-term use of THC/CBD spray relieved cancer-related pain and generally well tolerated in Goshajinkigandrug containing 10 medicinal herbs that has been advanced cancer patients. commonlyIn Japan, prescribed TJ-107 to (Goshajinkigan) improve symptoms is aof complexdiabetic peripheral neuropathy for example numbness, cold dose of THC/CBD spray overMoreover, time (100). patients Recently, who keptin a sensation, and paresthesias/dysesthesia. In a phase 2 usingdouble-blind, the study randomized, medication didplacebo-controlled, not seek to increase parallel their randomized, double-blind, placebo-controlled study, group study administration of THC/CBD oromucosal oral administration of TJ-107 had acceptable margins spray in patients with peripheral neuropathic pain clinically improved their pain, sleep quality and global delaying the onset of grade 2 or greater oxaliplatin- impression of change in the severity of their condition ofinduced safety peripheraland tolerability neurotoxicity and a promising in colorectal influence cancer in (101). More recently in a multicenter, open-label, patients treated with oxaliplatin (112). In a randomized open-labeled clinical trial study, long- follow-onpain associated study THC/CBDwith diabetes spray or was allodynia. beneficial THC/CBD for the effects on macrovascular diseases, retinopathy or majorityspray was of well patients tolerated that during have peripheral the study neuropathicperiod and termnephropathy administration in type of2 diabeticGoshajinkigan mellitus showed patients beneficial (113). time, with no new safety concerns arising from long- Incarvillateine alsoterm patientsuse (102). did not seek to increase their dose over is a big noniaceae plant distributed in Northern China. It has been widely used as a traditional herbal medicine for treatment of rheumatism, bruises Since ancient times, preparations of various species and wounds. It also is effective in decreasing pain and Lappaconitineof Aconitum have been widely used. Aconitine and Aconitum species, had various pharmacological effect such as analgesic inflammationof this plant. Administration in traditional of Chineseincarvillateine medicine attenuated (114). related , derived from Incarvillateineformalin-induced is considered pain in mice the majorwith aactive higher constituent potency Aconitum (including both Radix aconite preparata and than morphine (115). Furthermore, the antinociceptive Radixand anti-inflammatoryaconite kusnezoffii ), (103, mixture 104). with Treatment Huangqi Guizhi with action of incarvillateine attenuated by non-selective Wuwu Tang (i.e., astragalus, cassia twig, white peony receptor antagonist, non-selective opioid root, and spatholobi) in the four diabetic peripheral antagonists (116). Administration of incarvillateine in a receptordose-dependent antagonist, manner and decreased μ and acetic κ opioid acid-induced receptor neuropathicreactions were pain not subjects, observed lead during to remarkably the therapy reduction (105). writhing and also inhibited both thermal hyperalgesia of pain and the EMG profile was also improved. Adverse

Lappaconitineused as analgesic (LA) for is centuries aconitum in alkaloid the world, that especiallyextracted andincarvillateine paw edema, reduced and increased mechanical interleukin-1β allodynia induced levels from the root of the plant Aconitum species. LA has been inby CompleteSNI or Freund’spaclitaxel. AdjuvantAdditionally, model. incarvillateine- Furthermore, inhibitory effect on the nociceptive behaviors induced induced antinociception was reduced by , 1,3-dipropyl-8-cyclopentylxanthine, and 3,7-dimethyl- inby ChinaCCI, diminished and Japan the(106). expression Administration of the P2X of LA3 receptors showed in the dorsal root ganglion (DRG) neurons and inhibited 1-propargylxanthine, but not . It seems the mechanism of antinociceptive effects are mediated by the fast IATP and I in the DRG neurons of the CCI rats via regulating the purinergic signaling system at adenosine receptors, but not the opioid receptor system a,β-meATP

352 Iran J Basic Med Sci, Vol. 21, No. 4, Apr 2018 Neuropathic pain and herbal medicine Forouzanfar and Hosseinzadeh

Table 1. Herbal medicines and their constituents tested for neuropathic pain in human studies

Substance Neuropathic disorders Study type Results References A9- HIV-associated distal sensory Phase II, double-blind, Reduced (98) Tetrahydrocannabinol/Cannabidiol predominant polyneuropathy placebo-controlled, neuropathic pain (THC/CBD) crossover trial intensity THC/CBD Central neuropathic pain in Randomized controlled Improvement in (97) patients with multiple sclerosis trials neuropathic pain without evidence of tolerance THC/CBD Patients with intractable Multicenter, double- Reduced neuropathic (99) cancer-related pain blind, randomized, pain placebo-controlled, parallel-group study THC/CBD Patients with terminal cancer- An open-label extension Well tolerated and (100) related pain refractory to study reduced pain strong opioid analgesics THC/CBD Patients with peripheral A double‐blind, Improvement in (101) neuropathic pain randomized, placebo‐ neuropathic pain controlled, parallel group study THC/CBD Patients with peripheral A multicentre, open- Improvement in (102) neuropathic pain label, follow-on study neuropathic pain Aconitum Patients with diabetic Controlled clinical trials Reduced diabetic (105) peripheral neuropathic pain study peripheral neuropathic pain Citrullus colocynthis Painful diabetic Double‐blind Reduced diabetic (42) polyneuropathy patients randomized placebo‐ polyneuropathy pain controlled clinical trial

Goshajinkigan Oxaliplatin-induced Phase 2, multicenter, Delayed the onset of (112) neuropathy patients randomized, double- grade 2 or greater blind, placebo- oxaliplatin-induced controlled trial neuropathy

NMDA: N-methyl-D-aspartate; CNS: central nervous system; PNS: peripheral nervous system; STZ: streptozotocin; ROS: reactive oxygen species; CIPN: chemotherapy drugs that induce peripheral neuropathy; HAE-AC: hydroalcoholic extract of A. calamus; MPO: myeloperoxidase; TST: tibial

and sural nerve transection; CCI: chronic constriction injury; TBARS: thiobarbituric acid reactive substances; GSH: glutathione; PDPN: painful diabetic polyneuropathy; 6-OHDA: 6-Hydroxydopamine; PCPA: p-chlorophenylalanine; COX-2: cyclooxygenase 2; MDA: malondialdehyde; SNL: spinal nerve ligation; NOS: nitric oxide synthase; PSNL: partial sciatic nerve ligation; EEPp: ethanolic extract from P. pubescens fruits; THC/CBD, A9-Tetrahydrocannabinol/Cannabidiol; DRG: dorsal root ganglion; 3α-HSOR: 3α-Hydroxysteroid oxidoreductase; SOD: superoxide dismutase (114). Administration of naringin increased the level of Koumine nociceptive threshold, endogenous antioxidant and Gelsemium , membrane bound inorganic phosphate enzyme. It G. elegans Benth. has long been used in Chinese also diminished the oxidative–nitrosative stress level, is a genus of the family Loganiaceae cells in STZ induced diabetic neuropathic pain. The traditionalfound abundantly medicine in Gelsemium to relieve plants pain, (118). inflammation, Koumine inflammatoryresults may be mediators due to antioxidantas well as apoptosis and antiapoptotic in neural andattenuated cancer tactile (117). allodynia, Koumine isimprove an alkaloid sensory monomer nerve activity of naringin (120). conduction, and mitigate the pathology of sciatic In a recent study naringin in a dose dependent nerves in STZ-induced diabetic rats (119). In another manner reduced the mechanical allodynia and thermal mechanical allodynia more potently than gabapentin in inhibited peripheral neuropathy-induced activation studyCCI rats koumine (118). suppressed thermal hyperalgesia and hyperalgesiaof glial cells (astrocytes induced by and SNL, microglia) as well (121). as markedlyNaringin analgesia, indicating that allopregnanolone in the dismutase (SOD) contents, reduced MDA contents, and Upregulation of allopregnanolone induced significant significantly increased PPARγ expression and superoxide spinal cord (SC) may be an essential key modulator of improvedrats (122). the activities of main inflammatory cytokines neuropathic pain. 3α-Hydroxysteroid oxidoreductase including TNF-α, IL-1β, and IL-6 in the STZ induced diabetic (3α-HSOR) is responsible for allopregnanolone Quercetin upregulationcompared to inuntreated the SC. TheCCI activityrats. Also, of 3α-HSORthe intrathecal in the Quercetin is a phenolic compound extensively SC of koumine-treated CCI rats increased by 15.8% as consumed foods, including berries, onions, apples, tea injection of medroxyprogesterone acetate, a selective distributedand brassica in vegetables. the plant kingdom. Querc It is found in frequently 3α-HSOR inhibitor, dose-dependently reversed the effects on human health such as cardiovascular protection analgesic effect of koumine on CCI-induced mechanical etin has several beneficial painin the perception. SC of rat. Elevated The authors allopregnanolone suggested that levels koumine may alteredexert analgesic 3α-HSOR-regulated effects through allopregnanolone allosteric modulation levels andboth anti-inflammatory diabetic and nondiabetic effects (123).mice. Quercetin-induced Administration of of GABAA and by suppressing the release of microglia quercetinincrease in significantly nociceptive increased threshold in wastail-flick reversed latencies by anin opioid receptor antagonist (naloxone) in nondiabetic Naringin and diabetic mice. The protective effect of quercetin activation-inducedNaringin, a inflammatory-7-O-glycoside cytokines derived (118). from was probably mediated via modulation of grape fruit and related citrus species, has metal-chelating, mechanism in STZ induced diabetic mice (123). Another antioxidant and flavanonefree radical scavenging effects (120). study showed that quercetin can alleviate high glucose-

Iran J Basic Med Sci, Vol. 21, No. 4, Apr 2018 353 Forouzanfar and Hosseinzadeh Neuropathic pain and herbal medicine

Table 2. Mechanisms of actions of herbal medicines against neuropathic pain in animal models

Pterodon pubescens Shanzhiside ‐ methylester Emblica officinalis ‐ Microglial β – ‐ ‐ ‐ Rubia cordifolia ‐ ‐ Ocimum sanctum ‐ Acorus calamus ‐ Acorus calamus ‐ ‐ Acorus calamus ‐ ‐ ‐ Salvia officinalis ‐ ‐ ‐ Complete Freund’s ‐ ‐ Descending monoamine system (coupled with‐ spinal β2 Phyllanthus amarus ‐ Cannabis sativa Momordica charantia ‐ ‐

‐ Nigella sativa ‐ ‐ induced damage to Schwann cells by autophagy (124). actions.

In one study, quercetin reduced renal damage including: References epithelial desquamation, swelling, intracytoplasmic vacuolization, brush border loss and peritubular pain. Adv Drug Deliv Rev 2003;55:949-965. 1.2. WangRazavi LX, BM, Wang Hosseinzadeh ZJ. Animal andH. cellularA review models of the of chronicrole of (125). A recent study showed that the effect of quercetin orexin system in pain modulation. Biomed Pharmacother infiltration in STZ-induced diabetic nephropathy rats 2017;90:187-193. in terms of improving mechanical and thermal et al. washypersensitivity significantly in superior a rat model to gabapentin of CCI (126). and morphine 3.system Treede for RD, clinicalJensen TS,and Campbell research J, Cruccupurposes. G, Dostrovsky Neurology J, Griffin2008;70:1630-1635. J, Neuropathic pain redefinition and a grading Conclusion Agarwal A, et al. Management of chronic neuropathic pain: a can improve neuropathic pain effectively with few side 4.protocol Mulla for SM, a multiple Buckley treatment DN, Moulin comparison DE, Couban meta-analysis R, Izhar of Z, The urgent need to find an alternative therapy which randomised controlled trials. BMJ open. 2014;4(11):e006112. sources. This review suggests that herbal medicines are 5. Gilron I, Watson CPN, Cahill CM, Moulin DE. Neuropathic effectsalternative led options scientists to torelieve find and medicines manage from neuropathic natural pain. Results from the current study suggest that the 2006;175:265-275. pain:6. Forouzanfar a practical F, Amin guide B, for Ghorbani the clinician. A, Ghazavi ‎Can H, Med Ghasemi Assoc F, J most pathways involved in the analgesic effects of Sadri K, et al. New approach for the treatment of neuropathic pain: Fibroblast growth factor 1 gene‐transfected adipose‐ anti-apoptotic, neuroprotective and calcium inhibitory herbal remedies are antioxidant, anti-inflammatory,

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