Analgesic effects of medicinal plants and phytochemicals on chemotherapy‐induced neuropathic pain through glial modulation

Abstract Chemotherapy‐induced peripheral neuropathy (CIPN) frequently occurs in cancer patients. This side effect lowers the quality of life of patients and may cause the patients to abandon chemotherapy. Several medications (e.g., duloxetine and gabapentin) are recommended as remedies to treat CIPN; however, usage of these drugs is limited because of low efficacy or side effects such as dizziness, nausea, somnolence, and vomiting. From ancient East Asia, the decoction of medicinal herbal formulas or single herbs have been used to treat pain and could serve as alternative therapeutic option. Recently, the analgesic potency of medicinal plants and their phytochemicals on CIPN has been reported, and a majority of their effects have been shown to be mediated by glial modulation. In this review, we summarize the analgesic efficacy of medicinal plants and their phytochemicals, and discuss their possible mechanisms focusing on glial modulation in animal studies.

quarter of the currently-consumed drugs originate from plants. 18 Traditional medicine in East Asia including China, Japan and Korea contains various types of natural products for health. Thousands of years ago, "Breaking the code of damage from cold" (Korean name: Sang Han Lon) summarized and organized the prescriptions of natural products for drugs. Whole plants or disassembled plants (e.g., bark, berry, leaf, flower and root) were treated as a paste or decoction (water or hydroalcoholic). These medicinal herbs were administered either alone or as a composite formula. Medicinal herbs have been prescribed for the treatment of colds or various types of pain. Recent research has revealed that medicinal herbs have various pharmacological activities, such as antimicrobial, antioxidant, anti-inflammatory, and anti-nociceptive activities. 19 The potency of medicinal herbs is mediated by their bioactive compounds and phytochemicals. [20][21][22] Glial activation is commonly observed in various animal models of pain, such as inflammatory pain and neuropathic pain models. 23,24 Astrocytes and microglia in the central nervous system (CNS) respond to noxious stimulation or are activated in pathological pain conditions. [24][25][26] Upon the induction of pain, they change their morphologies: astrocytes show hypertrophy with thick branches; ameboid shape of soma and short and thick processes with hypertrophy appear in microglia. [27][28][29] Similarly, chemotherapeutic agents elicit microglial activation, followed by activation of astrocytes. 30 With their conformational changes, gliotransmitters, which act on nearby neurons and glia themselves, are released from activated glia. 31 Cytokines, well-known gliotransmitters, are also released as signaling molecules 32 and sensitize neurons, resulting in pain. 33 For example, IL-1β facilitates phosphorylation of ERK and NMDA receptors, and TNFα strengthens excitatory postsynaptic currents. 34,35 In the past few years, our group has elucidated the potency of medicinal herbs and their phytochemicals on chemotherapy-induced peripheral neuropathy (CIPN) using animal models. [36][37][38][39] We have shown the hypertrophy of glial cells in CIPN models and the analgesic effect of medicinal herbs and their phytochemicals through inhibition of glial activation. [36][37][38] According to the data reported by us and others, medicinal herbs and their phytochemicals are applicable to suppress CIPN, and these studies suggest that glia could be an efficient therapeutic target. Thus, in this review, we summarize and discuss the recent findings regarding the analgesic effects of medicinal herbs and phytochemicals and their glial modulation in CIPN animals (Table 1).

| Cinnamomum cassia (Korean name Yuk-gye)
Daily oral administration of the water extract of

| Ginseng (Korean name Insam)
Ginseng is a key component herb of Ninjin'yoeito, which is com-

| Synedrella nodiflora Gaertn
Eight days after the first paclitaxel (total 10 mg/kg, five times) injection, a single treatment with hydroethanolic extract of Synedrella nodiflora (100, 300 and 1000 mg/kg. p.o.) alleviated thermal hyperalgesia (hot plate: 55℃) in rats. 62 The same amounts of hydroethanolic extract of Synedrella nodiflora were administered to rats 5 times daily, and sup- Tanacetum parthenium extract also effectively suppressed pain behaviors in rat models of inflammatory, articular and neuropathic pain. 64

| Tithonia tubaeformis
In the vincristine mouse model (total
Intraperitoneally injected Incarvillateine (10 and 20 mg/kg) reversed the decreased mechanical withdrawal threshold by paclitaxel (total 10 mg/kg, 5 times). The incarvillateine treatment also lowered pain behaviors in inflammatory pain and nerve injuryinduced neuropathic pain models. Adenosine antagonists blocked the analgesic effects of incarvillateine on nerve injury-induced neuropathic pain. 74

| Melatonin
Melatonin, a hormone in vertebrates, has been found in several plants. 76

| Neoline
Neoline is an alkaloid found in Aconiti Tuber. In an oxaliplatin (

| Quercetin
Quercetin is a polyphenolic flavonoid found in various plants. administrations showed analgesic effects, and pretreatment also had prophylactic efficacy. Among the reviewed articles, analgesic effects accompanying glial modulation were reported in three medicinal herb formulas, six single medicinal herbs, and four phytochemicals (Table 1). A schematic diagram of this review is presented in Figure 1.

ACK N OWLED G M ENTS
The authors thank Dr. Geehoon Chung for his valuable comments on the manuscript.

D I SCLOS U R E
The authors declare no conflict of interest.

AUTH O R CO NTR I B UTI O N S
J. H. L. and S. K. K. conceived and designed the review article; J. H.
L., N. K. and S. P. wrote the manuscript draft; K. S. K. revised the manuscript.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing is not applicable to this review paper, because there are no new data in this article.