Table 1.

Composition and source of natural products, their ion channel targets and effects on heterologous cells and neurons, and analgesic actions in vivo.

Natural product	Chemical composition	Source	Target	Model and concentration tested	Ref.
-Not reported-	-	Allium macrostemon Bunge Water decoction	↓NaV1.7	HEK cells tested with 50 mg/L. Alleviates pain in Formalin-induced and Acetic-acid-induced pain.	[41]
Alpha-allocryptopine	Alkaloid	Corydalis decumbens	↑NaV1.5T353I	HEK cells tested with 30 µM. Rescues NaV1.5 T353I plasma membrane expression.	[44]
Alpha-bisabolol	Terpene	Cannibus sativa	↓CaV3.2 ↓CaV3.3 ↓CaV2.1	Inhibited recombinant human CaV3.2 in HEK cells with IC50 of 4.5 ± 1.1 μM	[98]
Astragalin	Flavonol glycoside	Roots of Astragalus membranaceus	↑L-type current	Rat pancreatic islets tested with 100 µM. Hypoglycemic effect in hyperglycemic rats.	[103]
Betulinic acid	Pentacyclic triterpenoid	Hyptis emoryi	↓CaV3.2 ↓CaV3.3 ↓CaV2.2	HEK cells and rat DRGs tested with 20 µM. Alleviates Chemotherapy-induced peripheral neuropathy, HIV-induced sensory neuropathy, and partial sciatic nerve ligation at 2 µg/5 µl.	[104]
Bulleyaconitine A	Diterpenoid alkaloid	Aconitum bulleyanum	↓NaV	Pituitary GH3 cells tested with 10 µM. Sensory and motor block of rat sciatic nerve, tested with 0.375 to 0.75 mM.	[46]
Camphene	Monoterpene	Cannibus sativa	↓CaV3.2 ↓CaV3.3 ↓CaV2.1	Inhibited recombinant human CaV3.2 in HEK cells with IC50 of 7.7 ± 1.8 μM	[98]
Cannabidiol, Δ9-tetrahydrocannabinol	Benzoic acid Diterpenoid	Cannabis sativa	↓CaV3.1–3.3	HEK cells tested with 10–30 μM. Mouse trigeminal ganglion neurons tested with 1 µM.	[114]
Changrolin	Phenol	Dichroa febrifuga Lour	↓NaV	Rat ventricular myocytes. IC50 = 10.19 µM.	[127]
			↓CaV (L-type)	Rat ventricular myocytes. IC50 = 74.73 µM.
Cordycepin	Nucleotide analog	Cordyceps spp.(fungus)	↓NaV	Rat hippocampal CA1 pyramidal neurons tested with 80 µM.	[51]
Curcumin	Polyphenol	Curcuma longa	↓TTX Nav	Rat DRG neurons tested with 100 mg/kg. Analgesic effect in diabetic neuropathic pain model induced with STZ.	[130]
			↓CaV3.2	Bovine adrenal cells tested with 5 µM.	[129]
Evodiamine	Alkaloid	Evodia rutaecarpa	↓L-type CaV	Rat colon smooth muscle cells tested with 10 and 100 µM.	[118]
Eugenol, essential oil	Phenolic acid	Cloves	↓CaV3	HEK cells stably transfected, trigeminal ganglion neurons. IC50 = 0.5 mM.	[131]
			↓NaV,	Dental primary afferent neurons. IC50 = 0.6 mM Alleviates neuropathic pain in SNL at 50 µg	[29][30]
Dodoneine	Phenolic	Agelanthus dodoneifolius	↓L-type CaV	Rat cardiac myocytes. IC50 = 10 mM	[115]
Gastrodin	Gastrodia	Gastrodia		IC50 NaV1.7 = 25.87 µM, HEK cells. IC50 NaV1.8 = 67.5 µM, DRGs. Alleviates peripheral neuropathic pain and reverts hyperexcitability.	[56]
[6]-gingerol and [6]-shogaol	Phenolic	Ginger, rhizome	↓NaV1.8 ↓Nav1.1 ↓NaV1.3 ↓NaV1.6 ↓NaV1.7 ↓CaV2.2	IC50 NaV1.8 = 45 µM. Analgesic effect in a rat oral ulcerative mucositis model at 300 µM and 150 µM.	[125]
			-	Attenuates pain-associated behavior in rats with SNL at 100–400 mg/kg.	[31]
(-)-hardwickiic acid ((-)-HDA)	Diterpenoid	Croton californicus (Euphorbiaceae)	↓NaV TTX-S	Rat DRGs tested with 20 µM.	[57]
			↓NaV1.1, NaV 1.3, NaV1.5	HEK cells tested with 20 µM.
				Alleviates HIV- and chemotherapy-induced neuropathy at 2 µg/5 µl.
Hautriwaic acid (HTA)	Diterpenoid	Eremocarpus setigerus (Euphorbiaceae)	↓NaV TTX-S	Rat DRGs tested with 20 µM.	[57]
				Alleviates HIV- and Chemotherapy-induced neuropathy at 2 µg/5 µl.
Imperatorin	Furocoumarin	Angelica biserrata	↓NaV1.7	IC50 = 28 nM. Analgesic activity in thermal pain and formalin-induced pain in mice.	[32][93]
Lappaconitine	Diterpene alkaloid	Aconitum sinimontanum roots	NaV1.5	HEK cells (Acute 30, 60, 100 µM). Irreversible block.	[61]
			↓NaV1.7	HEK cells tested with 30 µM. IC50 = 27.67 µM.	[62]
			↓NaV1.3, ↓NaV1.4, ↓NaV1.5, ↓NaV1.8	HEK cells tested with 100 µM.
Lavender essential oil Silexan, a standardized lavender oil preparation	Monoterpenoid	Lavender stoechas and angustifolia		Antihyperalgesia in mice with SNI at 100 mg/kg. ↓pERK1/2 and JNK1.	[33]
			↓CaV3.2 ↓CaV2.2 ↓CaV2.1	CHO cells, tested with 1 or 10 µg/ml. Murine synaptosomes and hippocampal neurons tested with 1 µM. Decrease of anxiety-related behavior in humans at 80 mg/d.	[34][35][36]
Linalool essential oil	Monoterpenoid	Lavender stoechas and angustifolia	↓CaV3.2	HEK cells. IC50 = 84 µM.	[138]
			↓NaV	Olfactory receptor cells (ORCs). IC50 = 0.56 mM	[133]
Methyl eugenol	Phenylpropene	Asari Radix et Rhizoma	↓NaV1.7	Transfected CHO cells. IC50 = 295 μM	[37]
Magnolol	Polyphenolic	Bark of Magnolia officinalis	↓NaV	NG108-15 cells. IC50 = 15 and 30 µM at −70 and −100 mV, respectively	[38]
			TTX-STTX-R	DRG neurons, TTX-S IC50 = 9.4 μM. TTX-R IC50 = 7 μM	[78]
Naringenin	Flavonoid	Citrus, tomatoes, and figs	↓NaV1.8 ↓CaV2.2	Rat DRG neurons tested with 100 µM. Reverses mechanical allodynia (pSNL), in males at 30 mg/kg.	[142]
Paeonol	Methoxybenzene	Paeonia suffruticosa	↓NaV total	Guinea pig ventricular myocytes. IC50 = 17 µM.	[80]
Peimine	Alkaloid	Fritillaria	↓NaV1.7	IC50 47.2 µM	[39]
Physalin F	Steroidal	Physalis acutifolia	↓CaV2.2 ↓CaV2.3	Rat DRG neurons tested with 1 µM. Antinociceptive effect on paclitaxel-induced peripheral neuropathy and SNL at 2 µg/5 µl.	[119]
L-Tetrahydropalmatine, protopine, and dehydrocorydaline	Alkaloids	Cordyalis yanhusuo	↓NaV1.5 ↓NaV1.7	L-Tetrahydropalmatine, IC50 = 7.05 µM. CHO cells stably expressing NaV1.7 and NaV1.5. Analgesic effects in formalin-induced pain model.	[67]
Puerarin	Isoflavonoid glycoside	Kudzu root	↓NaV1.8 through β1 ↓NaV1.7	Rat DRG neurons. IC50 = 481.5 µM. Analgesic effect in paclitaxel-induced neuropathic pain at 24 mg/kg.	[85]
Qishenkel Luteolin, cryptotanshinone, licochalcone A, and glycyrrhetinic acid	–	Mixture	↓CaV1.2	Pig cardiac myocytes tested with 0.33 g/kg. Luteolin, cryptotanshinone, licochalcone A, and glycyrrhetinic acid. IC50 = 1.5, 5.7, 4.3, and 12.8 µM, respectively.	[40]
Quercetin, Quercitrin, Hyperin, Rutin	Flavonoids	Acanthopanax senticosus	↓L-type CaV	Rat ventricular myocytes tested with 283.12 µg/mL.	[121]
Radix paeoniae rubra (paeoniflorin, benzoylpaeniflorin, albiflorin, lactiflorin, oxypaeoniflorin, paeonin, paeoniflorigenone, paenoside, paeonolide, paeonol, galloylpaeoniflorin, gallotannin)	–	Mixture	↓Total NaV	Rat hippocampal CA1 neurons tested with 0.8 mg/ml.	[50]
Rosmarinic acid	Phenolic acids	Rosmarinic officinalis	↓CaV3.2	IC50 = 53.5 µg/ml.	[138]
Saikosaponins A	Pentacyclic triterpenoid	Bupleurum Chinese root	↓NaV1.7	IC50 = 28.6 nM. Analgesic activity in thermal pain and formalin-induced pain in mice.	[32][93]
Sophoraflavanone G	Flavonoid	Root of Sophora flavescens	↓CaV3.1 ↓CaV3.2	HEK cells, IC50 CaV3.1 = 1.4 µM. HEK cells IC50 CaV3.2 = 0.75 µM. Alleviates mechanical allodynia.	[43]
Sophoraflavanone G	Flavonoid	Root of Sophora	↓HVA	NG108-15 cells IC50 HVA = 1.8 µM	[43]
Sophoraflavanone G Vincapusine, Vincarodine, Serpentine	Flavonoid Monoterpene indole alkaloid	Root of Sophora Bulbus Fritillaria Catharanthus roseus	-	Murine models of inflammatory or neuropathic pain. Inhibits acetic-acid-induced writhing response in the formalin test, paclitaxel-induced neuropathic pain (3 or 1.5 mg/kg p.o.).	[43][124]
			↓CaV3.1	HEK-293 cells transiently transfected. Vicapusine, IC50 = 11.83 µM. Vincarodine, IC50 = 14.3 µM. Serpentine, IC50 = 14.54 µM.