Table 1.
The therapeutic agents for paclitaxel-induced peripheral neuropathy in preclinical experiments.
| Therapeutic Targets | Therapeutic Agents | Dose | Animals | Symptoms that Showed Improvement | Mechanisms | References |
|---|---|---|---|---|---|---|
| Oxidative stress and mitochondrial disfunction | Anakinra, IL-1β antagonist | 50–100 mg/kg, i.p. | Rats | Pain threshold | Reductions of MDA, MPO and IL-1β and increase in GSH in paws | [19] |
| Antimycin A | 0.2–0.6 mg/kg, i.p. | Rats | Mechanical hypersensitivity | Inhibition of mitochondrial complex III | [20] | |
| Curcumin | 100–200 mg/kg, p.o. | Rats | Histological changes in spinal cord and sciatic nerve | Reduction of NF-κB, TNF-α, IL-6, iNOS and GFAP, p53, caspase-3, Apaf-1, LC3A, LC3B and beclin-1, and increase in Nrf2, HO-1, NQO1, Bcl-2, and Bcl-xL. | [21] | |
| Divya-Peedantak-Kwath, a herbal decoction | 69–615 mg/kg, p.o. | Mice | Thermal hyperalgesia, mechanical allodynia and hyperalgesia, and axonal degeneration | Suppression of oxidative stress and inflammation | [22] | |
| Duloxetine | 10–30 mg/kg, i.p. | Mice | Mechanical hyperalgesia and thermal nociception | Inhibiting PARP and p53 activation and regulating Bcl-2 family to reverse oxidative stress and apoptosis | [23] | |
| Evodiamine | 5 mg/kg | Rats | Mechanical hypersensitivity and thermal hypersensitivity | Downregulation of inflammatory and chemoattractant cytokines (IL-1β, IL-6, TNF-α, and MCP-1), oxidative stress, and mitochondrial dysfunction in DRG. | [24] | |
| Flavonol | 25–200 mg/kg, s.c. | Mice | Tactile allodynia, cold allodynia and thermal hyperalgesia | Inhibitions of TNF-α, IL-1β and free radicals | [25] | |
| Ghrelin | 300 nmol/kg, i.p. | Mice | Mechanical sensitivity, thermal sensitivity, DRG damage (ATF-3 positive cells), and density of IENF | Decreases in plasma oxidative and nitrosative stress and increases in UCP2, SOD2, and PGC-1α | [26] | |
| GKT137831, a NOX4 inhibitor | 1 mg/kg, i.p. | Rats | Mechanical sensitivity and thermal sensitivity | Decreases of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) in the DRG | [27] | |
| Lacosamide | 30 mg/kg, p.o. | Rats | Thermal hyperalgesia and cold allodynia | Upregulation of total antioxidant capacity and NGF, and downregulation of NF-kB p65, TNF-α, active caspase-3, Notch1 receptor, p-p38, and IL-6/p-JAK2/p-STAT3 | [28] | |
| Melatonin | 5–50 mg/kg, p.o. | Rats | Mechanical sensitivity | Reduction of mitochondrial damage | [29] | |
| Nicotinamide riboside | 200 mg/kg, p.o. | Rats | Tactile hypersensitivity | N.A. | [30] | |
| Phenyl-N-tert-butylnitrone | 100 mg/kg, i.p. | Mice | Mechanical hypersensitivity | N.A. | [31] | |
| Pregabalin | 30 mg/kg, p.o. | Rats | Thermal hyperalgesia and cold allodynia | Upregulation of total antioxidant capacity and NGF, and downregulation of NF-kB p65, TNF-α, active caspase-3, Notch1 receptor, p-p38, and IL-6/p-JAK2/p-STAT3 | [28] | |
| Rosuvastatin | 10 mg/kg, i.p. | Mice | Thermal hyperalgesia, cold hyperalgesia, and mechanical allodynia | Downregulations of IL-1β, oxidative stress | [32] | |
| Rotenone | 1–5 mg/kg, i.p. | Rats | Mechanical hypersensitivity | Inhibition of mitochondrial complex I | [20] | |
| Tempol, a mimetic of SOD | 20 mg/kg, i.p. | Rats | Mechanical sensitivity and thermal sensitivity | Decreases of proinflammatory cytokines such as IL-1β, IL-6 and TNF-α in the DRG | [27] | |
| Trimethoxy flavones | 25–200 mg/kg, s.c. | Mice | Tactile allodynia, cold allodynia, and thermal hyperalgesia | Inhibitions of TNF-α, IL-1β and free radicals | [33] | |
| Umbelliprenin, a prenylated coumarin | 12.5–25 mg/kg, i.p. | Mice | Thermal hyperalgesia | Decrease in serum IL-6 levels and oxidative stress | [34] | |
| Vitamin C | 500 mg/kg, i.p. | Rats | Mechanical sensitivity and thermal sensitivity | Decreases of proinflammatory cytokines (IL-1β, IL-6 and TNF-α) in the DRG | [27] | |
| Inflammatory | 3-Hydroxyflavone | 25–75 mg/kg, i.p. | Rats | Tactile allodynia, cold allodynia, thermal hyperalgesia, and heat-hyperalgesia | Suppressions of TNF-α, IL-1β, IL-6, CGRP, and substance P in the spinal cord, and inhibition of the receptor of substance P | [35] |
| AMD3100, a CXCR4 antagonist | 8 mg/kg, i.p. | Mice | Mechanical allodynia | N.A. | [36] | |
| Anakinra, IL-1β antagonist | 50–100 mg/kg, i.p. | Rats | Pain threshold | Reductions of MDA, MPO and IL-1β and increase in GSH in paws | [19] | |
| Anti-HMGB1-neutralizing antibody | 1 mg/kg, i.p. | Mice | Mechanical allodynia | N.A. | [36] | |
| Berberine | 5–20 mg/kg, i.p. | Mice | Thermal hyperalgesia | N.A. | [37] | |
| Choline-fenofibrate | 6–24 mg/kg, i.p., 15–60 mg/kg, p.o. | Mice | Mechanical hyperalgesia, cold hyperalgesia, and sensory nerve compound action potential amplitude | Regulation of PPAR-⍺ expression and decrease neuroinflammation in DRG | [38] | |
| Curcumin | 100–200 mg/kg, p.o. | Rats | Histological changes in the spinal cord and sciatic nerve | Reductions of NF-κB, TNF-α, IL-6, iNOS and GFAP, p53, caspase-3, Apaf-1, LC3A, LC3B and beclin-1, and increase in Nrf2, HO-1, NQO1, Bcl-2, and Bcl-xL. | [21] | |
| Divya-Peedantak-Kwath, a herbal decoction | 69–615 mg/kg, p.o. | Mice | Thermal hyperalgesia, mechanical allodynia and hyperalgesia, and axonal degeneration | Suppressions of oxidative stress and inflammation | [22] | |
| Duloxetine | 30 mg/kg/day, i.p. | Mice | Mechanical hyperalgesia, thermal hyperalgesia, and loss of IENF | Decreases in NF-κB, p-p38, IL-6, and TNF-α in DRG | [39] | |
| ESI-09, a Epac inhibitor | 20 mg/kg, p.o. | Mice | Mechanical allodynia and number of IENF | Suppression of spinal cord astrocyte activation | [40] | |
| Etanercept | 2 mg/kg, i.p. | Rats | Mechanical hypersensitivity and cold hypersensitivity | Blocking of TNF-α signaling | [41] | |
| Evodiamine | 5 mg/kg | Rats | Mechanical hypersensitivity and thermal hypersensitivity | Downregulation of inflammatory and chemoattractant cytokines (IL-1β, IL-6, TNF-α, and MCP-1), oxidative stress, and mitochondrial dysfunction in DRG. | [24] | |
| Fenofibrate | Diet with 0.2% or 0.4% fenofibrate | Mice | Mechanical allodynia, cold allodynia, SNAP amplitude, and intra-epidermal nerve fibers density | Regulation of PPAR-α expression and reduction in neuroinflammation | [42] | |
| Fenofibrate | 100–150 mg/kg, i.p., 300–600 mg/kg, p.o. | Mice | Mechanical hyperalgesia, cold hyperalgesia, and sensory nerve compound action potential amplitude | Regulation of PPAR-⍺ expression and decrease neuroinflammation in DRG | [38] | |
| Fenofibric acid | 6–24 mg/kg, i.p., 30–90 mg/kg, p.o. | Mice | Mechanical hyperalgesia, cold hyperalgesia, and sensory nerve compound action potential amplitude | Regulation of PPAR-⍺ expression and decrease neuroinflammation in DRG | [38] | |
| Flavonol | 25–200 mg/kg, s.c. | Mice | Tactile allodynia, cold allodynia, and thermal hyperalgesia | Inhibitions of TNF-α, IL-1β and free radicals | [25] | |
| FPS-ZM1, a RAGE antagonist | 1 mg/kg, i.p. | Mice | Mechanical allodynia | N.A. | [36] | |
| GKT137831, a NOX4 inhibitor | 1 mg/kg, i.p. | Rats | Mechanical sensitivity and thermal sensitivity | Decreases of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) in the DRG | [27] | |
| Human intravenous immunoglobulin | 1 g/kg, i.v. | Rats | Mechanical allodynia, loss of IENF, and distal axonal degeneration | Suppression of the axonopathy with macrophage infiltration | [43] | |
| Icariin | 100 mg/kg, p.o. | Rats | Mechanical allodynia | Downregulations of TNF-α, IL-1β, IL-6 and astrocyte activation in spinal cord via SIRT1 activation | [44] | |
| IL-1 receptor antagonist | 3 mg/kg, i.p. | Rats | Mechanical hypersensitivity and cold hypersensitivity | N.A. | [41] | |
| JTC-801 | 0.01–0.05 mg/kg, i.v. | Rats | Mechanical allodynia | Decreases in PI3K, p-Akt, and inflammatory cytokines in the DRG | [45] | |
| Lacosamide | 30 mg/kg, p.o. | Rats | Thermal hyperalgesia and cold allodynia | Upregulation of total antioxidant capacity and NGF, and downregulation of NF-kB p65, TNF-α, active caspase-3, Notch1 receptor, p-p38, and IL-6/p-JAK2/p-STAT3 | [28] | |
| Losartan | 20–100 mg/kg, i.p. | Rats | Mechanical hyperalgesia | Decrease in inflammatory cytokines including IL-1β and TNF-α in the DRG | [46] | |
| Losartan | 100 mg/kg, p.o. | Rats | Mechanical allodynia | Attenuations of neuroinflammatory changes and expression of pro-resolving markers (arginase 1 and IL-10) indicating a possible shift in macrophage polarization | [47] | |
| Low-molecular-weight heparin, a rage antagonist | 2.5 mg/kg. i.p. | Mice | Mechanical allodynia | N.A. | [36] | |
| LPS-R, a TLR4 antagonist | 0.5 mg/kg, i.p. | Mice | Mechanical allodynia | N.A. | [36] | |
| MDA7, a CB₂ agonist | 15 mg/kg, i.p. | Rats | Mechanical allodynia | Downregulations of IRF8, P2X4, CaMKIIα, p-CREB, FosB, BDNF, GluR1 and NR2B, and increase in the expression of K+-Cl- cotransporter | [48] | |
| MJN110, a MAGL inhibitor | 4–40 mg/kg, i.p. | Mice | Mechanical allodynia | Downregulations of MCP-1, CCL2 and p-p38 in DRG as well as MCP-1 in the spinal dorsal horn | [49] | |
| Polaprezinc | 3 mg/kg, p.o. | Rats | Mechanical allodynia | Suppression of macrophage migration into DRG | [50] | |
| Pregabalin | 30 mg/kg, p.o. | Rats | Thermal hyperalgesia and cold allodynia | Upregulation of total antioxidant capacity and NGF, and downregulation of NF-kB p65, TNF-α, active caspase-3, Notch1 receptor, p-p38, and IL-6/p-JAK2/p-STAT3 | [28] | |
| Rapamycin | 5 mg/kg, i.p. | Rats | Mechanical hypersensitivity and thermal hypersensitivity | Decreases of IL-1β, IL-6, TNF-α, substance P and CGRP in DRG. | [51] | |
| Reparixin | 8 mg/hr/kg using micro–osmotic pumps | Rats | Mechanical allodynia and cold allodynia | Inhibition of IL-8/CXCR1/2 pathway and suppressions of p-FAK, p-JAK2/p-STAT3, and PI3K-p-cortactin activation | [52] | |
| Rosuvastatin | 10 mg/kg, i.p. | Mice | Thermal hyperalgesia, cold hyperalgesia, and mechanical allodynia | Downregulations of IL-1β and oxidative stress | [32] | |
| S504393, a CCR2 antagonist | 5 mg/kg, i.p. | Rats | Mechanical hypersensitivity and cold hypersensitivity | N.A. | [41] | |
| Siwei Jianbu decoction | 5–10 g/kg, i.g. | Mice | Mechanical hyperalgesia and thermal nociception | Inhibiting the JNK, ERK1/2 phosphorylation, NF-κB, TNF-α, IL-1β, and IL-6. | [53] | |
| TAK242, a TLR4 antagonist | 1–3 mg/kg, i.p. | Rats | Mechanical hypersensitivity | Antagonism of TLR4 | [54] | |
| TAK242, a TLR4 antagonist | 3 mg/kg, i.p. | Mice | Mechanical allodynia | N.A. | [55] | |
| Tempol, a mimetic of SOD | 20 mg/kg, i.p. | Rats | Mechanical sensitivity and thermal sensitivity | Decreases of proinflammatory cytokines (IL-1β, IL-6 and TNF-α) in the DRG | [27] | |
| Thrombomodulin alfa | 1–3 mg/kg, i.p. | Mice | Mechanical allodynia | N.A. | [36] | |
| Trimethoxy flavones | 25–200 mg/kg, s.c. | Mice | Tactile allodynia, cold allodynia, and thermal hyperalgesia | Inhibitions of TNF-α, IL-1β and free radicals | [33] | |
| Umbelliprenin, a prenylated coumarin | 12.5–25 mg/kg, i.p. | Mice | Thermal hyperalgesia | Decreases in serum IL-6 levels and oxidative stress | [34] | |
| Vitamin C | 500 mg/kg, i.p. | Rats | Mechanical sensitivity and thermal sensitivity | Decreases of proinflammatory cytokines (IL-1β, IL-6 and TNF-α) in the DRG | [27] | |
| β-caryophyllene, a CB2 agonist | 25 mg/kg, p.o. | Mice | Mechanical allodynia | Through CB2-activation in the CNS and posterior inhibition of p38 MAPK/NF-κB activation and cytokine release | [56] | |
| K channel | 3-Carboxyphenyl isothiocyanate | 1.33–13.31 µmol/kg, s.c. | Mice | Cold hypersensitivity | Release H2S activating Kv7 channel | [57] |
| Allyl isothiocyanate | 1.33–13.31 µmol/kg, s.c. | Mice | Cold hypersensitivity | Release H2S activating Kv7 channel | [57] | |
| Phenyl isothiocyanate | 4.43–13.31 µmol/kg, s.c. | Mice | Cold hypersensitivity | Release H2S activating Kv7 channel | [57] | |
| Retigabine | 10 mg/kg, i.p. | Rats | Mechanical allodynia, IENF density, and morphological alteration of mitochondria in peripheral nerve | Specific KCNQ/Kv7 channel opener | [58] | |
| Sodium hydrosulfide hydrate | 13.31–38 µmol/kg, s.c. | Mice | Cold hypersensitivity | Release H2S activating Kv7 channel | [57] | |
| Ca channel | ML218, a T-type calcium channel blocker | 1–10 mg/kg, i.p. | Rats | Mechanical hypersensitivity | Inhibition of Cav3.2 | [54] |
| RQ-00311651, a T-type calcium channel blocker | 10–40 mg/kg, i.p. | Mice and rats | Mechanical hyperalgesia | Block of Cav3.1/Cav3.2 T channels | [59] | |
| TRP channel | AMG9810 | 30 mg/kg, p.o. | Rats | Mechanical allodynia, hyperalgesia, and thermal hyperalgesia | TRPV1 antagonism | [60] |
| Capsazepine | 30 mg/kg, s.c. | Rats | Thermal hyperalgesia | TRPV1 antagonism | [61] | |
| HC-067047, a TRPV4 antagonist | 10 mg/kg, i.p. | Mice | Mechanical hyperalgesia | TRPV4 antagonism | [62] | |
| Quercetin | 20–60 mg/kg, i.p. | Rats and mice | Heat hyperalgesia and mechanical allodynia | Suppression of PKCε and TRPV1 in the spinal cords and DRG | [63] | |
| Ruthenium red | 3 mg/kg, s.c. | Rats | Thermal hyperalgesia | TRP antagonism | [61] | |
| SB-366791, a TRPV1 antagonist | 0.5 mg/kg, i.p. | Mice | Visceral nociception, mechanical hypersensitivity and heat hypersensitivity | TRPA1 antagonism | [55] | |
| Tabernaemontana catharinensis ethyl acetate fraction | 100 mg/kg, p.o. | Mice | Mechanical allodynia | TRPA1 antagonism | [64] | |
| Glutamate | Memantine | 1–5 mg/kg | Rats | Mechanical hypersensitivity | Antagonism of NMDA receptor | [65] |
| Valproate | 200 mg/kg, i.p. | Rats | Mechanical allodynia | Suppressions HDAC2 upregulation, glutamate accumulation, and the corresponding changes in EAAT2/VGLUT/synaptophysin expression and HDAC2/YY1 interaction | [66] | |
| PDE | Cilostazol | Diet containing 0.3% cilostazol | Mice | Mechanical hyperalgesia and Schwann cell dedifferentiation within the sciatic nerve | Differentiation of Schwann cells via a mechanism involving cAMP/Epac signaling | [67] |
| Minoxidil | 25–50 mg/kg, i.p. | Mice | Mechanical hyperalgesia, thermal sensitivity, and damages of sciatic nerve | Suppression of neuroinflammation (macrophage and microglia) recruitments and remodeling of intracellular calcium homeostasis in DRG | [68] | |
| Cannabinoid receptor | Cannabidiol | 1–20 mg/kg, i.p. | Mice | Mechanical sensitivity | N.A. | [69] |
| Cannabidiol | 2.5–25 mg/kg, i.p., p.o. | Mice | Mechanical allodynia | N.A. | [70] | |
| JZL184, a MAGL inhibitor | 4–40 mg/kg, i.p. | Mice | Mechanical allodynia | N.A. | [49] | |
| KLS-13019 | 2.5–25 mg/kg, i.p. | Mice | Mechanical allodynia | N.A. | [70] | |
| MDA7, a CB₂ agonist | 15 mg/kg, i.p. | Rats | Mechanical allodynia | Downregulations of IRF8, P2X4, CaMKIIα, p-CREB, FosB, BDNF, GluR1 and NR2B, and increase in the expression of K+-Cl- cotransporter | [48] | |
| MJN110, a MAGL inhibitor | 4–40 mg/kg, i.p. | Mice | Mechanical allodynia | Downregulations of monocyte chemoattractant protein-1 (MCP-1 and CCL2) and p-p38 MAPK in dorsal root ganglia as well as MCP-1 in the spinal dorsal horn | [49] | |
| URB597, a centrally penetrant FAAH inhibitor | 1 mg/kg, i.p. | Mice | Mechanical hypersensitivity and cold hypersensitivity | Inhibition of FAAH, the major enzyme catalyzing the degradation of anandamide, an endocannabinoid, and other fatty acid amides | [71] | |
| URB937, a peripherally restricted FAAH inhibitor | 1 mg/kg, i.p. | Mice | Mechanical hypersensitivity and cold hypersensitivity | Inhibition of FAAH, the major enzyme catalyzing the degradation of anandamide, an endocannabinoid, and other fatty acid amides | [71] | |
| β-caryophyllene, a CB2 agonist | 25 mg/kg, p.o. | Mice | Mechanical allodynia | CB2-activation in the CNS and posterior inhibition of p38 MAPK/NF-κB activation and cytokine release | [56] | |
| Δ9-THC | 2.5–20 mg/kg, i.p. | Mice | Mechanical sensitivity | N.A. | [69] | |
| Opioid receptor | Morphine | 3–6 mg/kg, p.o. | Mice | Mechanical allodynia | N.A. | [72] |
| Oxycodone | 24 mg/kg/day, p.o. | Mice | Mechanical allodynia | N.A. | [72] | |
| Monoamines | SR-17018 | 1–48 mg/kg/day, p.o. | Mice | Mechanical allodynia | N.A. | [72] |
| Bee venom acupuncture | 1 mg/kg, s.c. | Rats | Mechanical hyperalgesia | Via spinal α₂-adrenergic receptor | [73] | |
| Bee venom acupuncture | 0.25–2.5 mg/kg, i.p. | Mice | Cold allodynia and mechanical allodynia | Via the spinal noradrenergic and serotonergic mechanism | [74] | |
| Quetiapine | 10–15 mg/kg, p.o. | Mice | Heat hyperalgesia, mechanical allodynia, and cold allodynia | Via α2-adrenoceptors | [75] | |
| Reboxetine | 10 mg/kg, i.p. | Rats | Mechanical allodynia and cold hyperalgesia | α2-AR mediated antinociception at the spinal cord | [76] | |
| Venlafaxine | 40–60 mg/kg, s.c. | Mice | Cold allodynia and mechanical allodynia | Via the spinal noradrenergic and serotonergic mechanism | [74] | |
| Acetylcholine receptor | Nicotine | 0.6–0.9 mg/kg, i.p. or 24 mg/kg, s.c. | Mice | Mechanical allodynia and density of IENF | Via α7 nicotinic acetylcholine receptor | [77] |
| Pirenzepine | 10 mg/kg, s.c. | Mice | Mechanical sensitivity and thermal sensitivity | Muscarinic ACh type 1 receptor (M1R) antagonism | [78] | |
| R-47, an α7 nAChR silent agonist | 5–10 mg/kg, i.p. | Mice | Mechanical hypersensitivity, loss of IENF and morphological changes of microglia | N.A. | [79] | |
| α-Conotoxin RgIA4 | 80 μg/kg, s.c. | Rats | Mechanical allodynia | N.A. | [80] | |
| cAMP/PKA | ESI-09, a Epac inhibitor | 20 mg/kg, p.o. | Mice | Mechanical allodynia and number of IENF | Suppression of spinal cord astrocyte activation | [40] |
| PKC | HOE140, a kinin B2 antagonist | 50 nmol/kg, i.p. | Mice | Mechanical hyperalgesia | inactivation of PKCε | [62] |
| DALBK, a kinin B1 antagonist | 150 nmol/kg, i.p. | Mice | Mechanical hyperalgesia | inactivation of PKCε | [62] | |
| Tamoxifen | 30 mg/kg, p.o. | Mice | Mechanical allodynia cold allodynia | Inhibition of PKC/ERK pathway | [81] | |
| MAPK | Duloxetine | 30 mg/kg/day, i.p. | Mice | Mechanical hyperalgesia, thermal hyperalgesia, and loss of IENF | Decreases in NF-κB, p-p38, IL-6, and TNF-α in DRG | [39] |
| Duloxetine | 10–30 mg/kg, p.o. | Mice | Mechanical allodynia and cold allodynia | Inhibiting ERK1/2 phosphorylation in spinal cord | [82] | |
| Gabapentin | 30–100 mg/kg, p.o. | Mice | Mechanical allodynia and cold allodynia | Inhibiting ERK1/2 phosphorylation in spinal cord | [82] | |
| Lacosamide | 30 mg/kg, p.o. | Rats | Thermal hyperalgesia and cold allodynia | Upregulation of total antioxidant capacity and NGF, and downregulation of NF-kB p65, TNF-α, active caspase-3, Notch1 receptor, p-p38, and IL-6/p-JAK2/p-STAT3 | [28] | |
| MJN110, a MAGL inhibitor | 4–40 mg/kg, i.p. | Mice | Mechanical allodynia | Downregulations of MCP-1, CCL2 and p-p38 in DRG as well as MCP-1 in the spinal dorsal horn | [49] | |
| PD0325901 | 30 mg/kg, p.o. | Mice | Mechanical allodynia and cold allodynia | Inhibiting ERK1/2 phosphorylation in spinal cord | [82] | |
| Pregabalin | 30 mg/kg, p.o. | Rats | Thermal hyperalgesia and cold allodynia | Upregulation of total antioxidant capacity and NGF, and downregulation of NF-kB p65, TNF-α, active caspase-3, Notch1 receptor, p-p38, and IL-6/p-JAK2/p-STAT3 | [28] | |
| Siwei Jianbu decoction | 5–10 g/kg, p.o. | Mice | Mechanical hyperalgesia and thermal nociception | Inhibiting the JNK, ERK1/2 phosphorylation, NF-κB, TNF-α, IL-1β, and IL-6 | [53] | |
| Tamoxifen | 30 mg/kg, p.o. | Mice | Mechanical allodynia cold allodynia | Inhibition of PKC/ERK pathway | [81] | |
| Trametinib | 0.5 mg/kg | Mice | Mechanical and cold allodynia | Inhibition of the MEK/ERK pathway | [83] | |
| β-caryophyllene, a CB2 agonist | 25 mg/kg, p.o. | Mice | Mechanical allodynia | Through CB2-activation in the CNS and posterior inhibition of p38 MAPK/NF-κB activation and cytokine release | [56] | |
| OATP1B2 | Nilotinib | 100 mg/kg, p.o. | Mice | Mechanical allodynia | Inhibition of paclitaxel intake to neuron via OATP1B2 inhibition | [84] |
| mTOR | Rapamaycin | 5 mg/kg, i.p. | Rats | Mechanical hypersensitivity and thermal hypersensitivity | Decreases of IL-1β, IL-6, TNF-α, substance P and CGRP in DRG. | [51] |
| Others | AM9053, a NAAA inhibitor | 1–10 mg/kg, i.p. | Mice | Mechanical allodynia | N.A. | [85] |
| Aucubin | 15–50 mg/kg, i.p. | Mice | Mechanical allodynia | N.A. | [86] | |
| Aucubin | 50 mg/kg, i.p. | Mice | Mechanical allodynia | Inhibition of ER stress in peripheral Schwann cells | [87] | |
| Bogijetong decoction, a herbal drug formulation | 400 mg/kg, p.o. | Rats | Heat sensitivity | Improvement of morphological abnormalities in the sciatic nerve axons and DRG tissue | [88] | |
| DALBK, a kinin B1 antagonist | 150 nmol/kg, i.p. | Mice | Mechanical allodynia | Antagonism of kinin B1 receptor | [89] | |
| FR173657, a kinin B2 antagonist | 100 nmol/kg, i.p. | Mice | Mechanical allodynia | Antagonism of kinin B2 receptor | [89] | |
| Gelsemium sempervirens | 1 mL, i.p. | Rats | Mechanical allodynia, mechanical hyperalgesia, cold allodynia, and density of IENF | N.A. | [90] | |
| HOE140, a kinin B2 antagonist | 100 nmol/kg, i.p. | Mice | Mechanical allodynia | Antagonism of kinin B2 receptor | [89] | |
| Iridoids isolated from Viticis Fructus | 15 mg/kg | Mice | Mechanical allodynia | N.A. | [91] | |
| Lepidium meyenii | 0.5–10 mg/kg, p.o. | Rats | Cold hypersensitivity | N.A. | [92] | |
| Metformin | 200 mg/kg, i.p. | Mice | Mechanical hypersensitivity | Activation of AMPK | [93] | |
| Narciclasine | 1 mg/kg, p.o. | Mice | Mechanical hypersensitivity | Activation of AMPK | [93] | |
| Neoline | 10 mg/kg/day, s.c. | Mice | Mechanical hyperalgesia | N.A. | [94] | |
| Nicotinamide riboside | 200 mg/kg, p.o. | Rats | Mechanical hyperalgesia and cold hyperalgesia | N.A. | [95] | |
| NO-711, a GAT-1 inhibitor | 3 mg/kg, i.p. | Mice | Thermal hyperalgesia and cold allodynia | Inhibition of GAT-1 | [96] | |
| Processed aconite root | 1 g/kg/day, s.c. | Mice | Mechanical hyperalgesia | N.A. | [94] | |
| Recombinant human soluble thrombomodulin | 3–10 mg/kg, i.p. | Rats | Mechanical hyperalgesia | Inactivation of HMGB1 | [97] | |
| Rikkunshito | 0.3–1 mg/kg, p.o. | Mice | Mechanical hyperalgesia | Suppression of p-NF-κB in spinal cord | [98] | |
| Salicylidene salicylhydrazide | 50–75 mg/kg, i.p. | Mice | Mechanical allodynia and cold allodynia | N.A. | [99] | |
| Sargassum glaucescens from the Persian Gulf | 100–200 mg/kg, i.p. | Mice | Cold allodynia | N.A. | [100] | |
| SLAB51, a probiotic formulation | 1.5 g (200 billion of bacteria) in 10 mL of drinking water | Mice | Mechanical allodynia and hyperalgesia | Increases in the expression of opioid and cannabinoid receptors in spinal cord, reduction in nerve fiber damage in the paws and modulation of the serum proinflammatory cytokines concentration | [101] | |
| SSR240612, a kinin B1 antagonist | 150 nmol/kg, i.p. | Mice | Mechanical allodynia | Antagonism of kinin B1 receptor | [89] | |
| Staurosporine | 0.1 mg/kg, i.p. | Mice | Mechanical allodynia | Inhibitory of PI3K signaling pathway | [102] | |
| Telmisartan | 5–10 mg/kg, i.p. | Mice | Mechanical hyperalgesia and thermal hyperalgesia | Inhibition of CYP2J isoforms and reductions of EpOME in DRGs and plasma | [103] | |
| Terfenadine | 1–2 mg/kg | Mice | Mechanical hyperalgesia | Inhibition of CYP2J isoforms | [103] | |
| Wortmannin | 0.6 mg/kg, i.p. | Mice | Mechanical allodynia | Inhibitory of PI3K signaling pathway | [102] |
Abbreviations: Ach, acetylcholine; AMPK, AMP-activated protein kinase; Apaf-1, apoptosis protease-activating factor 1; ATF-3, activating transcription factor 3; Bcl-2, B-cell lymphoma 2; Bcl-xL, B-cell lymphoma-extra-large; BDNF, brain derived neurotrophic factor; CaMKIIα, calmodulin-dependent protein kinase IIα; CCL2, C-C motif chemokine ligand 2; CCR2, C-C motif chemokine receptor 2; CGRP, calcitonin gene-related peptide; CREB, cAMP response element binding protein; CXCR, C-X-C motif chemokine receptor; CYP2J, Cytochrome P450 2J; DRG, dorsal root ganglia; EAAT2, excitatory amino acid transporter 2; Epac, exchange protein directly activated by cAMP; EpOME, epoxyoctadecamonoenoic acids; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; FAAH, fatty-acid amide hydrolase; FosB, FBJ murine osteosarcoma viral oncogene homolog B; GAT-1, gamma-aminobutyric acid (GABA) transporter 1; GFAP, glial fibrillary acidic protein; GluR1, glutamate ionotropic receptor AMPA type subunit 1; GSH, glutathione; HDAC2, histone deacetylase 2; HMGB1, high mobility group box 1; HO-1, heme oxygenase 1; i.p., intraperitoneal; i.v., intravenous; IENF, intra-epidermal nerve fibers; IL-10, interleukin-10; IL-1β, interleukin-1 beta; IL-6, interleukin-6; IL-8, interleukin-8; iNOS, inducible nitric oxide synthase; IRF8, interferon regulatory factor 8; JNK, c-Jun N-terminal kinase; MAGL, monoacylglycerol lipase; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemotactic protein 1; MDA, malondialdehyde; MEK, mitogen-activated protein kinase kinases; MPO, myeloperoxidase; NAAA, N-acylethanolamine-hydrolyzing acid amidase; nAChR, nicotinic acetylcholine receptor; NF-κB, nuclear factor kappa-B; NGF, nerve growth factor; NMDA, N-methyl-D-aspartate; NOX4, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4; NQO1, NAD(P)H dehydrogenase [quinone] 1; NR2B, N-methyl D-aspartate (NMDA) receptor subtype 2B; Nrf2, nuclear factor-erythroid 2-related factor 2; OATP1B2, organic anion-transporting polypeptide 1b2; p.o., per os; p-Akt, phospho-protein kinase B; PARP, poly ADP-ribose polymerase; p-CREB, phospho-cAMP response element binding protein; p-FAK, phospho-fokal adhesion kinase; PGC-1α, peroxisome proliferatoractivated receptor γ coactivator-1; PI3K, phosphatidylinositol-3 kinase; p-JAK2, phospho-janus kinase 2; PKC, protein kinase C; p-NF-κB, phospho-nuclear factor kappa-B; p-p38, phospho-p38; PPAR-α, peroxisome proliferator-activated receptor-α; p-STAT3, phospho-signal transducer and activator of transcription 3; RAGE, receptor for advanced glycation endproducts; s.c., subcutaneous; SIRT1, sirtuin-1; SNAP, sensory nerve action potential; SNCV, sensory nerve conduction velocity; SOD, superoxide dismutase; TLR4, Toll-like receptor 4; TNF-α, tumor necrosis factor-α; TRP, transient receptor potential; TRPA1, transient receptor potential ankyrin 1; TRPV1, transient receptor potential vanilloid 1; TRPV4, transient receptor potential vanilloid 4; UCP2, uncoupling protein 2; VGLUT, vesicular glutamate transporter 3; YY1, Yin-Yang 1.