TABLE 1.
Description of the chemical and pharmacological aspects of the preclinical studies included in the systematic review.
| Substance | Obtaining | Model | Evaluation methods | Dose (via) | Animal | Positive control | Results | Other outcomes | References |
|---|---|---|---|---|---|---|---|---|---|
| Alkaloids | |||||||||
| Berberine | Sigma Aldrich Ltd. (United States) | PTX (1 mg/kg, i.p. on alternate days for 4 days—4 mg/kg cumulative dose) | Thermal hyperalgesia and Cold allodynia (tail flick latency) | 10 or 20 mg/kg, i.p. | Male Wistar rats | Amytriptiline (10 mg/kg, i.p.) | Thermal hyperalgesia: inhibited decrease of latency in tail flick test Cold allodynia: no significant decrease in tail cold allodynia latencies | Increased expression of the NRf2 gene and antioxidant activity (decreased TBARS and increased SOD, GPx and GSH) | Singh et al. (2019) |
| Evodiamine | Kisshida Chemical Co., Ltd. (Osaka, Japan) | PTX (1 mg/kg, i.p., on alternate days for 4 days—4 mg/kg cumulative dose) | Mechanical allodynia (von Frey filaments) and Thermal hyperalgesia (hot plate test) | 5 mg/kg, i.p. | Male Sprague–Dawley rats | Not reported | Decreased the thermal sensitivity and inhibited the reduction of the hind paw withdrawal | Activation of mitochondrial function, decreased TNF-α, IL-1β, IL-6, MCP-1 and antioxidant activity (decreased MDA, NO and 8-isoprostane F2α) | Wu and Chen (2019) |
| Levo-tetrahydropalmatine | Shanghai Lei Yun Shang Pharmaceutical Co. | OXL (3 mg/kg, i.p., 5 consecutive days for 2 weeks with a total of 10 injections—30 mg/kg cumulative dose) | Mechanical hyperalgesia (von Frey filaments) | 1, 2 e 4 mg/kg, i.p. | Male C57BL/6 mice | Not reported | Increased the paw withdrawal threshold in mice | D1 dopamine receptor agonist | Guo et al. (2014) |
| Matrine | (Ningxia Zi Jing Hua Pharmacy, Yinchuan Ningxia) | VIN (100 µg/kg i.p., for seven consecutive days—700 µg/kg cumulative dose) | Mechanical allodynia (von Frey filaments), Thermal hyperalgesia and Cold allodynia (cold plate test) | 15, 30 or 60 mg/kg, i.p | Institute of Cancer Research (ICR) mice | Pregabalin (10 mg/kg, i.p.) | Mechanical allodynia: Repeated but not single administration had effect on mechanical allodynia. Cold allodynia: Single and repeated administration suppressed cold allodynia Thermal hyperalgesia: No difference between control and treatment | Not reported | Dun et al. (2014) |
| Nicotine | Sigma-Aldrich (St. Louis, MO, United States) | PTX (8 mg/kg i.p., every other day for a total of four injections—32 mg/kg cumulative dose) | Mechanical allodynia (von Frey filaments) | Acute: 0.3, 0.6, or 0.9 mg/kg, i.p.; Chronic: 6, 12, or 24 mg/kg, s.c. | Male C57BL/6J mice | Not reported | Acute: reversed mechanical allodynia in paclitaxel-treated mice in a time- and dose-dependent Chronic: prevented the development of mechanical allodynia throughout the entire duration of the experiment, up to 35 days post-paclitaxel injection | Increased Acetylcholinesterase Activity | Kyte et al. (2018) |
| Nicotine | Not reported | OXL (2.4 mg/kg, i.p., 5 consecutive days every week for 3 weeks with a total of 15 injections—36 mg/kg cumulative dose) | Cold allodynia (cold plate test), Mechanical allodynia (paw pressure test) and Mechanical hyperalgesia (von Frey digital) | 0.5, 1.0 or 1.5 mg/kg, i.p. | Male Sprague-Dawley rats | Not reported | The higher dose (1.5 mg/kg) was able to completely revert the cold allodynia, mechanical allodynia and mechanical hyperalgesia | Not reported | Di Cesare Mannelli et al. (2013) |
| Cannabinoids | |||||||||
| Cannabidiol | INSYS Therapeutics, Inc. (Austin, TX) | PTX (8 mg/kg, i.p., for 4 days—32 mg/kg cumulative dose), OXL (6 mg/kg, i.p. for 1 day) and VIN (0.1 mg/kg, i.p. for 7 days—0.7 mg/kg cumulative dose) | Mechanical allodynia (von Frey filaments) | 0.0625—20 mg/kg, i.p. (PTX) 1.25—10 mg/kg, i.p. (OXL and VIN) | Male C57BL/6 mice | Not reported | Attenuation of mechanical sensitivity (PTX and OXL) | Not reported | King et al. (2017) |
| Cannabidiol | National Institute on Drug Abuse drug supply program (Bethesda, MD, United States) | PTX (8 mg/kg, i.p., on alternate days for 4 days—32 mg/kg cumulative dose) | Cold (acetone test) and Mechanical allodynia (von Frey filaments) | 5 or 10 mg/kg, i.p | Male and Female C57BL/6 mice | Not reported | Prevented the development of paclitaxel-induced cold and mechanical allodynia | Not reported | Ward et al. (2011) |
| Cannabidiol | National Institute on Drug Abuse drug supply program (Bethesda, MD, United States) | PTX (8 mg/kg, i.p., on alternate days for 4 days—32 mg/kg cumulative dose) | Mechanical allodynia (von Frey filaments) | 2.5, 5 or 10 mg/kg, i.p. | Female C57BL/6 mice | Not reported | Prevented paclitaxel-induced mechanical sensitivity. | 5-HT1A receptors agonist | Ward et al. (2014) |
| Delta-9-tetrahydrocannabinol | National Institute on Drug Abuse drug supply program (Bethesda, MD, United States) | PTX (8 mg/kg, i.p., for 4 days—32 mg/kg cumulative dose), OXL (6 mg/kg, i.p. for 1 day) and VIN (0.1 mg/kg, i.p. for 7 days—0.7 mg/kg cumulative dose) | Mechanical allodynia (von Frey filaments) | 0.0625—20 mg/kg, i.p. (PTX) 10 mg/kg, i.p. (OXL and VIN) | Male C57BL/6 mice | Not Reported | Attenuation of mechanical sensitivity (PTX and VIN) | Not Reported | King et al. (2017) |
| Curcuminoids | |||||||||
| Curcumin | Himedia Laboratories, (Mumbai, India) | VIN (0.1 mg/kg, i.p.—once a day for 7 days) | Thermal hyperalgesia (hot plate test), thermal allodynia (cold plate test), mechanical hyperalgesia (pin prick test) | 15, 30 or 60 mg/kg, p.o. | Male Swiss mice | Pregabalin (10 mg/kg, p.o.) | Attenuated thermal hyperalgesia (30 and 60 mg/kg), thermal allodynia and mechanical hyperalgesia | Calcium inhibitory, and antioxidative activity (increased SOD, CAT, GPx and GSH, and decreased LPO and NO) | Babu et al. (2015) |
| Tetrahydrocurcumin | Sami labs (Bangalore) | VIN (75 µg/kg, i.p., once per day for 10 consecutive days—750 µg/kg cumulative dose) | Thermal hyperalgesia (hot plate test), thermal allodynia (cold plate test) and mechanical hyperalgesia (Randall and Sellito test) | 40 or 80 mg/kg, p.o. | Male Wistar rats | Pregabalin (10 mg/kg, p.o.) | Increased the pain threshold | Decreased TNF-α, calcium inhibitory and antioxidant activity (Increased CAT, SOD, GPx, GSH and decreased LPO, NO) | Greeshma et al. (2015) |
| Flavonoids | |||||||||
| 6-Methoxyflavanone | Sigma-Aldrich, (United States) | CIS (3 mg/kg, i.p./week for 4 weeks—12 mg/kg cumulative dose) | Mechanical Allodynia [static (von Frey filaments) and dynamic (cotton bud pressure)] | 25, 50, or 75 mg/kg, i.p. | Sprague-Dawley rats | Gapapentine (75 mg/kg, i.p) | Reduced the cisplatin-induced static allodynia and increased the dynamic allodynia through increasing the paw withdrawal latency | COX-1 and 2 antagonists (in vitro) | Akbar et al. (2020) |
| 6-Methoxyflavone | Sigma-Aldrich (St. Louis, MO, United States) | CIS (3.0 mg/kg, i.p. once a week for 4 weeks—12 mg/kg cumulative dose) | Mechanical allodynia (abdominal constriction test) and Thermal hyperalgesia (hot plate and tail immersion tests) | 25, 50 or 75 mg/kg, i.p. | Male Sprague-Dawley rats | Gabapentine (75 mg/kg, i.p.) | Increased the paw withdrawal threshold and protected against temporal expression of hypoalgesia | Not reported | Shahid et al. (2017) |
| Icariin | Shanghai CIVI Chemical Technology Co. (China) | PTX (8 mg/kg, i.p., for 3 days—24 mg/kg cumulative dose) | Mechanical allodynia (von Frey digital) | 25, 50 or 100 mg/kg, i.p. | Male Sprague-Dawley rats | Not reported | Alleviated paclitaxel-induced mechanical allodynia in the long term (100 mg/kg) | Decreased expression of TNF-a, IL-1b and IL-6, NF-kB and GFAP, SIRT1 downregulation and H4 acetylation in the spinal cord (100 mg/kg) | Gui et al. (2018) |
| Quercetin | Not reported | OXL (1 mg/kg, i.v., twice a week with a total of nine injections—9 mg/kg cumulative dose) | Mechanical hyperalgesia (von Frey digital) and Cold allodynia (tail immersion test) | 25, 50 or 100 mg/kg, i.p. | Male Swiss mice | Not reported | Increased mechanical and cold nociceptive threshold | Prevention of lipid peroxidation and tyrosine nitrosylation, Decreased iNOS expression | Azevedo et al. (2013) |
| Quercetin | Not reported | PTX (2 mg/kg, i.p., every other day with a total of 4 injections—8 mg/kg cumulative dose) | Mechanical allodynia (von Frey filaments) and Thermal hyperalgesia (tail immersion test) | 20 or 60 mg/kg, intragastrically | Male Sprague-Dawley rats and Institute of Cancer Research (ICR) mice | Not reported | Reduced mechanical nociceptive threshold and increased tail withdrawal latency | Decreased levels of proteins PKCε and expression of TRPV1 | Gao et al. (2016) |
| Rutin | Not reported | OXL (1 mg/kg, i.v., twice a week with a total of nine injections—9 mg/kg cumulative dose) | Mechanical hyperalgesia (von Frey digital) and Cold allodynia (tail immersion test) | 25, 50 or 100 mg/kg, i.p. | Male Swiss mice | Not reported | Increased mechanical and cold nociceptive threshold | Prevention of lipid peroxidation and tyrosine nitrosylation, Decreased iNOS expression | Azevedo et al. (2013) |
| Terpenes | |||||||||
| Aucubin | Wako Pure Chemical Industries (Osaka, Japan) | PTX (5 mg/kg, i.p.—single administration) | Mechanical Allodynia (von Frey filaments) | 5, 15 or 50 mg/kg, i.p. | Male C57BL/6NCr mice | Not reported | Significantly inhibited the exacerbation of allodynia (15 and 50 mg/kg) | Not reported | Andoh et al. (2016) |
| Aucubin | Wako Pure Chemical Industries (Osaka, Japan) | PTX (5 mg/kg, i.p.—single administration) | Mechanical Allodynia (von Frey filaments) | 50 mg/kg, i.p. | Male C57BL/6NCr mice | Not reported | Inhibited exacerbation of paclitaxel-induced mechanical allodynia | Inhibition of Endoplasmic Reticulum (CCAAT/enhancer-binding protein) ER Stress (inhibited CHOP expression) Schwann Cells | Andoh et al. (2017) |
| Betulinic acid | Extracted and isolated in Hyptis emoryi | PTX (2 mg/kg, i.p., every other day with a total of 4 injections—8 mg/kg cumulative dose) | Mechanical allodynia (von Frey filaments) | 2 µg/5 µl, i.th. | Male and female Sprague-Dawley rats | Not reported | Significant reversal of mechanical allodynia at 1 h after injection, lasting for 2 additional hours | Block of N- and T-type calcium channels | Bellampalli et al. (2019) |
| (−)-Hardwickiic Acid | Isolated in Croton calcifornicus | PTX (2 mg/kg, i.p., every other day with a total of 4 injections—8 mg/kg cumulative dose) | Mechanical allodynia (von Frey filaments) | 2 µg/5 µl, i.th. | Male and female Sprague-Dawley rats | Not reported | Significant relief of mechanical allodynia | Blockade of Tetrodotoxin-Sensitive Voltage-Dependent Sodium Channels | Cai et al. (2019) |
| Hautriwaic Acid | Isolated in Eremocarpus setigerus | PTX (2 mg/kg, i.p., every other day with a total of 4 injections—8 mg/kg cumulative dose) | Mechanical allodynia (von Frey filaments) | 2 µg/5 µl, i.th. | Male and female Sprague-Dawley rats | Not reported | No reversal of mechanical allodynia | Blockade of Tetrodotoxin-Sensitive Voltage-Dependent Sodium Channels | Cai et al. (2019) |
| Pedicularis-lactone | Extraction and isolation in Viticis Fructus | PTX (5 mg/kg, i.p., single injection) | Mechanical allodynia (von Frey filaments) | 15 mg/kg p.o. (considering purity 10.1 mg/kg) | Male C57BL/6NCr mice | Not reported | Inhibited PTX-induced allodynia | Not reported | Yu et al. (2021) |
| Viteoid I | Extraction and isolation in Viticis Fructus | PTX (5 mg/kg, i.p., single injection) | Mechanical allodynia (von Frey filaments) | 15 mg/kg p.o. (considering purity 13.8 mg/kg) | Male C57BL/6NCr mice | Not reported | Inhibited PTX-induced allodynia | Not reported | Yu et al. (2021) |
| Viteoid II | Extraction and isolation in Viticis Fructus | PTX (5 mg/kg, i.p., single injection) | Mechanical allodynia (von Frey filaments) | 15 mg/kg p.o. (considering purity 13.0 mg/kg) | Male C57BL/6NCr mice | Not reported | Inhibited PTX-induced allodynia | Not reported | Yu et al. (2021) |
| Xanthines | |||||||||
| Propentofylline | Not reported | VIN (75 µg/kg i.v. 5 injections daily, 3 days of interval then 4 more doses, total 9 injections—675 µg/kg cumulative dose) | Mechanical allodynia (von Frey filaments) | 10 mg/kg, i.p. | Male Holtzman rats | Not reported | Treatment inhibited any mechanical allodynia | Glial modulation | Sweitzer et al. (2006) |
PTX: paclitaxel; CIS: cisplatin; OXL: oxaliplatin; VIN: vincristine.