Palmitoylethanolamide Reverses Paclitaxel-Induced Allodynia in Mice.
Chemotherapy-induced peripheral neuropathy (CIPN) represents a serious complication associated with antineoplastic drugs. Although there are no medications available that effectively prevent CIPN, many classes of drugs have been used to treat this condition, including anticonvulsants, serotonin and noradrenaline reuptake inhibitors, and opioids. However, these therapeutic options yielded inconclusive results in CIPN clinical trials and produced assorted side effects with their prolonged use. Thus, there is an urgent need to develop efficacious and safe treatments for CIPN. In this report, we tested whether the endogenous lipid palmitoylethanolamide (PEA) alone or in combination with the anticonvulsant gabapentin would reduce allodynia in a mouse paclitaxel model of CIPN. Gabapentin and PEA reversed paclitaxel-induced allodynia with respective ED50doses (95% confidence interval) of 67.4 (61.52-73.94) and 9.2 (8.39-10.16) mg/kg. Isobolographic analysis of these drugs in combination revealed synergistic antiallodynic effects. The PPAR-α antagonist receptor antagonist GW6471 [N-((2S)-2-(((1Z)-1-methyl-3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-enyl)amino)-3-(4-(2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy)phenyl)propyl)propanamide] completely blocked the antinociceptive effects of PEA. In addition, PEA administered via intraplantar injection into a paw, intrathecal injection, and intracerebroventricular injection reversed paclitaxel-induced allodynia, suggesting that it may act at multiple sites in the neuroaxis and periphery. Finally, repeated administration of PEA (30 mg/kg, 7 days) preserved the antiallodynic effects with no evidence of tolerance. These findings taken together suggest that PEA possesses potential to treat peripheral neuropathy in cancer patients undergoing chemotherapy.
Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia (G.D.; J.L.W.; M.I.D.; A.H.L.); and Department of Biotechnology and Bioscience, University of Milano-Bicocca, Milan, Italy (G.D.) giulia.donvito@vcuhealth.org.
Giulia
G
Donvito
Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia (G.D.; J.L.W.; M.I.D.; A.H.L.); and Department of Biotechnology and Bioscience, University of Milano-Bicocca, Milan, Italy (G.D.).
Jenny L
JL
Wilkerson
Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia (G.D.; J.L.W.; M.I.D.; A.H.L.); and Department of Biotechnology and Bioscience, University of Milano-Bicocca, Milan, Italy (G.D.).
M Imad
MI
Damaj
Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia (G.D.; J.L.W.; M.I.D.; A.H.L.); and Department of Biotechnology and Bioscience, University of Milano-Bicocca, Milan, Italy (G.D.).
Aron H
AH
Lichtman
D000577:Amides; D000588:Amines / Q000494:pharmacology; D000818:Animals; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D004357:Drug Synergism; D004983:Ethanolamines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000077206:Gabapentin; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D047493:PPAR alpha / Q000378:metabolism; D017239:Paclitaxel / Q000009:adverse effects*; D010169:Palmitic Acids / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D000577:Amides; D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D004983:Ethanolamines; D047493:PPAR alpha; D010169:Palmitic Acids; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; C005958:palmidrol; D017239:Paclitaxel