title: Antiallodynic and antihyperalgesic activity of 3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one compared to pregabalin in chemotherapy-induced neuropathic pain in mice.
abstract: BACKGROUND
  Anticancer drugs - oxaliplatin (OXPT) and paclitaxel (PACLI) cause painful peripheral neuropathy activating Transient Receptor Potential (TRP) channels. Here we investigated the influence of 3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one (LPP1) and pregabalin on nociceptive thresholds in neuropathic pain models elicited by these drugs. Pharmacokinetics of LPP1 and its ability to attenuate neurogenic pain caused by TRP agonists: capsaicin and allyl isothiocyanate (AITC) were also investigated.
  
  
  METHODS
  Antiallodynic and antihyperalgesic effects of intraperitoneally administered LPP1 and pregabalin were tested in the von Frey, hot plate and cold water tests. The influence of LPP1 on locomotor activity and motor coordination was assessed using actimeters and rotarod. Serum and tissue concentrations of LPP1 were measured using the HPLC method with fluorimetric detection.
  
  
  RESULTS
  In OXPT-treated mice LPP1 and pregabalin dose-dependently reduced tactile allodynia (41-106% and 6-122%, respectively, p<0.01). At the dose of 10mg/kg LPP1 attenuated cold allodynia. In PACLI-treated mice LPP1 and pregabalin reduced tactile allodynia by 12-63% and 8-50%, respectively (p<0.01). Both drugs did not affect cold allodynia, whereas pregabalin (30 mg/kg) attenuated heat hyperalgesia (80% vs. baseline latency time; p<0.01). No motor impairments were observed in LPP1 or pregabalin-treated neuropathic mice in the rotarod test, while severe sedation was noted in the locomotor activity test. LPP1 reduced pain induced by capsaicin (51%; p<0.01) and AITC (41%; p<0.05). The mean serum concentration of LPP1 measured 30 min following i.p. administration was 7904.6 ± 1066.1 ng/ml. Similar levels were attained in muscles, whereas brain concentrations were 62% lower. Relatively high concentrations of LPP1 were also determined in the cerebrospinal fluid and the sciatic nerve.
  
  
  CONCLUSIONS
  LPP1 and pregabalin reduce pain in OXPT and PACLI-treated mice. This activity of LPP1 might be in part attributed to the inhibition of TRPV1 and TRPA1 channels, but also central mechanisms of action cannot be ruled out.
authors.affiliation: Department of Pharmacodynamics, Chair of Pharmacodynamics, Jagiellonian University, Medical College, Medyczna 9, 30-688 Cracow, Poland. Electronic address: salat.kinga@gmail.com.
authors.forename: Kinga
authors.initials: K
authors.lastname: Sałat
authors.affiliation: Department of Pharmacokinetics and Physical Pharmacy, Jagiellonian University, Medical College, Medyczna 9, 30-688 Cracow, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Cios
authors.affiliation: Department of Pharmacokinetics and Physical Pharmacy, Jagiellonian University, Medical College, Medyczna 9, 30-688 Cracow, Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Wyska
authors.affiliation: Department of Fundamental Engineering, Faculty of Production Engineering, Warsaw University of Life Sciences, Nowoursynowska 164, 02-787 Warsaw, Poland.
authors.forename: Robert
authors.initials: R
authors.lastname: Sałat
authors.affiliation: Department of Pharmacodynamics, Chair of Pharmacodynamics, Jagiellonian University, Medical College, Medyczna 9, 30-688 Cracow, Poland.
authors.forename: Szczepan
authors.initials: S
authors.lastname: Mogilski
authors.affiliation: Department of Pharmacodynamics, Chair of Pharmacodynamics, Jagiellonian University, Medical College, Medyczna 9, 30-688 Cracow, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Filipek
authors.affiliation: Department of Physicochemical Drug Analysis, Chair of Pharmaceutical Chemistry, Jagiellonian University, Medical College, Medyczna 9, 30-688 Cracow, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Więckowski
authors.affiliation: Department of Physicochemical Drug Analysis, Chair of Pharmaceutical Chemistry, Jagiellonian University, Medical College, Medyczna 9, 30-688 Cracow, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Malawska
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D006358:Hot Temperature / Q000009:adverse effects; D006930:Hyperalgesia / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D000069583:Pregabalin; D014110:Touch / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C547282:3-(4-(3-trifluoromethylphenyl)piperazin-1-yl)dihydrofuran-2-one; D000700:Analgesics; D000970:Antineoplastic Agents; D010879:Piperazines; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D015107:4-Butyrolactone
keywords: Chemotherapy-induced neuropathic pain; Dihydrofuran-2-one; Pain threshold; Pharmacokinetics; Pregabalin; Transient Receptor Potential channels