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.
Keywords: Chemotherapy-induced neuropathic pain; Dihydrofuran-2-one; Pain threshold; Pharmacokinetics; Pregabalin; Transient Receptor Potential channels.
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