Effects of tetramethylpyrazine on pharmacokinetics in plasma and brain dialysate and neuropathic pain in rat model of spared sciatic nerve injury
This study aims to explore the effects of tetramethylpyrazine(TMP)on pharmacokinetics in plasma and brain dialysate and neuropathic pain in the rat model of partial sciatic nerve injury(SNI),and to investigate the correlation between the analgesic effect of TMP and its concentrations in the plasma and brain dialysate.Male SD rats were randomized into Sham,SNI,and SNI+TMP groups.Mechanical stimulation with von frey filaments and cold spray method were employed to evaluate the mechanical sensitivity and cold sensitivity of rats.Another two groups,Sham+TMP and SNI+TMP,were used to intubate the common jugular vein and implant microdialysis probes into the anterior cingulate gyrus(ACC),respectively.After intraperitoneal injection of TMP at a dose of 80 mg·kg-1,automatic blood collection and intracerebral microdialysis(perfusion rate of 1 μL·min-1)systems were used to collect the blood and brain dialysate for 24 h.HSS T3 C18 reversed-phase chromatographic column(2.1 mm×50 mm,2.5 μm)was used for liquid chromatographic separation.Gradient elution was carried out with the mobile phase of methanol-water(containing 0.005%formic acid)at a flow rate of 0.25 mL·min-1.Electrospray ion source was used for mass spectrometry,and the scanning mode was multi-reaction monitoring under the positive ion mode.The ion pairs for quantitative analysis were TMP m/z 137/122 and aspirin m/z 179/137,respectively.DAS 2.11 was used to calculate the pharmacokinetic parameters.The optimal time of TMP to exert the analgesia effect and inhibit cold pain sensitivity was 60 min after treatment.The TMP in the plasma and brain dialysate of SNI rats showed the Tmax of 15 min and 30 min,the Cmax of(2 866.43±135.39)and(1 462.14±197.38)μg·L-1,the AUC0-t of(241 463.30±28 070.31)and(213 115.62±32 570.07)μg·min·L-1,the MRT0-t of(353.13±47.73)and(172.16±12.72)min,and the CLZ of 0.73 and 0.36 L·min·kg-1,respectively.The analgesic effect of TMP had a significant correlation with the blood drug concentration in the ACC,which indicated that this method was suitable for the detection of TMP in rat plasma and brain dialysate.The method is accurate,reliable,and sensitive and can realize the important value of the application of correlation analysis theory of"automatic blood collection-microdialysis/PK-PD"in the research on neuropathic pain.
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