论文部分内容阅读
AIM: To investigate anti-hypersensitive effects of α2δ-1 ligands in non-inflammatory and inflammationassociated colonic hypersensitivity(CHS) mouse models.METHODS: To induce an inflammation-associated CHS, 1% dextran sulfate sodium(DSS) was administered to C57Bl/6J male mice, in drinking water, for 14 d. Regarding the non-inflammatory neonatal maternal separation(NMS)-induced CHS model, wild-type C57BI/6J pups were isolated from their mother from day 2 to day 14(P2 to P14), three hours per day(from 9:00 a.m. to 12:00 p.m.). Colorectal distension was performed by inflating distension probe from 20 μL to 100 μL by 20 μL increment step every 10 s. After a first colorectal distension(CRD), drugs were administered subcutaneously, in a cumulative manner,(Gabapentin at 30 mg/kg and 100 mg/kg; Pregabalin at 10 mg/kg and 30 mg/kg; Carbamazepine at 10 mg/kg and 30 mg/kg) and a second CRD was performed one hour after each injection.RESULTS: The visceromotor response(VMR) to CRD was increased by our NMS paradigm protocol in comparison to non-handled(NH) mice, considering the highest distension volumes(80 μL: 0.783 ± 0.056 mV /s vs 0.531 ± 0.034 m V/s, P < 0.05 and 100 μL: 1.087 ± 0.056 m V/s vs 0.634 ± 0.038 m V/s, P < 0.05 for NMS and NH mice, respectively). In the inflammationassociated CHS, DSS-treated mice showed a dramatic and significant increase in VMR at 60 and 80 μL distension volumes when compared to control mice(60 μL: 0.920 ± 0.079 m V/s vs 0.426 ± 0.100 m V/s P < 0.05 and 80 μL: 1.193 ± 0.097 mV /s vs 0.681 ± 0.094 mV /s P < 0.05 for DSS- and Water-treated mice, respectively). Carbamazepine failed to significantly reduce CHS in both models. Gabapentin significantly reduced CHS in the DSS-induced model for both subcutaneous injections at 30 or 100 mg/kg. Pregabalin s i g n i f i c a n t l y r e d u c e d V M R t o C R D i n t h e n o n-inflammatory NMS-induced CHS model for the acute subcutaneous administration of the highest cumulative dose(30 mg/kg) and significantly reduced CHS in lowdose DSS-treated mice in a dose-dependent manner. Finally, the percent decrease of AUC induced by acute GBP or Pregabalin treatment were higher in the inflammatory DSS-induced CHS model in comparison to the non-inflammatory NMS-induced CHS model.CONCLUSION: This preclinical study demonstrates α2δ-1 ligands efficacy on inflammation-associated CHS, highlighting their potential clinical interest in patients with chronic abdominal pain and moderate intestinal inflammation.
To investigate anti-hypersensitive effects of α2δ-1 ligands in non-inflammatory and inflammationassociated colonic hypersensitivity (CHS) mouse models. METHODS: To induce an inflammation-associated CHS, 1% dextran sulfate sodium (DSS) was administered to C57Bl / 6J male mice, in drinking water, for 14 d. Regarding the non-inflammatory neonatal maternal separation (NMS) -induced CHS model, wild-type C57BI / 6J pups were isolated from their mother from day 2 to day 14 (P2 to P14 (from 9:00 am to 12:00 pm). Colorectal distension was performed by inflating distension probe from 20 μL to 100 μL by 20 μL increment step every 10 s. After a first colorectal distension (CRD) , drugs were administered subcutaneously in a cumulative manner (Gabapentin at 30 mg / kg and 100 mg / kg; Pregabalin at 10 mg / kg and 30 mg / kg; Carbamazepine at 10 mg / kg and 30 mg / kg) and a second CRD was performed one hour after each injection .RESULTS: The visceromotor response (VMR) to CRD was increased by our NMS paradigm protocol in comparison to non-handled (NH) mice, considering the highest distension volumes (80 μL: 0.783 ± 0.056 mV / s vs. 0.531 ± 0.034 mV / s, P <0.05 and 100 μL: 1.087 ± 0.056 mV / s vs 0.634 ± 0.038 mV / s, P <0.05 for NMS and NH mice, respectively). In the inflammationassociated CHS, DSS-treated mice showed a dramatic and significant increase in VMR at 60 and 80 μL distension volumes when compared to control mice (60 μL: 0.920 ± 0.079 mV / s vs 0.426 ± 0.100 mV / s P <0.05 and 80 μL: 1.193 ± 0.097 mV / s vs 0.681 ± 0.094 mV / s P <0.05 for DSS- and Water-treated mice, respectively). Carbamazepine failed to significantly reduce CHS in both models. Gabapentin significantly reduced CHS in the DSS-induced model for both subcutaneous injections at 30 or 100 mg / kg. Pregabalin significantly reduced VMR to CRD intheno n-inflammatory NMS -induced CHS model for the acute subcutaneous administration of the highest cumulative dose (30 mg / kg) and significanFinally, the percent decrease of AUC induced by acute GBP or Pregabalin treatment were higher in the inflammatory DSS-induced CHS model in comparison to the non-inflammatory NMS-induced CHS model. CONCLUSION: This preclinical study demonstrates that α2δ-1 ligands efficacy on inflammation-associated CHS, highlighting their potential clinical interest in patients with chronic abdominal pain and moderate intestinal inflammation.