Comparative effects of alpha 2 delta-1 ligands in mouse models of colonic hypersensitivity

Mathieu Meleine (1) , Ludivine Boudieu (1) , Agathe Gelot (1) , Emilie Muller (1) , Amandine Lashermes (1) , Julien Matricon (1) , Celine Silberberg (1) , Vassilia Theodorou (2) , Alain Eschalier (1) , Denis Ardid (1) , Frederic A. Carvalho (1)

1 Neuro-Dol - Neuro-Dol
2 NGN - Neuro-Gastroentérologie et Nutrition

AIM: To investigate anti-hypersensitive effects of alpha 2 delta-1 ligands in non-inflammatory and inflammation-associated 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 mu L to 100 mu L by 20 mu L 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 mu L: 0.783 +/- 0.056 mV/s vs 0.531 +/- 0.034 mV/s, p < 0.05 and 100 mu L: 1.087 +/- 0.056 mV/s vs 0.634 +/- 0.038 mV/s, p < 0.05 for NMS and NH mice, respectively). In the inflammation-associated CHS, DSS-treated mice showed a dramatic and significant increase in VMR at 60 and 80 mu L distension volumes when compared to control mice (60 mu L: 0.920 +/- 0.079 mV/s vs 0.426 +/- 0.100 mV/s p < 0.05 and 80 mu L: 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 in the noninflammatory NMS-induced CHS model for the acute subcutaneous administration of the highest cumulative dose (30 mg/kg) and significantly reduced CHS in low-dose 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 alpha 2 delta-1 ligands efficacy on inflammation-associated CHS, highlighting their potential clinical interest in patients with chronic abdominal pain and moderate intestinal inflammation.

Mots clés: Neonatal maternal separation; Dextran sulfate sodium; Colonic hypersensitivity mouse models; Neonatal maternal separation

Mots clés: Colorectal distension; Colorectal distension

Domaines: Sciences du Vivant [q-bio]

Mathieu Meleine, Ludivine Boudieu, Agathe Gelot, Emilie Muller, Amandine Lashermes, et al.. Comparative effects of alpha 2 delta-1 ligands in mouse models of colonic hypersensitivity. World Journal of Gastroenterology, 2016, 22 (31), pp.7111-7123. ⟨10.3748/wjg.v22.i31.7111⟩. ⟨hal-02636301⟩