Comparative effects of α2δ-1 ligands in mouse models of colonic hypersensitivity.
OBJECTIVE
To investigate anti-hypersensitive effects of α2δ-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 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 inflammation-associated 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 in the non-inflammatory 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.


CONCLUSIONS
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.
Mathieu Meleine, Ludivine Boudieu, Agathe Gelot, Emilie Muller, Amandine Lashermes, Julien Matricon, Celine Silberberg, Alain Eschalier, Denis Ardid, Frederic A Carvalho, Clermont Université, Université d'Auvergne, INSERM 1107 Neuro-Dol, F-63000 Clermont-Ferrand, France.
Mathieu
M
Meleine
Mathieu Meleine, Ludivine Boudieu, Agathe Gelot, Emilie Muller, Amandine Lashermes, Julien Matricon, Celine Silberberg, Alain Eschalier, Denis Ardid, Frederic A Carvalho, Clermont Université, Université d'Auvergne, INSERM 1107 Neuro-Dol, F-63000 Clermont-Ferrand, France.
Ludivine
L
Boudieu
Mathieu Meleine, Ludivine Boudieu, Agathe Gelot, Emilie Muller, Amandine Lashermes, Julien Matricon, Celine Silberberg, Alain Eschalier, Denis Ardid, Frederic A Carvalho, Clermont Université, Université d'Auvergne, INSERM 1107 Neuro-Dol, F-63000 Clermont-Ferrand, France.
Agathe
A
Gelot
Mathieu Meleine, Ludivine Boudieu, Agathe Gelot, Emilie Muller, Amandine Lashermes, Julien Matricon, Celine Silberberg, Alain Eschalier, Denis Ardid, Frederic A Carvalho, Clermont Université, Université d'Auvergne, INSERM 1107 Neuro-Dol, F-63000 Clermont-Ferrand, France.
Emilie
E
Muller
Mathieu Meleine, Ludivine Boudieu, Agathe Gelot, Emilie Muller, Amandine Lashermes, Julien Matricon, Celine Silberberg, Alain Eschalier, Denis Ardid, Frederic A Carvalho, Clermont Université, Université d'Auvergne, INSERM 1107 Neuro-Dol, F-63000 Clermont-Ferrand, France.
Amandine
A
Lashermes
Mathieu Meleine, Ludivine Boudieu, Agathe Gelot, Emilie Muller, Amandine Lashermes, Julien Matricon, Celine Silberberg, Alain Eschalier, Denis Ardid, Frederic A Carvalho, Clermont Université, Université d'Auvergne, INSERM 1107 Neuro-Dol, F-63000 Clermont-Ferrand, France.
Julien
J
Matricon
Mathieu Meleine, Ludivine Boudieu, Agathe Gelot, Emilie Muller, Amandine Lashermes, Julien Matricon, Celine Silberberg, Alain Eschalier, Denis Ardid, Frederic A Carvalho, Clermont Université, Université d'Auvergne, INSERM 1107 Neuro-Dol, F-63000 Clermont-Ferrand, France.
Celine
C
Silberberg
Mathieu Meleine, Ludivine Boudieu, Agathe Gelot, Emilie Muller, Amandine Lashermes, Julien Matricon, Celine Silberberg, Alain Eschalier, Denis Ardid, Frederic A Carvalho, Clermont Université, Université d'Auvergne, INSERM 1107 Neuro-Dol, F-63000 Clermont-Ferrand, France.
Vassilia
V
Theodorou
Mathieu Meleine, Ludivine Boudieu, Agathe Gelot, Emilie Muller, Amandine Lashermes, Julien Matricon, Celine Silberberg, Alain Eschalier, Denis Ardid, Frederic A Carvalho, Clermont Université, Université d'Auvergne, INSERM 1107 Neuro-Dol, F-63000 Clermont-Ferrand, France.
Alain
A
Eschalier
Mathieu Meleine, Ludivine Boudieu, Agathe Gelot, Emilie Muller, Amandine Lashermes, Julien Matricon, Celine Silberberg, Alain Eschalier, Denis Ardid, Frederic A Carvalho, Clermont Université, Université d'Auvergne, INSERM 1107 Neuro-Dol, F-63000 Clermont-Ferrand, France.
Denis
D
Ardid
Mathieu Meleine, Ludivine Boudieu, Agathe Gelot, Emilie Muller, Amandine Lashermes, Julien Matricon, Celine Silberberg, Alain Eschalier, Denis Ardid, Frederic A Carvalho, Clermont Université, Université d'Auvergne, INSERM 1107 Neuro-Dol, F-63000 Clermont-Ferrand, France.
Frederic A
FA
Carvalho
D000588:Amines / Q000627:therapeutic use; D000818:Animals; D015220:Calcium Channels / Q000502:physiology*; D003509:Cyclohexanecarboxylic Acids / Q000627:therapeutic use; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D000077206:Gabapentin; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000069583:Pregabalin / Q000627:therapeutic use; D005680:gamma-Aminobutyric Acid / Q000627:therapeutic use
D000588:Amines; C512066:CACNA2D1 protein, mouse; D015220:Calcium Channels; D003509:Cyclohexanecarboxylic Acids; D008024:Ligands; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D016264:Dextran Sulfate
Colonic hypersensitivity mouse models; Colorectal distension; Dextran sulfate sodium; Neonatal maternal separation; α2δ-1 ligands