Effects of pregabalin on visceral pain responses and colonic compliance in rats.
OBJECTIVE
Pregabalin, which binds to the alpha2-delta subunit of voltage-gated calcium channels, increased the threshold for pain during colorectal distension (CRD) in irritable bowel syndrome (IBS) patients. We tested the effects of oral pregabalin on the visceral pain-related viscerosomatic and autonomic cardiovascular responses to CRD and colonic compliance in rats.


METHODS
The activity of the abdominal musculature (viscerosomatic response), monitored by electromyography and intracolonic manometry, and changes in blood pressure and heart rate, monitored by telemetry, were assessed simultaneously in conscious rats during CRD.


RESULTS
Pregabalin (10-200 micromol kg(-1), p.o.) inhibited dose dependently the viscerosomatic response to phasic, noxious CRD (12 distensions at 80 mm Hg). At 200 mumol kg(-1), pregabalin also reduced the increase in blood pressure and heart rate associated with noxious CRD. Moreover, pregabalin (200 micromol kg(-1), p.o.) reduced the visceromotor response to ascending phasic CRD (10-80 mm Hg) and significantly increased the threshold pressure for response. During phasic CRD (2-20 mm Hg), pregabalin (200 micromol kg(-1), p.o.) increased intracolonic volume, resulting in a shift to the left of the pressure-volume relationship curve, indicative of an increase of compliance.


CONCLUSIONS
Pregabalin reduced the viscerosomatic and autonomic responses associated with CRD-induced visceral pain and increased colonic compliance in rats. These observations confirm the analgesic activity of pregabalin on visceral pain and support the translational value of the CRD model to humans. Ligands for the alpha2-delta subunit might represent interesting compounds for the treatment of visceral pain disorders, such as IBS.
AstraZeneca R&D, Integrative Pharmacology--GI Biology, Mölndal, Sweden.
A
A
Ravnefjord
M
M
Brusberg
H
H
Larsson
E
E
Lindström
V
V
Martínez
D015746:Abdominal Pain / Q000188:drug therapy* / Q000209:etiology; D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015220:Calcium Channels / Q000187:drug effects*; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D003187:Compliance / Q000187:drug effects; D004108:Dilatation, Pathologic; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D043183:Irritable Bowel Syndrome / Q000188:drug therapy / Q000503:physiopathology; D008365:Manometry; D000069583:Pregabalin; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
D000700:Analgesics; D015220:Calcium Channels; D021122:Protein Subunits; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid