title: Oral baclofen reduces visceral pain-related pseudo-affective responses to colorectal distension in rats: relation between plasma exposure and efficacy.
abstract: OBJECTIVE
  We previously showed that activation of GABA(B) receptors by intravenous baclofen reduces pseudo-affective responses to colorectal distension in rats. Here we evaluate the potential clinical significance of these observations.
  
  
  METHODS
  Clinically relevant colorectal distension protocols were used to assess the effects of oral baclofen on visceromotor and autonomic cardiovascular responses in conscious rats. Plasma levels of baclofen were monitored to provide clinical relevance to the doses used. Conscious female Sprague-Dawley rats were subjected to repeated noxious colorectal distension (12 × 80 mmHg), ascending-phasic colorectal distension (10-80 mmHg, 10 mmHg increments) or ramp colorectal distension (10 min ramp at 8 mmHg/min). Visceromotor and cardiovascular responses (mean arterial blood pressure and heart rate) were monitored. Pain-related response thresholds were assessed using ascending-phasic and ramp colorectal distension.
  
  
  RESULTS
  Baclofen (1-10 μmol/kg, p.o.) reduced the visceromotor response to colorectal distension, reaching a 40% maximal inhibition (p < 0.05). The highest dose (10 μmol/kg, p.o.) also inhibited pain-related cardiovascular responses in telemetrized rats (50-55% reduction in colorectal distension-evoked hypertensive and tachycardic responses; p < 0.05). Similar thresholds for pain-related visceromotor responses were determined during ramp or ascending-phasic colorectal distension (34.1 ± 1.9 and 31.7 ± 3.2 mmHg, respectively). Baclofen (10 μmol/kg, p.o.) increased thresholds to 71.1 ± 3.7 and 77.5 ± 1.8 mmHg during ramp and ascending-phasic colorectal distension, respectively (p < 0.001). Plasma levels of baclofen were 3.3 ± 0.2 μmol/l at 90 min post-dosing, corresponding to the end of the colorectal distension procedure.
  
  
  CONCLUSIONS
  Oral baclofen, at plasma levels similar to those reported safe and within a therapeutic range in humans, produced significant visceral anti-nociceptive effects in rats.
authors: AstraZeneca R&D, Mölndal, Sweden. Erik.Lindstrom@medivir.se
authors: Erik
authors: E
authors: Lindström
authors: Mikael
authors: M
authors: Brusberg
authors: Anna
authors: A
authors: Ravnefjord
authors: Dorota
authors: D
authors: Kakol-Palm
authors: Ingrid
authors: I
authors: Påhlman
authors: Anna
authors: A
authors: Novén
authors: Håkan
authors: H
authors: Larsson
authors: Vicente
authors: V
authors: Martinez
mesh_terms: D015746:Abdominal Pain / Q000188:drug therapy* / Q000209:etiology; D000284:Administration, Oral; D000818:Animals; D001418:Baclofen / Q000097:blood / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects / Q000503:physiopathology; D003106:Colon / Q000294:innervation; D004108:Dilatation, Pathologic / Q000150:complications; D005260:Female; D058786:GABA-B Receptor Agonists / Q000097:blood / Q000627:therapeutic use*; D006339:Heart Rate / Q000187:drug effects; D043183:Irritable Bowel Syndrome / Q000150:complications*; D009412:Nerve Fibers / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects; D016896:Treatment Outcome; D014781:Viscera
chemical_list: D058786:GABA-B Receptor Agonists; D001418:Baclofen