Oral baclofen reduces visceral pain-related pseudo-affective responses to colorectal distension in rats: Relation between plasma exposure and efficacy

Objective. We previously showed that activation of GABAB receptors by intravenous baclofen reduces pseudo-affective responses to colorectal distension in rats. Here we evaluate the potential clinical significance of these observations. Material and 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. © 2011 Informa Healthcare.