title: Oral clonidine inhibits visceral pain-related viscerosomatic and cardiovascular responses to colorectal distension in rats.
abstract: The alpha(2)-adrenoceptor agonist, clonidine, modulates colorectal sensorimotor functions in humans and, given intrathecally, has analgesic effects in the colorectal distension (CRD) model in rats. We tested the effects of systemic clonidine on the visceral pain-related viscerosomatic and autonomic cardiovascular responses to CRD and colonic compliance in rats using clinically relevant CRD protocols. The activity of the abdominal musculature (viscerosomatic response), monitored by electromyography and intracolonic manometry, and changes in arterial blood pressure and heart rate, monitored by telemetry, were assessed simultaneously in conscious rats during CRD. Pressure-volume relationships during CRD served as a measure of colonic compliance. Clonidine (50-200 nmol/kg, p.o.) dose-dependently inhibited the viscerosomatic response to phasic, noxious CRD (12 distension at 80 mm Hg). At 200 nmol/kg clonidine also attenuated the increase in blood pressure (70+/-7% inhibition, P<0.05) and heart rate (67+/-16% inhibition, P<0.05) associated to noxious CRD. Similar effects were observed after i.v. administration. Likewise, clonidine (200 nmol/kg, p.o.) reduced the response to ascending phasic CRD (10-80 mm Hg) and significantly increased the threshold pressure for pain-related responses. Clonidine (50 or 150 nmol/kg, i.p.) did not affect the pressure-volume relationship during phasic CRD (2-20 mm Hg). These results show that systemic clonidine, at doses devoid of visible side effects, has analgesic effects in the CRD model of visceral pain in rats without affecting colonic compliance. These observations confirm the analgesic activity of systemic clonidine on visceral pain, support the translational value of the rat CRD model to humans and show that manometry is more sensitive than electromyography detecting pain-related responses.
authors.affiliation: AstraZeneca R&D, Integrative Pharmacology - GI Biology, Mölndal, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Brusberg
authors.forename: Anna
authors.initials: A
authors.lastname: Ravnefjord
authors.forename: Magnus
authors.initials: M
authors.lastname: Lindgreen
authors.forename: Håkan
authors.initials: H
authors.lastname: Larsson
authors.forename: Erik
authors.initials: E
authors.lastname: Lindström
authors.forename: Vicente
authors.initials: V
authors.lastname: Martinez
mesh_terms: D015746:Abdominal Pain / Q000188:drug therapy* / Q000209:etiology; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003000:Clonidine / Q000008:administration & dosage / Q000494:pharmacology*; D003108:Colonic Diseases / Q000150:complications / Q000188:drug therapy*; D004108:Dilatation, Pathologic / Q000150:complications / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004576:Electromyography / Q000379:methods; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008365:Manometry / Q000379:methods; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity
chemical_list: D000700:Analgesics; D003000:Clonidine