TY - JOUR

T1 - Pharmacological modulation of colorectal distension evoked potentials in conscious rats

AU - Nissen, Thomas Dahl

AU - Brock, Christina

AU - Lykkesfeldt, Jens

AU - Lindström, Erik

AU - Hultin, Leif

PY - 2018

Y1 - 2018

N2 - Background: Cerebral evoked potentials (CEP) induced by colorectal distension (CRD) in conscious rats provides a novel method in studies of visceral sensitivity. The aim of this study was to explore the pharmacological effect on CEP of compounds known to reduce the visceromotor response to CRD. Methods: Epidural electrodes were chronically implanted in eight female Sprague-Dawley rats. Evoked potentials were elicited by colorectal rapid balloon distensions (100 ms, 80 mmHg) and the effect of WIN55 (cannabinoid CB receptor agonist), clonidine (adrenergic α2 receptor agonist), MPEP (mGluR5 receptor antagonist), pregabalin (ligand of α2δ subunits in voltage-gated calcium channels) and baclofen (GABA-B receptor agonist) on amplitudes and latency of CEP were determined. Results: WIN55 (0.1 μmol kg−1), clonidine (0.05 μmol kg−1), MPEP (10 μmol kg−1) and pregabalin (200 μmol kg−1) caused a significant, p < 0.05, reduction of the N2 to P2 peak-to-peak amplitude by 23 ± 8%, 25 ± 8%, 39 ± 5%, and 47 ± 6% respectively. Baclofen (9 μmol kg−1) induced a prolongation of the N2 peak latency of 18 ± 4% but had no significant effect on the amplitudes. Conclusion: The obtained results suggest that MPEP, WIN55, clonidine, and pregabalin reduce visceral nociceptive input to the brain, whereas the lack of effect of baclofen on CRD evoked CEP amplitudes suggest that the effect on VMR is not due to a direct analgesic effect. Brain responses to colorectal distension provide a useful tool to evaluate pharmacological effects in rats and may serve as a valuable preclinical model for understanding pharmacological mechanisms related to visceral sensitivity.

AB - Background: Cerebral evoked potentials (CEP) induced by colorectal distension (CRD) in conscious rats provides a novel method in studies of visceral sensitivity. The aim of this study was to explore the pharmacological effect on CEP of compounds known to reduce the visceromotor response to CRD. Methods: Epidural electrodes were chronically implanted in eight female Sprague-Dawley rats. Evoked potentials were elicited by colorectal rapid balloon distensions (100 ms, 80 mmHg) and the effect of WIN55 (cannabinoid CB receptor agonist), clonidine (adrenergic α2 receptor agonist), MPEP (mGluR5 receptor antagonist), pregabalin (ligand of α2δ subunits in voltage-gated calcium channels) and baclofen (GABA-B receptor agonist) on amplitudes and latency of CEP were determined. Results: WIN55 (0.1 μmol kg−1), clonidine (0.05 μmol kg−1), MPEP (10 μmol kg−1) and pregabalin (200 μmol kg−1) caused a significant, p < 0.05, reduction of the N2 to P2 peak-to-peak amplitude by 23 ± 8%, 25 ± 8%, 39 ± 5%, and 47 ± 6% respectively. Baclofen (9 μmol kg−1) induced a prolongation of the N2 peak latency of 18 ± 4% but had no significant effect on the amplitudes. Conclusion: The obtained results suggest that MPEP, WIN55, clonidine, and pregabalin reduce visceral nociceptive input to the brain, whereas the lack of effect of baclofen on CRD evoked CEP amplitudes suggest that the effect on VMR is not due to a direct analgesic effect. Brain responses to colorectal distension provide a useful tool to evaluate pharmacological effects in rats and may serve as a valuable preclinical model for understanding pharmacological mechanisms related to visceral sensitivity.

KW - (2-methyl-6-(phenylethynyl)-pyridine) hydrochloride

KW - Analgesics

KW - Cannabinoid receptor 1

KW - CB1

KW - CEP

KW - Cerebral evoked potential

KW - Colorectal distension

KW - CRD

KW - GABAB

KW - IBS

KW - ICC

KW - Intra-class correlation coefficients

KW - Irritable bowel syndrome

KW - MPEP

KW - Rats

KW - Visceral pain

KW - Visceromotor response

KW - VMR

KW - WIN55

KW - WIN55,212-2 [[(R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinyl-methyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenyl-methanone], mesylate form]

KW - γ-aminobutyric acid B receptor

U2 - 10.1016/j.neuropharm.2018.07.028

DO - 10.1016/j.neuropharm.2018.07.028

M3 - Journal article

C2 - 30059662

AN - SCOPUS:85051400594

VL - 140

SP - 193

EP - 200

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

ER -