GABA(B) receptors inhibit mechanosensitivity of primary afferent endings.
The modulatory effects of baclofen on the sensitivity of peripheral afferent endings to mechanical stimulation were investigated using an in vitro ferret gastroesophageal vagal afferent preparation. Changes in sensitivity of three types of gastroesophageal vagal afferent endings previously categorized as mucosal, tension, and tension-mucosal (TM) receptors according to their mechanoreceptive field characteristics were investigated. Baclofen (30-200 microM) dose dependently reduced responses of mucosal afferents to mucosal stroking with calibrated von Frey hairs (10-1000 mg). This was reversed by the GABA(B) receptor antagonist SCH50911 (1 microM). TM afferent responses to mucosal stroking (10-1000 mg) were unaffected by baclofen (30-200 microM). However, baclofen (30-200 microM) significantly inhibited the response of 11 of 18 TM afferents to circumferential tension. This was reversed by SCH50911 (1 microM). Baclofen (100 and 200 microM) significantly inhibited the response of all tension receptor afferents to circumferential tension in the lower range (1-3 gm) but not in the higher range (4-7 gm). This inhibition was reversed by SCH50911 (1 microM; n = 3). This study provides the first direct evidence for the inhibitory modulation of peripheral mechanosensory endings by the G-protein-coupled GABA(B) receptor. Inhibition was dose-dependent, pharmacologically reversible, and selective to certain aspects of mechanosensitivity. These findings have important relevance to strategies for selective reduction of sensory input to the CNS at a peripheral site.
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Nerve-Gut Research Laboratory, Department of Gastrointestinal Medicine, Royal Adelaide Hospital, North Terrace, Adelaide SA 5000, Australia.
Blackshaw
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D000344:Afferent Pathways / Q000502:physiology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology*; D002138:Calibration; D004947:Esophagus / Q000294:innervation; D005289:Ferrets; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D005753:Gastric Mucosa / Q000294:innervation; D008465:Mechanoreceptors / Q000187:drug effects / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D009092:Mucous Membrane / Q000294:innervation; D010812:Physical Stimulation / Q000379:methods; D018080:Receptors, GABA-B / Q000502:physiology*; D013270:Stomach / Q000294:innervation; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology*
C095804:(+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid; D018755:GABA Agonists; D018756:GABA Antagonists; D009025:Morpholines; D018080:Receptors, GABA-B; D001418:Baclofen