GABA(B) receptors inhibit mechanosensitivity of primary afferent endings

Abstract

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.

Fig. 1.

Conduction velocities of gastroesophageal vagal afferent fibers. The bars denote the interquartile range of the mucosal (n = 12), TM (n = 18), and tension (n = 13) receptor fiber conduction velocity. The bold line within the bar represents the median. The circles are individual values outside the interquartile range. Conduction velocities of tension receptor fibers were significantly less than those of mucosal and TM receptor fibers. *p < 0.05; Kruskal–Wallis test.

Fig. 2.

Group data for responses of mucosal (A), tension (B), and TM (C, D) gastroesophageal vagal afferents to mechanical stimulation. The effects of baclofen are shown on the responses to mucosal stroking [impulses (imp.) per stroke, mean of eight strokes] of mucosal (A) and TM (C) afferents. The effects of baclofen are shown also on the response to circumferential tension (average impulses per second over stimulus duration of 1 min) of tension (B) and TM (D) afferents. The graphs and histograms show the mean ± SE (n ≥ 5). Significant differences between treated and control (assessed using one-way ANOVA with a Dunnett’s post hoc test) are shown nearest each treated curve or histogram. *p < 0.05, **p < 0.01, control versus baclofen-treated (200 μm) responses; †p < 0.05, ††p < 0.01, control versus baclofen-treated (100 μm) responses; #p < 0.05, control versus baclofen-treated (30 μm) responses.

Fig. 3.

Typical response of a mucosal afferent to mucosal stroking with a calibrated von Frey hair (200 mg). The responses were obtained in the absence of baclofen (A), the presence of baclofen (100 μm) (B), and the presence of baclofen (100 μm) with SCH50911 (1 μm) (C). Dillustrates the average spike shape of the mucosal unit in response to mucosal stroking with a calibrated von Frey hair in the absence (a) and presence (b) of baclofen (100 μm) and SCH50911 (1 μm), showing that both responses were obtained from the same unit. Thehorizontal bars below the raw traces indicate where mucosal stroking occurred.

Fig. 4.

Typical response of a tension receptor afferent to circumferential tension (5 gm). The responses were obtained in the absence of baclofen (A), the presence of baclofen (100 μm) (B), and the presence of baclofen (100 μm) and SCH50911 (1 μm) (C). The horizontal bar below the raw traces indicate when the tension stimulus was applied. Inhibition by baclofen is most obvious during the static phase of the slowly adapting response. See Figure 2 for mean group data.

Fig. 5.

Typical response of a tension–mucosal afferent to circumferential tension (5 gm) and mucosal stroking (200 mg). The responses were obtained in the absence of baclofen (A), the presence of baclofen (100 μm) (B), and the presence of baclofen (100 μm) with SCH50911 (1 μm) (C). The horizontal bars below the raw traces indicate when the mechanical stimuli were applied. Although responses to circular tension are reversibly reduced by baclofen, no effect occurs on the response of this fiber to mucosal stroking.

Fig. 6.

Group data for responses of mucosal afferents to mucosal stroking (impulses per stroke, mean 8 strokes) (A) and tension–mucosal afferents to circumferential tension (average impulses per second over stimulus time of 1 min) (B). The graphs and histograms show data mean ± SE (n ≥ 5) obtained in the presence of baclofen (100 μm) and baclofen (100 μm) plus SCH50911 (1 μm). Significant differences were assessed using one-way ANOVA with a Tukey post hoc test. *p < 0.05, **p < 0.01, control versus baclofen (100 μm); †p < 0.05; ††p < 0.01, baclofen (100 μm)-treated versus baclofen (100 μm) and SCH50911 (1 μm)-treated.