GABA_BReceptors 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.

Contributions of Voltage- and Ca2+-Activated Conductances to GABA-Induced Depolarization in Spider Mechanosensory Neurons

“…Our results show that intracellular [Ca 2ϩ ] is actually increased by GABA-mediated depolarization in the VS-3 neurons. Similar to the spider VS-3 neurons, GABA A and GABA B receptors are both present in the primary afferent terminals of mammalian spinal cord (Curtis and Lacey 1994;Page and Blackshaw 1999). Although GABA B -receptor activation leads to reduction in Ca 2ϩ influx in the VS-3 neurons (Panek et al 2003) and spinal neurons (Dolphin 1995), it is a slower effect and may be designed to turn off the reaction initiated by GABA A -receptor activation, rather than be a primary cause of inhibition.…”

Nitric Oxide as an Endogenous Peripheral Modulator of Visceral Sensory Neuronal Function

“…Using these preparations, we have shown that GABA and glutamate are coupled to inhibition of afferent mechanosensitivity (Page and Blackshaw, 1999;Page et al, 2005b), effects that translate to changes in gastrointestinal function in vivo (Blackshaw, 2001;Zhang et al, 2002). We considered the possibility that NO may have peripheral actions on sensory neurons, which may be important in modulation of visceral sensation and reflex control of gastrointestinal function.…”

GABAergic Excitation of Spider Mechanoreceptors Increases Information Capacity by Increasing Entropy Rather than Decreasing Jitter

“…Neuromodulation can increase or decrease excitability, as seen by changes in membrane potential and action potential firing rates (Matheson, 1997;Page and Blackshaw, 1999;Rudomin and Schmidt, 1999;Torkkeli and Panek, 2002;Birmingham et al, 2003;Widmer et al, 2005). It can also affect dynamic properties of neuronal responses or spontaneous firing patterns (Ramirez et al, 1993;Matheson, 1997;Birmingham et al, 2003;Pfeiffer et al, 2009).…”