Tonic GABA_A receptor conductance in medial subnucleus of the tractus solitarius neurons is inhibited by activation of μ-opioid receptors

Abstract

Herman MA, Gillis RA, Vicini S, Dretchen KL, Sahibzada N. Tonic GABA A receptor conductance in medial subnucleus of the tractus solitarius neurons is inhibited by activation of -opioid receptors. J Neurophysiol 107: 1022-1031, 2012. First published November 23, 2011; doi:10.1152/jn.00853.2011.-Our laboratory previously reported that gastric activity is controlled by a robust GABA A receptor-mediated inhibition in the medial nucleus of the tractus solitarius (mNTS) (Herman et al. 2009), and that -opioid receptor activation inhibits gastric tone by suppression of this GABA signaling (Herman et al. 2010). These data raised two questions: 1) whether any of this inhibition was due to tonic GABA A receptor-mediated conductance in the mNTS; and 2) whether -opioid receptor activation suppressed both tonic and phasic GABA signaling. In whole cell recordings from rat mNTS neurons, application of three GABA A receptor antagonists (gabazine, bicuculline, and picrotoxin) produced a persistent reduction in holding current and decrease in population variance or root mean square (RMS) noise, suggesting a blockade of tonic GABA signaling. Application of gabazine at a lower concentration abolished phasic currents, but had no effect on tonic currents or RMS noise. Application of the ␦-subunit preferring agonist gaboxadol (THIP) produced a dose-dependent persistent increase in holding current and RMS noise. Pretreatment with tetrodotoxin prevented the action of gabazine, but had no effect on the THIP-induced current. Membrane excitability was unaffected by the selective blockade of phasic inhibition, but was increased by blockade of both phasic and tonic currents. In contrast, activation of tonic currents decreased membrane excitability. Application of the -opioid receptor agonist DAMGO produced a persistent reduction in holding current that was not observed following pretreatment with a GABA A receptor antagonist and was not evident in mice lacking the ␦-subunit. These data suggest that mNTS neurons possess a robust tonic inhibition that is mediated by GABA A receptors containing the ␦-subunit, that determines membrane excitability, and that is partially regulated by -opioid receptors. brain stem; tonic; ␥-aminobutyric acid; opioid; vagus OUR LABORATORY PREVIOUSLY reported that GABA A receptormediated signaling in the medial subnucleus of the tractus solitarius (mNTS) is a major determinant of vago-vagal reflex activity in the basal state (Herman et al. 2009). These findings compelled us to investigate the types of GABA A receptor signaling in the mNTS present and their impact on neurons that comprise the circuitry controlling gastric activity.There are two types of GABA A receptor signaling that function in a cell-and region-specific manner. Phasic signaling involves the generation of inhibitory postsynaptic currents (IPSCs) that are the result of "point to point" transmission that occurs at synapses and results in 10 -100 ms of inhibition. Tonic signaling is characterized by the presence of persistent inhibitory currents that ar...

The μ-opioid receptor agonist DAMGO presynaptically suppresses solitary tract-evoked input to neurons in the rostral solitary nucleus

“…In addition, MOR activation in this region has a powerful effect on vago-vagal reflexes controlling gastric function and tone. Interestingly, a recent study (Herman et al 2012) demonstrated gastric effects due to interactions between the manipulation of cNST -opioid and GABAergic receptors consistent with effects on cNST neurons observed in vitro (Herman et al 2010). …”

“…DAMGO was bath applied to each cell at 0.3 M for 5.5 min, followed by a washout period in normal ACSF. This concentration fell in the middle of the range of concentrations reported in the literature (Herman et al 2012;Poole et al 2007;Rhim et al 1993;Rhim and Miller 1994) and was ideal for our purposes because in most cases it caused considerable but incomplete suppression of the evoked response, which allowed us to measure a PPR throughout the protocol. One of three baseline drug conditions was used: normal ACSF as described above, normal ACSF containing 5 M gabazine and 5 M strychnine, or normal ACSF containing gabazine, strychnine, and 1 M CTAP, a MOR antagonist (Glatzer et al 2007;Glatzer and Smith 2005).…”

Role of the dorsomedial medulla in suppression of cough by codeine in cats

“…Codeine and other agonists of μ-opioid receptors may mediate neuronal inhibition in the several subdivisions of the NTS (Poole et al, 2007) by both pre- and post-synaptic mechanisms (Endoh, 2006; Ohi et al, 2007; Boxwell et al, 2013) including modulation of glutamatergic neurotransmission (Andresen et al, 2013) and local GABA activity (Herman et al, 2012). The antitussive activity of codeine in cat is likely mediated also via non-opioid receptor mechanisms (Nosalova, 1998; for the discussion see Poliacek et al, 2010).…”

Enhancing GABAergic Tone in the Rostral Nucleus of the Solitary Tract Reconfigures Sensorimotor Neural Activity

“…Another potential source of GABAergic influence may be the AMG. While anatomical evidence suggests that AMG input to the NTS is inhibitory Saha et al, 2002), physiological studies suggest that the effect of stimulation of AMG-NTS input is excitatory (Cho et al, 2003), suggesting the possibility that the AMG generates a disinhibitory effect in the NTS (see Herman et al, 2012). If true, that might contribute to the enhanced responses that became apparent following optical stimulation of GABA release.…”