GABAB receptor-mediated tonic inhibition of noradrenergic A7 neurons in the rat

Abstract

Noradrenergic (NAergic) A7 neurons that project axonal terminals to the dorsal horn of the spinal cord to modulate nociceptive signaling are suggested to receive tonic inhibition from local GABAergic interneurons, which are under the regulation of descending analgesic pathways. In support of this argument, we presently report GABAB receptor (GABABR)-mediated tonic inhibition of NAergic A7 neurons. Bath application of baclofen induced an outward current ( IBac) in NAergic A7 neurons that was blocked by CGP 54626, a GABABR blocker. The IBac was reversed at about −99 mV, displayed inward rectification, and was blocked by Ba2+ or Tertipian-Q, showing it was mediated by G protein-activated inward-rectifying K+ (GIRK) channels. Single-cell RT-PCR results suggested that GIRK1/3 heterotetramers might dominate functional GIRK channels in NAergic A7 neurons. Under conditions in which GABAA and glycine receptors were blocked, bath application of GABA inhibited the spontaneous firing of NAergic A7 neurons in a dose-dependent manner. Interestingly, CGP 54626 application not only blocked the effect of GABA but also increased the firing rate to 126.9% of the control level, showing that GABABRs were constitutively active at an ambient GABA concentration of 2.8 μM and inhibited NAergic A7 neurons. GABABRs were also found at presynaptic excitatory and inhibitory axonal terminals in the A7 area. Pharmacological activation of these GABABRs inhibited the release of neurotransmitters. No physiological role was found for GABABRs on excitatory terminals, whereas those on the inhibitory terminals were found to exert autoregulatory control of GABA release.