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 GABA(B) receptor (GABA(B)R)-mediated tonic inhibition of NAergic A7 neurons. Bath application of baclofen induced an outward current (I(Bac)) in NAergic A7 neurons that was blocked by CGP 54626, a GABA(B)R blocker. The I(Bac) was reversed at about -99 mV, displayed inward rectification, and was blocked by Ba(2+) 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 GABA(A) 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 GABA(B)Rs were constitutively active at an ambient GABA concentration of 2.8 μM and inhibited NAergic A7 neurons. GABA(B)Rs were also found at presynaptic excitatory and inhibitory axonal terminals in the A7 area. Pharmacological activation of these GABA(B)Rs inhibited the release of neurotransmitters. No physiological role was found for GABA(B)Rs on excitatory terminals, whereas those on the inhibitory terminals were found to exert autoregulatory control of GABA release.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Analysis of Variance
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Animals
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Anisoles / pharmacology
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Baclofen / pharmacology
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Barium / pharmacology
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Bee Venoms / pharmacology
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Dopamine beta-Hydroxylase / metabolism
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Dose-Response Relationship, Drug
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Electric Stimulation / methods
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Excitatory Amino Acid Antagonists / pharmacology
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Excitatory Postsynaptic Potentials / drug effects
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Female
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G Protein-Coupled Inwardly-Rectifying Potassium Channels / genetics
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G Protein-Coupled Inwardly-Rectifying Potassium Channels / metabolism
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GABA Antagonists / pharmacology
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GABA-B Receptor Agonists / pharmacology
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Gene Expression Regulation / drug effects
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In Vitro Techniques
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Lysine / analogs & derivatives
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Lysine / metabolism
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Male
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Morpholines / pharmacology
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Neural Inhibition / drug effects
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Neural Inhibition / physiology*
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Neurons / drug effects
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Neurons / physiology*
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Nipecotic Acids / pharmacology
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Norepinephrine / metabolism*
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Organophosphorus Compounds / pharmacology
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Oximes / pharmacology
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Patch-Clamp Techniques / methods
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Pons / cytology*
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Potassium Channel Blockers / pharmacology
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Potassium Chloride / pharmacology
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RNA, Messenger / metabolism
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Rats
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Rats, Sprague-Dawley
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Receptors, GABA-B / metabolism*
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gamma-Aminobutyric Acid / pharmacology
Substances
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(+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid
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1-(2-(tris(4-methoxyphenyl)methoxy)ethyl)-3-piperidinecarboxylic acid
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Anisoles
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Bee Venoms
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Excitatory Amino Acid Antagonists
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G Protein-Coupled Inwardly-Rectifying Potassium Channels
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GABA Antagonists
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GABA-B Receptor Agonists
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Morpholines
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Nipecotic Acids
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Organophosphorus Compounds
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Oximes
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Potassium Channel Blockers
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RNA, Messenger
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Receptors, GABA-B
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NNC 711
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CGP 54626
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Barium
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tertiapin
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gamma-Aminobutyric Acid
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Potassium Chloride
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Dopamine beta-Hydroxylase
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biocytin
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Baclofen
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Lysine
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Norepinephrine