4.6 Article

Inhibitory interneurons with differential plasticities at their connections tune excitatory-inhibitory balance in the spinal nociceptive system

Journal

PAIN
Volume 163, Issue 5, Pages E675-E688

Publisher

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/j.pain.0000000000002460

Keywords

Nociceptive information processing; Synaptic plasticity; Excitation-inhibition balance; Frequency-coded information; Spinal cord stimulation; GABA; Adenosine

Funding

  1. Centre National de la Recherche Scientifique, Universite de Strasbourg
  2. French National Research agency (ANR) [ANR-17EURE-0022]
  3. EURIDOL Graduate School of Pain, Neuropole Strasbourg
  4. Societe Francaise d'Etude et de Traitement de la Douleur (SFETD)

Ask authors/readers for more resources

The networks in the dorsal horn of the spinal cord play a crucial role in processing nociceptive information and shaping pain perception. Short-term plasticity of inhibitory connections, particularly in lamina II, can modulate the balance between excitation and inhibition, thus influencing pain transmission. This study showed that GABAergic interneurons in lamina II had target-specific and frequency-specific plasticity, with connections onto eGFP+ (putative excitatory) interneurons showing frequency-dependent depression and connections onto eGFP- (putative inhibitory) interneurons displaying limited frequency-dependent changes. These findings suggest that the modulation of inhibitory connections may be a potential target for pain relief strategies.
Networks of the dorsal horn of the spinal cord process nociceptive information from the periphery. In these networks, the excitation-inhibition balance is critical to shape this nociceptive information and to gate it to the brain where it is interpreted as pain. Our aim was to define whether short-term plasticity of inhibitory connections could tune this inhibition-excitation balance by differentially controlling excitatory and inhibitory microcircuits. To this end, we used spinal cord slices from adult mice expressing enhanced green fluorescent protein (eGFP) under the GAD65 promoter and recorded from both eGFP+ (putative inhibitory) and eGFP- (putative excitatory) neurons of lamina II while stimulating single presynaptic GABAergic interneurons at various frequencies. Our results indicate that GABAergic neurons of lamina II simultaneously contact eGFP- and eGFP+ neurons, but these connections display very different frequency-dependent short-term plasticities. Connections onto eGFP- interneurons displayed limited frequency-dependent changes and strong time-dependent summation of inhibitory synaptic currents that was however subjected to a tonic activity-dependent inhibition involving A1 adenosine receptors. By contrast, GABAergic connections onto eGFP+ interneurons expressed pronounced frequency-dependent depression, thus favoring disinhibition at these synapses by a mechanism involving the activation of GABA(B) autoreceptors at low frequency. Interestingly, the balance favors inhibition at frequencies associated with intense pain, whereas it favors excitation at frequencies associated with low pain. Therefore, these target-specific and frequency-specific plasticities allow to tune the balance between inhibition and disinhibition while processing frequency-coded information from primary afferents. These short-term plasticities and their modulation by A1 and GABA(B) receptors might represent an interesting target in pain-alleviating strategies.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.6
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available