Dataset Information

Chemogenetic silencing of GABAergic dorsal horn interneurons induces morphine-resistant spontaneous nocifensive behaviours.

ABSTRACT: Inhibitory interneurons in the spinal dorsal horn (SDH) are crucial for processing somatosensory information originating in the periphery. However, the effects of the acute and selective inactivation of GABAergic SDH interneurons on pain processing are not fully understood. In this study, we used designer receptors exclusively activated by designer drugs (DREADD) technology and vesicular GABA transporter-Cre (Vgat-Cre) mice to selectively express a modified human muscarinic Gi protein-coupled receptor (hM4Di) in Vgat-Cre ⁺ GABAergic SDH interneurons in the fourth lumbar segment. We found that clozapine-N-oxide (CNO) treatment rapidly hyperpolarized these neurons and induced spontaneous nocifensive behaviours in these mice. In Vgat-Cre ^neg lamina II neurons, CNO produced facilitation of A fibre-mediated polysynaptic excitatory responses, an effect that required N-methyl-D-aspartate (NMDA) receptor activation. The CNO-induced nocifensive behaviours were also reduced by NMDA receptor antagonism. Moreover, these nocifensive behaviours were suppressed by pregabalin but resistant to morphine. Our findings indicate that Vgat-Cre ⁺ SDH interneurons play an important role in morphine-resistant nocifensive behaviours and suggest that this approach may provide a useful model for understanding the mechanisms of opioid-resistant pain signalling and for developing novel analgesics.

SUBMITTER: Koga K

PROVIDER: S-EPMC5498492 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Chemogenetic silencing of GABAergic dorsal horn interneurons induces morphine-resistant spontaneous nocifensive behaviours.

Koga Keisuke K Kanehisa Kensho K Kohro Yuta Y Shiratori-Hayashi Miho M Tozaki-Saitoh Hidetoshi H Inoue Kazuhide K Furue Hidemasa H Tsuda Makoto M

Scientific reports 20170705 1

Inhibitory interneurons in the spinal dorsal horn (SDH) are crucial for processing somatosensory information originating in the periphery. However, the effects of the acute and selective inactivation of GABAergic SDH interneurons on pain processing are not fully understood. In this study, we used designer receptors exclusively activated by designer drugs (DREADD) technology and vesicular GABA transporter-Cre (Vgat-Cre) mice to selectively express a modified human muscarinic Gi protein-coupled re ...[more]

PMID: 28680103

Similar Datasets

Project description:Substantia gelatinosa (SG) neurons, which are located in the spinal dorsal horn (lamina II), have been identified as the "central gate" for the transmission and modulation of nociceptive information. Rebound depolarization (RD), a biophysical property mediated by membrane hyperpolarization that is frequently recorded in the central nervous system, contributes to shaping neuronal intrinsic excitability and, in turn, contributes to neuronal output and network function. However, the electrophysiological and morphological properties of SG neurons exhibiting RD remain unclarified. In this study, whole-cell patch-clamp recordings were performed on SG neurons from parasagittal spinal cord slices. RD was detected in 44.44% (84 out of 189) of the SG neurons recorded. We found that RD-expressing neurons had more depolarized resting membrane potentials, more hyperpolarized action potential (AP) thresholds, higher AP amplitudes, shorter AP durations, and higher spike frequencies in response to depolarizing current injection than neurons without RD. Based on their firing patterns and morphological characteristics, we propose that most of the SG neurons with RD mainly displayed tonic firing (69.05%) and corresponded to islet cell morphology (58.82%). Meanwhile, subthreshold currents, including the hyperpolarization-activated cation current (I h ) and T-type calcium current (I T ), were identified in SG neurons with RD. Blockage of I h delayed the onset of the first spike in RD, while abolishment of I T significantly blunted the amplitude of RD. Regarding synaptic inputs, SG neurons with RD showed lower frequencies in both spontaneous and miniature excitatory synaptic currents. Furthermore, RD-expressing neurons received either Aδ- or C-afferent-mediated monosynaptic and polysynaptic inputs. However, RD-lacking neurons received afferents from monosynaptic and polysynaptic Aδ fibers and predominantly polysynaptic C-fibers. These findings demonstrate that SG neurons with RD have a specific cell-type distribution, and may differentially process somatosensory information compared to those without RD.

Dataset Information

Chemogenetic silencing of GABAergic dorsal horn interneurons induces morphine-resistant spontaneous nocifensive behaviours.

Publications

Chemogenetic silencing of GABAergic dorsal horn interneurons induces morphine-resistant spontaneous nocifensive behaviours.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets