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.

• Authors: Keisuke Koga, Kensho Kanehisa, Yuta Kohro, Miho Shiratori-Hayashi, Hidetoshi Tozaki-Saitoh, Kazuhide Inoue, Hidemasa Furue, Makoto Tsuda
• Journal: Scientific reports (Sci Rep) Vol. 7 Issue 1 Pg. 4739 (07 05 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28680103 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics
• Vesicular Inhibitory Amino Acid Transport Proteins
• Viaat protein, mouse
• Pregabalin
• Morphine
• Clozapine
• clozapine N-oxide

Topics

• Analgesics (administration & dosage, pharmacology)
• Animals
• Behavior, Animal (drug effects)
• Cell Polarity (drug effects)
• Clozapine (administration & dosage, analogs & derivatives, pharmacology)
• GABAergic Neurons (cytology, drug effects, metabolism)
• Gene Knockdown Techniques
• HEK293 Cells
• Humans
• Interneurons (cytology, drug effects, metabolism)
• Mice
• Morphine (pharmacology)
• Pregabalin (administration & dosage, pharmacology)
• Spinal Cord Dorsal Horn (cytology, drug effects, metabolism)
• Vesicular Inhibitory Amino Acid Transport Proteins (genetics)