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Regulating nociceptive transmission by VG luT2‐expressing spinal dorsal horn neurons
Author(s) -
Wang Li,
Chen ShaoRui,
Ma Huijie,
Chen Hong,
Hittelman Walter N.,
Pan HuiLin
Publication year - 2018
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14588
Subject(s) - glutamate receptor , neuroscience , excitatory postsynaptic potential , nociception , spinal cord , neurotransmission , inhibitory postsynaptic potential , biology , microbiology and biotechnology , receptor , chemistry , biochemistry
Vesicular glutamate transporter‐2 ( VG luT2) mediates the uptake of glutamate into synaptic vesicles in neurons. Spinal cord dorsal horn interneurons are highly heterogeneous and molecularly diverse. The functional significance of VG luT2‐expressing dorsal horn neurons in physiological and pathological pain conditions has not been explicitly demonstrated. Designer receptors exclusively activated by designer drugs ( DREADD s) are a powerful chemogenetic tool to reversibly control neuronal excitability and behavior. Here, we used transgenic mice with Cre recombinase expression driven by the VG luT2 promoter, combined with the chemogenetic approach, to determine the contribution of VG luT2‐expressing dorsal horn neurons to nociceptive regulation. Adeno‐associated viral vectors expressing double‐floxed Cre‐dependent Gαq‐coupled human M3 muscarinic receptor DREADD ( hM 3D)‐ mC herry or Gαi‐coupled κ‐opioid receptor DREADD ( KORD )‐ IRES ‐ mC itrine were microinjected into the superficial spinal dorsal horn of VG luT2‐Cre mice. Immunofluorescence labeling showed that VG luT2 was predominantly expressed in lamina II excitatory interneurons. Activation of excitatory hM 3D in VG luT2‐expressing neurons with clozapine N‐oxide caused a profound increase in neuronal firing and synaptic glutamate release. Conversely, activation of inhibitory KORD in VG luT2‐expressing neurons with salvinorin B markedly inhibited neuronal activity and synaptic glutamate release. In addition, chemogenetic stimulation of VG luT2‐expressing neurons increased mechanical and thermal sensitivities in naive mice, whereas chemogenetic silencing of VG luT2‐expressing neurons reversed pain hypersensitivity induced by tissue inflammation and peripheral nerve injury. These findings indicate that VG luT2‐expressing excitatory neurons play a crucial role in mediating nociceptive transmission in the spinal dorsal horn. Targeting glutamatergic dorsal horn neurons with inhibitory DREADD s may be a new strategy for treating inflammatory pain and neuropathic pain.