title: Divergent Modulation of Nociception by Glutamatergic and GABAergic Neuronal Subpopulations in the Periaqueductal Gray.
abstract: The ventrolateral periaqueductal gray (vlPAG) constitutes a major descending pain modulatory system and is a crucial site for opioid-induced analgesia. A number of previous studies have demonstrated that glutamate and GABA play critical opposing roles in nociceptive processing in the vlPAG. It has been suggested that glutamatergic neurotransmission exerts antinociceptive effects, whereas GABAergic neurotransmission exert pronociceptive effects on pain transmission, through descending pathways. The inability to exclusively manipulate subpopulations of neurons in the PAG has prevented direct testing of this hypothesis. Here, we demonstrate the different contributions of genetically defined glutamatergic and GABAergic vlPAG neurons in nociceptive processing by employing cell type-specific chemogenetic approaches in mice. Global chemogenetic manipulation of vlPAG neuronal activity suggests that vlPAG neural circuits exert tonic suppression of nociception, consistent with previous pharmacological and electrophysiological studies. However, selective modulation of GABAergic or glutamatergic neurons demonstrates an inverse regulation of nociceptive behaviors by these cell populations. Selective chemogenetic activation of glutamatergic neurons, or inhibition of GABAergic neurons, in vlPAG suppresses nociception. In contrast, inhibition of glutamatergic neurons, or activation of GABAergic neurons, in vlPAG facilitates nociception. Our findings provide direct experimental support for a model in which excitatory and inhibitory neurons in the PAG bidirectionally modulate nociception.
authors.affiliation: Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110; Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Vijay K
authors.identifier: 0000-0002-9491-2793
authors.initials: VK
authors.lastname: Samineni
authors.affiliation: Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110; Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO 63110; Division of Biomedical and Biological Sciences Graduate Program in Neuroscience, Washington University School of Medicine, St. Louis, MO 63110; Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Jose G
authors.initials: JG
authors.lastname: Grajales-Reyes
authors.affiliation: Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110; Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Bryan A
authors.initials: BA
authors.lastname: Copits
authors.affiliation: Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110; Division of Biomedical and Biological Sciences Graduate Program in Neuroscience, Washington University School of Medicine, St. Louis, MO 63110; Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: O'Brien
authors.affiliation: Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110; Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Trigg
authors.affiliation: Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine , St. Louis, MO 63110.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Gomez
authors.affiliation: Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110; Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Michael R
authors.identifier: 0000-0003-4713-7816
authors.initials: MR
authors.lastname: Bruchas
authors.affiliation: Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110; Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Robert W
authors.identifier: 0000-0002-5428-4251
authors.initials: RW
authors.lastname: Gereau
mesh_terms: D000818:Animals; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D059225:Nociception / Q000187:drug effects / Q000502:physiology*; D058748:Pain Perception / Q000187:drug effects / Q000502:physiology*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010487:Periaqueductal Gray / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D046509:Tissue Culture Techniques; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018377:Neurotransmitter Agents; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid
keywords: DREADDs; Descending modulation; PAG; RVM; chemogenetics; pain