Dorsal Horn Circuits for Persistent Mechanical Pain.
Persistent mechanical hypersensitivity that occurs in the setting of injury or disease remains a major clinical problem largely because the underlying neural circuitry is still not known. Here we report the functional identification of key components of the elusive dorsal horn circuit for mechanical allodynia. We show that the transient expression of VGLUT3 by a discrete population of neurons in the deep dorsal horn is required for mechanical pain and that activation of the cells in the adult conveys mechanical hypersensitivity. The cells, which receive direct low threshold input, point to a novel location for circuit initiation. Subsequent analysis of c-Fos reveals the circuit extends dorsally to nociceptive lamina I projection neurons, and includes lamina II calretinin neurons, which we show also convey mechanical allodynia. Lastly, using inflammatory and neuropathic pain models, we show that multiple microcircuits in the dorsal horn encode this form of pain.
Departments of Neurobiology and Otolaryngology, University of Pittsburgh School of Medicine, 3501 Fifth Avenue, BST3, Pittsburgh, PA 15213, USA; Pittsburgh Center for Pain Research, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
Cedric
C
Peirs
Departments of Neurobiology and Otolaryngology, University of Pittsburgh School of Medicine, 3501 Fifth Avenue, BST3, Pittsburgh, PA 15213, USA; Pittsburgh Center for Pain Research, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
Sean-Paul G
SP
Williams
Departments of Neurobiology and Otolaryngology, University of Pittsburgh School of Medicine, 3501 Fifth Avenue, BST3, Pittsburgh, PA 15213, USA; Pittsburgh Center for Pain Research, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA; Tsinghua M.D. Program, Tsinghua University School of Medicine, 30 Shuang Qing Road, Haidian District, Beijing 100084, China.
Xinyi
X
Zhao
Departments of Neurobiology and Otolaryngology, University of Pittsburgh School of Medicine, 3501 Fifth Avenue, BST3, Pittsburgh, PA 15213, USA.
Claire E
CE
Walsh
Departments of Neurobiology and Otolaryngology, University of Pittsburgh School of Medicine, 3501 Fifth Avenue, BST3, Pittsburgh, PA 15213, USA.
Jeremy Y
JY
Gedeon
Departments of Neurobiology and Otolaryngology, University of Pittsburgh School of Medicine, 3501 Fifth Avenue, BST3, Pittsburgh, PA 15213, USA.
Natalie E
NE
Cagle
Departments of Neurobiology and Otolaryngology, University of Pittsburgh School of Medicine, 3501 Fifth Avenue, BST3, Pittsburgh, PA 15213, USA.
Adam C
AC
Goldring
Department of Morphological Brain Science, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Hiroyuki
H
Hioki
Departments of Neurobiology and Otolaryngology, University of Pittsburgh School of Medicine, 3501 Fifth Avenue, BST3, Pittsburgh, PA 15213, USA.
Zheng
Z
Liu
Departments of Neurobiology and Otolaryngology, University of Pittsburgh School of Medicine, 3501 Fifth Avenue, BST3, Pittsburgh, PA 15213, USA.
Paulina S
PS
Marell
Departments of Neurobiology and Otolaryngology, University of Pittsburgh School of Medicine, 3501 Fifth Avenue, BST3, Pittsburgh, PA 15213, USA; Pittsburgh Center for Pain Research, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA. Electronic address: rpseal@pitt.edu.
Rebecca P
RP
Seal
D026922:Amino Acid Transport Systems, Acidic / Q000096:biosynthesis*; D000818:Animals; D006930:Hyperalgesia / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009415:Nerve Net / Q000378:metabolism* / Q000473:pathology; D009924:Organ Culture Techniques; D010146:Pain / Q000378:metabolism* / Q000473:pathology; D066148:Spinal Cord Dorsal Horn / Q000378:metabolism* / Q000473:pathology; D014110:Touch
D026922:Amino Acid Transport Systems, Acidic; C504941:Slc17a8 protein, mouse