Central terminal sensitization of TRPV1 by descending serotonergic facilitation modulates chronic pain.
The peripheral terminals of primary nociceptive neurons play an essential role in pain detection mediated by membrane receptors like TRPV1, a molecular sensor of heat and capsaicin. However, the contribution of central terminal TRPV1 in the dorsal horn to chronic pain has not been investigated directly. Combining primary sensory neuron-specific GCaMP3 imaging with a trigeminal neuropathic pain model, we detected robust neuronal hyperactivity in injured and uninjured nerves in the skin, soma in trigeminal ganglion, and central terminals in the spinal trigeminal nucleus. Extensive TRPV1 hyperactivity was observed in central terminals innervating all dorsal horn laminae. The central terminal TRPV1 sensitization was maintained by descending serotonergic (5-HT) input from the brainstem. Central blockade of TRPV1 or 5-HT/5-HT3A receptors attenuated central terminal sensitization, excitatory primary afferent inputs, and mechanical hyperalgesia in the territories of injured and uninjured nerves. Our results reveal central mechanisms facilitating central terminal sensitization underlying chronic pain.
Department of Neuroscience, Center of Sensory Biology, the Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Yu Shin
YS
Kim
Department of Neural and Pain Sciences, Program in Neuroscience, Dental School, University of Maryland, Baltimore, Maryland 21201.
Yuxia
Y
Chu
Department of Neuroscience, Center of Sensory Biology, the Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Liang
L
Han
Department of Neural and Pain Sciences, Program in Neuroscience, Dental School, University of Maryland, Baltimore, Maryland 21201.|Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Man
M
Li
Department of Neuroscience, Center of Sensory Biology, the Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Zhe
Z
Li
Department of Neuroscience, Center of Sensory Biology, the Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Pamela Colleen
PC
LaVinka
Department of Neuroscience, Center of Sensory Biology, the Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Shuohao
S
Sun
Nanjing University of Chinese Medicine, Nanjing, China.
Zongxiang
Z
Tang
Department of Neuroscience, Center of Sensory Biology, the Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Kyoungsook
K
Park
Department of Neuroscience, Center of Sensory Biology, the Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Biological Chemistry, the Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Michael J
MJ
Caterina
Department of Neural and Pain Sciences, Program in Neuroscience, Dental School, University of Maryland, Baltimore, Maryland 21201.
Ke
K
Ren
Department of Neural and Pain Sciences, Program in Neuroscience, Dental School, University of Maryland, Baltimore, Maryland 21201.
Ronald
R
Dubner
Department of Neural and Pain Sciences, Program in Neuroscience, Dental School, University of Maryland, Baltimore, Maryland 21201.
Feng
F
Wei
Department of Neuroscience, Center of Sensory Biology, the Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Howard Hughes Medical Institute, the Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Xinzhong
X
Dong
D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D059350:Chronic Pain / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism*; D012668:Trigeminal Ganglion / Q000187:drug effects
D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D002211:Capsaicin