TY - JOUR
T1 - Central terminal sensitization of TRPV1 by descending serotonergic facilitation modulates chronic pain
AU - Kim, Yu Shin
AU - Chu, Yuxia
AU - Han, Liang
AU - Li, Man
AU - Li, Zhe
AU - LaVinka, Pamela Colleen
AU - Sun, Shuohao
AU - Tang, Zongxiang
AU - Park, Kyoungsook
AU - Caterina, Michael J.
AU - Ren, Ke
AU - Dubner, Ronald
AU - Wei, Feng
AU - Dong, Xinzhong
N1 - Funding Information:
We thank Dr. Loren Looger at the Howard Hughes Medical Institute Janelia Farm for providing us GCaMP3 cDNA, Yixun Geng for technical assistance, and Matthias Ringkamp and David Ginty for their helpful comments and discussion. We thank Chip Hawkins and Holly Wellington of Mouse ES Cell Core (P30NS050274) and Transgenic Core at Johns Hopkins University School of Medicine for assistance with Pirt-GCaMP3 mouse generation. This work was supported by grants from the National Institutes of Health (R01DE022750 and R01GM087369 [to X.D.], R01DE018573 [to F.W.], and T32NS070201 [to Y.S.K.]) and Johns Hopkins University Brain Science Institute. Dr. Caterina is an inventor on a patent on the use of products related to TRPV1, which is licensed through the University of California, San Francisco and Merck, and may be entitled to royalties related to these products. He is on the Scientific Advisory Board for Hydra Biosciences, which develops products related to TRP channels. These conflicts are being managed by the Johns Hopkins Office on Policy Coordination.
PY - 2014/2/19
Y1 - 2014/2/19
N2 - The peripheral terminals of primary nociceptive neurons play an essential role in pain detection mediatedby membrane receptors like TRPV1, a molecular sensor of heat and capsaicin. However, the contribution of central terminal TRPV1 in the dorsal hornto 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.
AB - The peripheral terminals of primary nociceptive neurons play an essential role in pain detection mediatedby membrane receptors like TRPV1, a molecular sensor of heat and capsaicin. However, the contribution of central terminal TRPV1 in the dorsal hornto 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.
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U2 - 10.1016/j.neuron.2013.12.011
DO - 10.1016/j.neuron.2013.12.011
M3 - Article
C2 - 24462040
AN - SCOPUS:84896700036
VL - 81
SP - 873
EP - 887
JO - Neuron
JF - Neuron
SN - 0896-6273
IS - 4
ER -