TRPV1 in GABAergic Interneurons Mediates Neuropathic Mechanical Allodynia and Disinhibition of the Nociceptive Circuitry in the Spinal Cord

Yong Ho Kim; Seung Keun Back; Alexander J. Davies; Heejin Jeong; Hyun Jung Jo; Geehoon Chung; Heung Sik Na; Yong Chul Bae; Sang Jeong Kim; Joong Soo Kim; Sung Jun Jung; Seog Bae Oh

doi:10.1016/j.neuron.2012.02.039

TRPV1 in GABAergic Interneurons Mediates Neuropathic Mechanical Allodynia and Disinhibition of the Nociceptive Circuitry in the Spinal Cord

Yong Ho Kim
, Seung Keun Back
, Alexander J. Davies
, Heejin Jeong
, Hyun Jung Jo
, Geehoon Chung
, Heung Sik Na
, Yong Chul Bae
, Sang Jeong Kim
, Joong Soo Kim
, Sung Jun Jung^*
, Seog Bae Oh

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

144 Citations (Scopus)

Abstract

Neuropathic pain and allodynia may arise from sensitization of central circuits. We report a mechanism of disinhibition-based central sensitization resulting from long-term depression (LTD) of GABAergic interneurons as a consequence of TRPV1 activation in the spinal cord. Intrathecal administration of TRPV1 agonists led to mechanical allodynia that was not dependent on peripheral TRPV1 neurons. TRPV1 was functionally expressed in GABAergic spinal interneurons and activation of spinal TRPV1 resulted in LTD of excitatory inputs and a reduction of inhibitory signaling to spinothalamic tract (STT) projection neurons. Mechanical hypersensitivity after peripheral nerve injury was attenuated in TRPV1^-/- mice but not in mice lacking TRPV1-expressing peripheral neurons. Mechanical pain was reversed by a spinally applied TRPV1 antagonist while avoiding the hyperthermic side effect of systemic treatment. Our results demonstrate that spinal TRPV1 plays a critical role as a synaptic regulator and suggest the utility of central nervous system-specific TRPV1 antagonists for treating neuropathic pain.

Original language	English
Pages (from-to)	640-647
Number of pages	8
Journal	Neuron
Volume	74
Issue number	4
DOIs	https://doi.org/10.1016/j.neuron.2012.02.039
Publication status	Published - 2012 May 24

Bibliographical note

Funding Information:
Thanks to Dr. Bruce P. Bean (Harvard Medical School) for helpful comments. This work was supported by grant (20110018614) from National Research Laboratory Program, grant (2011K000275) from Brain Research Center of the 21st Century Frontier Research Program, grant (2010-0015669) from Basic Research Program, and grant (2011-0030737 to S.J.K.) funded by the Ministry of Education, Science and Technology, the Republic of Korea.

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2012.02.039

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title = "TRPV1 in GABAergic Interneurons Mediates Neuropathic Mechanical Allodynia and Disinhibition of the Nociceptive Circuitry in the Spinal Cord",

abstract = "Neuropathic pain and allodynia may arise from sensitization of central circuits. We report a mechanism of disinhibition-based central sensitization resulting from long-term depression (LTD) of GABAergic interneurons as a consequence of TRPV1 activation in the spinal cord. Intrathecal administration of TRPV1 agonists led to mechanical allodynia that was not dependent on peripheral TRPV1 neurons. TRPV1 was functionally expressed in GABAergic spinal interneurons and activation of spinal TRPV1 resulted in LTD of excitatory inputs and a reduction of inhibitory signaling to spinothalamic tract (STT) projection neurons. Mechanical hypersensitivity after peripheral nerve injury was attenuated in TRPV1-/- mice but not in mice lacking TRPV1-expressing peripheral neurons. Mechanical pain was reversed by a spinally applied TRPV1 antagonist while avoiding the hyperthermic side effect of systemic treatment. Our results demonstrate that spinal TRPV1 plays a critical role as a synaptic regulator and suggest the utility of central nervous system-specific TRPV1 antagonists for treating neuropathic pain.",

author = "Kim, \{Yong Ho\} and Back, \{Seung Keun\} and Davies, \{Alexander J.\} and Heejin Jeong and Jo, \{Hyun Jung\} and Geehoon Chung and Na, \{Heung Sik\} and Bae, \{Yong Chul\} and Kim, \{Sang Jeong\} and Kim, \{Joong Soo\} and Jung, \{Sung Jun\} and Oh, \{Seog Bae\}",

note = "Funding Information: Thanks to Dr. Bruce P. Bean (Harvard Medical School) for helpful comments. This work was supported by grant (20110018614) from National Research Laboratory Program, grant (2011K000275) from Brain Research Center of the 21st Century Frontier Research Program, grant (2010-0015669) from Basic Research Program, and grant (2011-0030737 to S.J.K.) funded by the Ministry of Education, Science and Technology, the Republic of Korea. ",

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AU - Davies, Alexander J.

AU - Jeong, Heejin

AU - Jo, Hyun Jung

AU - Chung, Geehoon

AU - Na, Heung Sik

AU - Bae, Yong Chul

AU - Kim, Sang Jeong

AU - Kim, Joong Soo

AU - Jung, Sung Jun

AU - Oh, Seog Bae

N1 - Funding Information: Thanks to Dr. Bruce P. Bean (Harvard Medical School) for helpful comments. This work was supported by grant (20110018614) from National Research Laboratory Program, grant (2011K000275) from Brain Research Center of the 21st Century Frontier Research Program, grant (2010-0015669) from Basic Research Program, and grant (2011-0030737 to S.J.K.) funded by the Ministry of Education, Science and Technology, the Republic of Korea.

PY - 2012/5/24

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TRPV1 in GABAergic Interneurons Mediates Neuropathic Mechanical Allodynia and Disinhibition of the Nociceptive Circuitry in the Spinal Cord

Abstract

Bibliographical note

ASJC Scopus subject areas

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