TRPV1 in GABAergic interneurons mediates neuropathic mechanical allodynia and disinhibition of the nociceptive circuitry in the spinal cord.
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.
National Research Laboratory for Pain, Dental Research Institute and Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul 110-749, Republic of Korea.
Yong Ho
YH
Kim
Seung Keun
SK
Back
Alexander J
AJ
Davies
Heejin
H
Jeong
Hyun Jung
HJ
Jo
Geehoon
G
Chung
Heung Sik
HS
Na
Yong Chul
YC
Bae
Sang Jeong
SJ
Kim
Joong Soo
JS
Kim
Sung Jun
SJ
Jung
Seog Bae
SB
Oh
D000818:Animals; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism*; D006930:Hyperalgesia / Q000209:etiology / Q000378:metabolism*; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism*; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000209:etiology / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D059348:Peripheral Nerve Injuries / Q000150:complications / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse