Alleviating neuropathic pain hypersensitivity by inhibiting PKMzeta in the anterior cingulate cortex.
Synaptic plasticity is a key mechanism for chronic pain. It occurs at different levels of the central nervous system, including spinal cord and cortex. Studies have mainly focused on signaling proteins that trigger these plastic changes, whereas few have addressed the maintenance of plastic changes related to chronic pain. We found that protein kinase M zeta (PKMζ) maintains pain-induced persistent changes in the mouse anterior cingulate cortex (ACC). Peripheral nerve injury caused activation of PKMζ in the ACC, and inhibiting PKMζ by a selective inhibitor, ζ-pseudosubstrate inhibitory peptide (ZIP), erased synaptic potentiation. Microinjection of ZIP into the ACC blocked behavioral sensitization. These results suggest that PKMζ in the ACC acts to maintain neuropathic pain. PKMζ could thus be a new therapeutic target for treating chronic pain.
Department of Physiology, Faculty of Medicine, Center for the Study of Pain, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
Xiang-Yao
XY
Li
Hyoung-Gon
HG
Ko
Tao
T
Chen
Giannina
G
Descalzi
Kohei
K
Koga
Hansen
H
Wang
Susan S
SS
Kim
Yuze
Y
Shang
Chuljung
C
Kwak
Soo-Won
SW
Park
Jaehoon
J
Shim
Kyungmin
K
Lee
Graham L
GL
Collingridge
Bong-Kiun
BK
Kaang
Min
M
Zhuo
D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006179:Gyrus Cinguli / Q000201:enzymology* / Q000502:physiology; D017774:Long-Term Potentiation; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009437:Neuralgia / Q000188:drug therapy* / Q000201:enzymology*; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D010543:Peroneal Nerve / Q000293:injuries; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D018091:Receptors, AMPA / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000502:physiology; D013003:Somatosensory Cortex / Q000502:physiology; D013569:Synapses / Q000502:physiology; D009435:Synaptic Transmission; D000099221:Protein Kinase C zeta
D000262:Adenylyl Cyclases; D000700:Analgesics; D004791:Enzyme Inhibitors; D010455:Peptides; D011493:Protein Kinase C; D018091:Receptors, AMPA; D000099221:Protein Kinase C zeta; C106670:adenylyl cyclase 1