Calcium channel α2δ1 proteins mediate trigeminal neuropathic pain states associated with aberrant excitatory synaptogenesis.
To investigate a potential mechanism underlying trigeminal nerve injury-induced orofacial hypersensitivity, we used a rat model of chronic constriction injury to the infraorbital nerve (CCI-ION) to study whether CCI-ION caused calcium channel α2δ1 (Cavα2δ1) protein dysregulation in trigeminal ganglia and associated spinal subnucleus caudalis and C1/C2 cervical dorsal spinal cord (Vc/C2). Furthermore, we studied whether this neuroplasticity contributed to spinal neuron sensitization and neuropathic pain states. CCI-ION caused orofacial hypersensitivity that correlated with Cavα2δ1 up-regulation in trigeminal ganglion neurons and Vc/C2. Blocking Cavα2δ1 with gabapentin, a ligand for the Cavα2δ1 proteins, or Cavα2δ1 antisense oligodeoxynucleotides led to a reversal of orofacial hypersensitivity, supporting an important role of Cavα2δ1 in orofacial pain processing. Importantly, increased Cavα2δ1 in Vc/C2 superficial dorsal horn was associated with increased excitatory synaptogenesis and increased frequency, but not the amplitude, of miniature excitatory postsynaptic currents in dorsal horn neurons that could be blocked by gabapentin. Thus, CCI-ION-induced Cavα2δ1 up-regulation may contribute to orofacial neuropathic pain states through abnormal excitatory synapse formation and enhanced presynaptic excitatory neurotransmitter release in Vc/C2.
Department of Anesthesiology and Perioperative Care, University of California School of Medicine, Irvine, California 92697.
Kang-Wu
KW
Li
Department of Pharmacology, University of California School of Medicine, Irvine, California 92697.
Yanhui Peter
YP
Yu
Department of Pharmacology, University of California School of Medicine, Irvine, California 92697.
Chunyi
C
Zhou
Department of Anesthesiology and Perioperative Care, University of California School of Medicine, Irvine, California 92697.
Doo-Sik
DS
Kim
Department of Anesthesiology and Perioperative Care, University of California School of Medicine, Irvine, California 92697.
Bin
B
Lin
Reeve-Irvine Research Center, University of California School of Medicine, Irvine, California 92697.
Kelli
K
Sharp
Reeve-Irvine Research Center, University of California School of Medicine, Irvine, California 92697.
Oswald
O
Steward
Department of Anesthesiology and Perioperative Care, University of California School of Medicine, Irvine, California 92697; Department of Pharmacology, University of California School of Medicine, Irvine, California 92697; Reeve-Irvine Research Center, University of California School of Medicine, Irvine, California 92697. Electronic address: zluo@uci.edu.
Z David
ZD
Luo
D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020746:Calcium Channels, L-Type; D004195:Disease Models, Animal; D005157:Facial Pain / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009437:Neuralgia / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014275:Trigeminal Caudal Nucleus / Q000378:metabolism; D012668:Trigeminal Ganglion / Q000378:metabolism*; D061221:Trigeminal Nerve Injuries / Q000150:complications*
C486060:Cacna2d1 protein, rat; D015220:Calcium Channels; D020746:Calcium Channels, L-Type
Gene Regulation; Molecular Pharmacology; Neuroscience; Pain; Synaptic Plasticity