Calcium Channel α2δ1 Proteins Mediate Trigeminal Neuropathic Pain States Associated with Aberrant Excitatory Synaptogenesis

Background: Factors mediating orofacial neuropathic pain are not well defined. Results: Trigeminal nerve injury-induced calcium channel (21) protein up-regulation in trigeminal ganglia and spinal complex correlated with enhanced spinal presynaptic neurotransmission, excitatory synaptogenesis, and orofacial pain states. Conclusion: This neuroplasticity may mediate orofacial neuropathic pain states by enhancing dorsal horn excitatory synaptic neurotransmission. Significance: This reveals a mechanism underlying orofacial neuropathic pain states.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 (21) (Ca-v21) 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 Ca-v21 up-regulation in trigeminal ganglion neurons and Vc/C2. Blocking Ca-v21 with gabapentin, a ligand for the Ca-v21 proteins, or Ca-v21 antisense oligodeoxynucleotides led to a reversal of orofacial hypersensitivity, supporting an important role of Ca-v21 in orofacial pain processing. Importantly, increased Ca-v21 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 Ca-v21 up-regulation may contribute to orofacial neuropathic pain states through abnormal excitatory synapse formation and enhanced presynaptic excitatory neurotransmitter release in Vc/C2.