Nerve injury-induced calcium channel alpha-2-delta-1 protein dysregulation leads to increased pre-synaptic excitatory input into deep dorsal horn neurons and neuropathic allodynia

Background: Up-regulation of voltage-gated calcium channel alpha(2)delta(1) subunit post spinal nerve ligation (SNL) injury or in alpha(2)delta(1)-overexpressing transgenic (Tg) mice correlates with tactile allodynia, a pain state mediated mainly by A beta sensory fibres forming synaptic connections with deep dorsal horn (DDH) neurons. It is not clear, however, whether dysregulated alpha(2)delta(1) alters DDH synaptic neurotransmission that underlies tactile allodynia development post nerve injury. Methods: Tactile allodynia was tested in the SNL and alpha(2)delta(1) Tg models. Miniature excitatory/inhibitory post-synaptic currents were recorded in DDH neurons from these animal models using whole-cell patch clamp slice recording techniques. Results: There was a significant increase in the frequency, but not amplitude, of miniature excitatory post-synaptic currents (mEPSC) in DDH neurons that correlated with tactile allodynia in SNL and alpha(2)delta(1) Tg mice. Gabapentin, an alpha(2)delta(1) ligand that is known to block tactile allodynia in these models, also normalized mEPSC frequency dose-dependently in DDH neurons from SNL and alpha(2)delta(1) Tg mice. In contrast, neither frequency nor amplitude of miniature inhibitory post-synaptic currents was altered in DDH neurons from SNL and alpha(2)delta(1) Tg mice. Conclusion: Our data suggest that alpha(2)delta(1) dysregulation is highly likely contributing to tactile allodynia through a pre-synaptic mechanism involving facilitation of excitatory synaptic neurotransmission in DDH of spinal cord.