Pain After Spinal Cord Injury Is Associated With Abnormal Presynaptic Inhibition in the Posterior Nucleus of the Thalamus.

UNLABELLED: Pain after spinal cord injury (SCI-Pain) is one of the most debilitating sequelae of spinal cord injury, characterized as relentless, excruciating pain that is largely refractory to treatments. Although it is generally agreed that SCI-Pain results from maladaptive plasticity in the pain processing pathway that includes the spinothalamic tract and somatosensory thalamus, the specific mechanisms underlying the development and maintenance of such pain are yet unclear. However, accumulating evidence suggests that SCI-Pain may be causally related to abnormal thalamic disinhibition, leading to hyperactivity in the posterior thalamic nucleus (PO), a higher-order nucleus involved in somatosensory and pain processing. We previously described several presynaptic mechanisms by which activity in PO is regulated, including the regulation of GABAergic as well as glutamatergic release by presynaptic metabotropic gamma-aminobutyric acid (GABAB) receptors. Using acute slices from a mouse model of SCI-Pain, we tested whether such mechanisms are affected by SCI-Pain. We reveal 2 abnormal changes in presynaptic signaling in the SCI-Pain condition. The substantial tonic activation of presynaptic GABAB receptors on GABAergic projections to PO-characteristic of normal animals-was absent in mice with SCI-Pain. Also absent in mice with SCI-Pain was the normal presynaptic regulation of glutamatergic projections to the PO by GABAB receptors. The loss of these regulatory presynaptic mechanisms in SCI-Pain may be an element of maladaptive plasticity leading to PO hyperexcitability and behavioral pain, and may suggest targets for development of novel treatments.

PERSPECTIVE: This report presents synaptic mechanisms that may underlie the development and maintenance of SCI-Pain. Because of the difficulty in treating SCI-Pain, a better understanding of the underlying neurobiological mechanisms is critical, and may allow development of better treatment modalities.