Dynorphins are endogenous
opioid peptide products of the
prodynorphin gene. An extensive literature suggests that
dynorphins have deleterious effects on CNS injury outcome. We thus examined whether a deficiency of
dynorphin would protect against tissue damage after
spinal cord injury (SCI), and if individual cell types would be specifically affected. Wild-type and
prodynorphin(-/-) mice received a moderate
contusion injury at 10th thoracic vertebrae (T10).
Caspase-3 activity at the injury site was significantly decreased in tissue homogenates from
prodynorphin(-/-) mice after 4 h. We examined frozen sections at 4 h post-injury by immunostaining for active
caspase-3. At 3-4 mm rostral or caudal to the injury, >90% of all neurons, astrocytes and oligodendrocytes expressed active
caspase-3 in both wild-type and knockout mice. At 6-7 mm, there were fewer
caspase-3(+) oligodendrocytes and astrocytes than at 3-4 mm. Importantly,
caspase-3 activation was significantly lower in
prodynorphin(-/-) oligodendrocytes and astrocytes, as compared with wild-type mice. In contrast, while
caspase-3 expression in neurons also declined with further distance from the injury, there was no effect of genotype. Radioimmunoassay showed that
dynorphin A(1-17) was regionally increased in wild-type injured versus
sham-injured tissues, although levels of the
prodynorphin processing product Arg(6)-Leu-enkephalin were unchanged. Our results indicate that
dynorphin peptides affect the extent of post-injury
caspase-3 activation, and that glia are especially sensitive to these effects. By promoting
caspase-3 activation,
dynorphin peptides likely increase the probability of glial apoptosis after SCI. While normally beneficial, our findings suggest that
prodynorphin or its
peptide products become maladaptive following SCI and contribute to secondary injury.