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.
