Alterations in the opioidergic system have been found in
cerebral ischemia. Neuroprotection studies have demonstrated the involvement of the opioidergic system in
cerebral ischemia/reperfusion (I/R). However, the neuroprotective mechanisms remain largely unclear. This study was conducted to investigate whether intracerebroventricular administration of opioidergic agonists has a
neuroprotective effect against
cerebral ischemia in rats and, if this proved to be the case, to determine the potential neuroprotective mechanisms. Using a focal cerebral I/R rat model, we demonstrated that the opioidergic agents,
BW373U86 (delta agonist) and
Dynorphin A 1-13 (kappa agonist), but not
TAPP (mu agonist), attenuated cerebral ischemic injury as manifested in the reduction of
cerebral infarction and preservation of neurons. The antagonism assay showed that the
neuroprotective effect of
Dynorphin A was attenuated by
nor-Binaltorphimine (kappa antagonist). Surprisingly, BW373U86-induced neuroprotection was not changed by
Naltrindole (delta antagonist). These findings indicate that
BW373U86 and
Dynorphin A exerted distinct neuroprotection against
ischemia via
opioid-independent and -dependent mechanisms, respectively. The post-ischemic protection in beneficial treatments was accompanied by alleviations in
brain edema, inflammatory cell infiltration, and pro-inflammatory
cytokine interleukin 6 (IL-6) expression. In vitro cell study further demonstrated that the opioidergic agonists, delta and kappa, but not mu, attenuated
IL-6 production from stimulated glial cells. Our findings indicate that opioidergic agents have a role in post-ischemic progression through both
opioid-dependent and -independent mechanisms. In spite of the distinct-involved action mechanism, the potential
neuroprotective effect of opioidergic compounds was associated with immune suppression. Taken together, these findings suggest a potential role for opioidergic agents in the therapeutic consideration of
neuroinflammatory diseases. However, a better understanding of the mechanisms involved is necessary before this therapeutic potential can be realized.