Opioid Preconditioning Induces Opioid Receptor-Dependent Delayed Neuroprotection Against Ischemia in Rats

Abstract

We have shown that exposure of neurons to opioid immediately before ischemia induces ischemia tolerance. This phenomenon is called acute opioid preconditioning. In this study, we test the hypothesis that opioids induce delayed neuropreconditioning (from hours to days after opioid exposure). Exposure to morphine, an agonist for delta-, mu-, and kappa-opioid receptors, or Tan-67, a selective delta1-receptor agonist, for 30 minutes at 24 hours before a 35-minute oxygen-glucose deprivation (OGD, to simulate ischemia in vitro) dose-dependently reduced the OGD-induced neuronal death in the CA1 region of the rat organotypic hippocampal slice cultures. The morphine preconditioning-induced neuroprotection was inhibited by beta-funaltrexamine, a mu-opioid receptor antagonist, but not by 7-benzylidenenaltrexone, a delta1-receptor antagonist, or nor-binaltorphimine, a kappa-receptor antagonist. The Tan-67 preconditioning-induced neuroprotection was inhibited by 7-benzylidenenaltrexone. The combination of morphine and Tan-67 did not induce a better preconditioning effect than did morphine or Tan-67 alone. Application of morphine and Tan-67 at 24 hours before permanent right middle cerebral arterial occlusion reduced brain infarct volume and improved neurologic functional outcome assessed 24 hours after the occlusion in adult male rats. These results suggest that morphine and Tan-67 induce a delayed preconditioning effect in the brain under in vivo and in vitro conditions. Whereas the delayed phase of morphine preconditioning may involve mu-opioid receptors, Tan-67 preconditioning may be mediated by delta1-opioid receptors. Morphine and Tan-67 may activate a shared intracellular signaling pathway to induce the delayed preconditioning effects in the brain.

β-Funaltrexamine Inhibits Inducible Nitric-oxide Synthase Expression in Human Astroglial Cells

“…In particular, opioids such as morphine have neuroprotective properties (Zhao et al 2006). While the mechanism for the neuroprotective effects of morphine are not completely understood, under certain conditions, morphine attenuates oxidative and proinflammatory stress (Lee et al 2004).…”

“…For instance, administration of 1400W (a selective inhibitor of iNOS) within 18 h of traumatic brain injury reduces neuropathogenic insult (Jafarian-Tehrani et al 2005). More recently, opioids such as morphine have gained attention for their potential neuroprotective actions (Zhao et al 2006). However, very little is known about the specific effects of opioids on iNOS activation in astroglia.…”

The neuroprotective mechanism of brain ischemic preconditioning

“…These results suggest that the delayed phase of morphine preconditioning may involve μ opioid receptors and δ opioid receptors. Morphine and Tan-67 may activate a shared intracellular signaling pathway to induce the delayed preconditioning effects in the brain [27] .…”

Morphine Protects against Intracellular Amyloid Toxicity by Inducing Estradiol Release and Upregulation of Hsp70

“…Exogenous morphine preincubation improves the population of spike amplitudes of evoked field potentials, indicating that preconditioning with morphine might be neuroprotective (Ammon-Treiber et al, 2005). Morphine preconditioning induces opioid receptor-dependent neuroprotection against ischemia in rats and reduced ischemia-induced cell death in the CA1 regions of hippocampal slices (Zhao et al, 2006). In mouse hippocampal slices with oxygen-glucose deprivation, morphine preconditioning improves neuronal cell survival rate through protein kinase C (PKC) (Liu et al, 2008).…”