Role Of PI3K/nNOS/cGMP Signaling In The Cardioprotection Induced By Remote Intrathecal Morphine Postconditioning

Objective: Morphine as classical opioid analgesics, which can mimic endogenous enkephalin to produce strong analgesic effects by stimulating the opioid receptors in the central nerve system. According to research, remote intrathecal morphine postconditioning(RMPC) can offer cardioprotection against ischemic reperfusion injury. The potential mechanism of cardioprotection produced by RMPC in the spinal cord is still under clear. The signaling of PI3K/n NOS/c GMP have been identified to mediate the antinociceptive effect of morphine in the primary nociceptive neurons. The objective of our research was to investigate the role of PI3K/n NOS/c GMP in the cardioprotective effects of remote intrathecal morphine postconditioning against myocardial ischemia-reperfusion injury in rats.Methods: Weight 280 ~ 320 g, Male SD Rats were successfully established the model of intrathecal catheter placement and ischemia/reperfusion model without complication. Experiments were divided to two parts. First, to clarify the role of PI3K/n NOS/c GMP in the cardioprotection induced by RMPC. Rats were randomly assigned to 13 groups. Sham-operated group(SHAM), Control group of saline(CON), Remote intrathecal morphine postconditioning group(RMPC), Wortmannin(PI3K inhibitor)+RMPC group(W+RMPC), L-NAME(NO synthase inhibitor)+RMPC group(L-NAME+RMPC), 7-NI(n NOS inhibitor)+RMPC group(7-NI+RMPC), ODQ(s GC inhibitor) +RMPC(ODQ+RMPC), KT5823(PKG inhibitor)+RMPC(KT5823+RMPC), Wortmannin group(W), L-NAME group(L-NAME), 7-NI group(7-NI), ODQgroup(ODQ), KT5823 group(KT5823). Second, to observe the content of c GMP in thoracic spinal cord produced by RMPC at different point. Rats were randomly assigned to 9 groups, 0 min group, 30 min group, 60 min group, 90 min group, 120 min group, W+RMPC group, L-NAME+RMPC group, 7-NI+RMPC group, ODQ+RMPC group. During the experiment we observed hemodynamic parameters, infarct size(demonstrated by IS/AAR), c GMP EIA value of optical density value of the reactants(OD). Finally, all data were expressed as Mean±SD. Data of different groups were analyzed using one-way analysis of variance(ANOVN) with Newman-Keuls test for multiple comparisons. Statistical differences were considered significant if the P value was <0.05.Results: Hemodynamic parameters: MAP and HR of all groups were reduced during Ischemia, Treatment and Reperfusion compared with baseline(P < 0.05 vs Baseline); the MAP of RMPC group were elevated at reperfusion period compared with that of CON(P < 0.05 vs CON). Infarct size: The volume of IS and IS/AAR were reduced in RMPC(P ﹤0.05 vs CON); the protective effects of RMPC were attenuated by pretreatment with W, 7-NI, L-NAME, ODQ and KT5823( P < 0.05 vs RMPC). The c GMP content was increased to 45.3±8.36 pmol/g tissue at 30 min after RMPC( P < 0.05 vs 0 min), and 24.7±2.31 pmol/g tissue at 60 min RMPC( P < 0.05 vs 0 min). 90 min later, the c GMP levels returned to basal level; Interestingly, intrathecally administrated with the inhibitors(L-NAME, 7-NI, ODQ) before morphine, The production of c GMP was decreased compared with RMPC(P < 0.05 vs RMPC).Conclusions: Taken together these results suggest a novel role of PI3K/n NOS/c GMP signaling in the cardioprotective effects due to remote intrathecal morphine postconditioning; The augmentation of c GMP produced by RMPC might be involved in this cardioprotection.