Morphine stimulates angiogenesis through Akt/mTOR/eIF4E activation under serum deprivation or H₂O₂‐induced oxidative stress condition

Abstract

Morphine is an opioid analgesic drug routinely used to treat pain in several medical conditions including cancer. Increasing evidence has shown that morphine can directly modulate cancer growth via regulating angiogenesis. In this work, we investigated the effect of morphine on angiogenesis under pathological conditions. We showed that morphine, in a concentration typical of that observed in patient's blood, stimulates tumour angiogenesis under serum deprivation and H2O2‐induced oxidative stress conditions. We found that morphine protected human lung tumour associated‐endothelial cell (HLT‐EC) against serum deprivation or H2O2‐induced inhibition of capillary network formation. Furthermore, morphine stimulated other biological functions of HLT‐EC under serum deprivation and H2O2‐induced pathological conditions, such as growth, migration and survival, without affecting HLT‐EC adhesion. Interestingly, morphine at the same concentration did not affect lung tumour cell growth and survival, suggesting the specific protective role of morphine at low micromolar concentrations on tumour angiogenesis. Using in vivo Matrigel angiogenesis assay, it was found that morphine stimulated in vivo angiogenesis under H2O2‐induced pathological condition. The opioid receptor antagonist, naloxone, did not inhibit the protective activity of morphine in in vivo angiogenesis, indicating that the effect was less likely to be mediated by the typical opioid receptors. Mechanism analysis indicated that morphine alleviated serum deprivation and H2O2‐induced angiogenesis inhibition via reducing oxidative stress and damage, and activating Akt/mTOR/eIF4E signalling. We demonstrate the protective role of morphine on tumour angiogenesis under pathological conditions. Our work suggests that clinical use of morphine may be harmful in patients with angiogenesis‐dependent cancers.

Comparative analysis of the effects of opioids in angiogenesis

“…The reason behind this discrepancy is unclear, but it may be a result of differences in model systems, endothelial type, drug concentrations and experimental conditions. In support of this possibility, our finding is consistent with the recent study by Zhang et al that morphine stimulates angiogenesis after serum deprivation [ 9 ] because our experimental settings are similar to Zhang et al’s work. We next showed that oxycodone at the same concentration range also displayed pro-angiogenic activity, but was less potent than morphine.…”

“…Morphine, fentanyl, oxycodone and codeine are μ-opioid receptor agonists but can bind to and activate δ and κ with differential affinity [ 8 ]. Among these four commonly used opioids, morphine has been mostly studied under preclinical settings for its direct effect on tumor cell and angiogenesis but the conclusions are contradictory [ 9 – 12 ]. Morphine stimulates angiogenesis under serum deprivation and oxidative stress conditions [ 9 ] whereas also suppresses angiogenesis associated with tumor growth in mice [ 13 ].…”

“…Among these four commonly used opioids, morphine has been mostly studied under preclinical settings for its direct effect on tumor cell and angiogenesis but the conclusions are contradictory [ 9 – 12 ]. Morphine stimulates angiogenesis under serum deprivation and oxidative stress conditions [ 9 ] whereas also suppresses angiogenesis associated with tumor growth in mice [ 13 ]. One study demonstrates that fentanyl stimulates angiogenesis in diabetic rats and promotes wound healing [ 14 ].…”

Disentangling the molecular mechanisms underlying the retrieval and extinction of morphine withdrawal-associated memories in the basolateral amygdala and dentate gyrus

“…The diminution in mTOR phosphorylation in the DG after the expression of CPA was due to the recall of aversive memories associated with morphine withdrawal and not to opiates exposure given that, when other group of morphine-treated rats were tested for CPA extinction, mTOR phosphorylation in their DG was similar to that of controls. Moreover, several studies have reported an activation (phosphorylation) of mTOR induced by opiates that mediates some of their effects, such as tolerance, hyperalgesia and angiogenesis, among others [40][41][42][43][44]. mTOR activity, through protein synthesis and actin dynamics mediated by mTORC1 and mTORC2, respectively, has been related as well with distinct aspects of learning and memory, such as late long-term potentiation (L-LTP) that underlies LTM [39].…”