Effects of Different Opioid Drugs on Oxidative Status and Proteasome Activity in SH-SY5Y Cells

Abstract

Opioids are the most effective drugs used for the management of moderate to severe pain; however, their chronic use is often associated with numerous adverse effects. Some results indicate the involvement of oxidative stress as well as of proteasome function in the development of some opioid-related side effects including analgesic tolerance, opioid-induced hyperalgesia (OIH) and dependence. Based on the evidence, this study investigated the impact of morphine, buprenorphine or tapentadol on intracellular reactive oxygen species levels (ROS), superoxide dismutase activity/gene expression, as well as β2 and β5 subunit proteasome activity/biosynthesis in SH-SY5Y cells. Results showed that tested opioids differently altered ROS production and SOD activity/biosynthesis. Indeed, the increase in ROS production and the reduction in SOD function elicited by morphine were not shared by the other opioids. Moreover, tested drugs produced distinct changes in β2(trypsin-like) and β5(chymotrypsin-like) proteasome activity and biosynthesis. In fact, while prolonged morphine exposure significantly increased the proteolytic activity of both subunits and β5 mRNA levels, buprenorphine and tapentadol either reduced or did not alter these parameters. These results, showing different actions of the selected opioid drugs on the investigated parameters, suggest that a low µ receptor intrinsic efficacy could be related to a smaller oxidative stress and proteasome activation and could be useful to shed more light on the role of the investigated cellular processes in the occurrence of these opioid drug side effects.

Amelioration of morphine withdrawal syndrome by systemic and intranasal administration of mesenchymal stem cell‐derived secretome in preclinical models of morphine dependence

“…Recent evidence suggests that the effects of morphine on oxidative stress may be dose-and time-dependent. [94][95][96] This is aligned with previous findings in an animal model of voluntary morphine intake, in which four weeks of morphine consumption induced a three-fold increase in GSSG/ GSH ratio and MDA levels in the hippocampus compared with rats drinking only water, 26 increases that were fully normalized by hMSC-derived secretome administration. 26 Another possible explanation for the absence of increased oxidative stress in our animal model could be attributed to sex differences observed in response to opioid exposure.…”

“…The reasons for these differences are not clear but may be associated with several factors. Recent evidence suggests that the effects of morphine on oxidative stress may be dose‐ and time‐dependent 94–96 . This is aligned with previous findings in an animal model of voluntary morphine intake, in which four weeks of morphine consumption induced a three‐fold increase in GSSG/GSH ratio and MDA levels in the hippocampus compared with rats drinking only water, 26 increases that were fully normalized by hMSC‐derived secretome administration 26 .…”

Exploring neuroadaptive cellular pathways in chronic morphine exposure: An in‐vitro analysis of cabergoline and Mdivi‐1 co‐treatment effects on the autophagy–apoptosis axis

“…Chronic morphine exposure leads to decreased DRD2 expression and increased levels of a‐synuclein, β‐arrestin 2, p‐MEK2, autophagy, and apoptosis in SK‐N‐MC cells. The ubiquitin‐proteasome pathway plays a crucial role in DRD2 degradation, influencing dopaminergic signaling and opioid receptor dynamics, as morphine's sustained activation of MOR leads to proteasomal degradation of Gβγ, underpinning adenylate cyclase sensitization and opiate dependence 98–101 . The observed increase in autophagy and apoptosis, indicators of cellular stress, may be symptomatic of enhanced proteasome system activity, a notion confirmed by Martini et al 102 …”

“…The proteasome system's role in DRD2 receptor degradation is significant in the context of morphine addiction and tolerance 98 . Chronic morphine exposure leads to decreased DRD2 expression and increased levels of a‐synuclein, β‐arrestin 2, p‐MEK2, autophagy, and apoptosis in SK‐N‐MC cells.…”

Assessment of the Antioxidant and Hypolipidemic Properties of Salicornia europaea for the Prevention of TAFLD in Rats

“…The advantageous attributes of antioxidants stem from their capacity to neutralize free radicals, commonly originating from molecules incorporating oxygen, nitrogen, or sulfur, collectively referred to as reactive free radicals (RRS) [69]. The EPR 'radical probe' technique was previously applied to assess the RRS yield in different animal and human tissues, as well as cell cultures [70,71], due to its high sensibility in measuring reactive radical species through all cell compartments. As depicted in Figure 3, no significant differences in RRS were observed between the control group and the Salicornia-treated group.…”