Morphine-Mediated Brain Region-Specific Astrocytosis Involves the ER Stress-Autophagy Axis

Abstract

A recent study from our lab has revealed a link between morphine-mediated autophagy and synaptic impairment. The current study was aimed at investigating whether morphine-mediated activation of astrocytes involved the ER stress/autophagy axis. Our in vitro findings demonstrated upregulation of GFAP indicating astrocyte activation with a concomitant increase in the production of proinflammatory cytokines in morphine-exposed human astrocytes. Using both pharmacological and gene-silencing approaches, it was demonstrated that morphine-mediated defective autophagy involved upstream activation of ER stress with subsequent downstream astrocyte activation via the μ-opioid receptor (MOR). In vivo validation demonstrated preferential activation of ER stress/autophagy axis in the areas of the brain not associated with pain such as the basal ganglia, frontal cortex, occipital cortex, and the cerebellum of morphine-dependent rhesus macaques, and this correlated with increased astrocyte activation and neuroinflammation. Interventions aimed at blocking either the MOR or ER stress could thus likely be developed as promising therapeutic targets for abrogating morphine-mediated astrocytosis.

The cellular basis of fetal endoplasmic reticulum stress and oxidative stress in drug-induced neurodevelopmental deficits

“…For example, cocaine and METH can induce neurotoxicity via ER stress and oxidative stress pathways as revealed by studies in which both acute and chronic cocaine and/or METH exposure generated reactive oxygen species and altered CNS activities in various brain subregions ( Bashkatova et al, 2005 ; Dietrich et al, 2005 ; Macedo et al, 2005 ; Pubill et al, 2005 ; Yamamoto and Zhu, 1998 ). Similar results of imbalanced ROS and dysregulated ER stress were observed in studies examining neurotoxicity of opioids and nicotine ( Cai et al, 2016 ; Sil et al, 2018 ; Wong et al, 2016 ). Therefore, induction of ER and oxidative stress as a result of in utero substance exposure can be detrimental to brain development and impair neurological functions of affected infants.…”

“…Recent studies have shed light on ER stress-integrated mechanisms of opioid-mediated impairments on brain development and cognitive functions. Sil et al (2018) revealed morphine exposure induced astrocytosis and subsequent inflammatory responses via ER stress-autophagy axis. Morphine exposure not only resulted in upregulation of the ER chaperone BiP, also led to induction of autophagy and autophagasome accumulation as indicated by elevated autophagy markers BECN1, LC3-II, and p62.…”

Cocaine Mediated Neuroinflammation: Role of Dysregulated Autophagy in Pericytes

“…Treated cells were lysed using the Mammalian Cell Lysis kit (Sigma-Aldrich, MCL1-1KT) as described previously [40]. Cell lysates were centrifuged at 12000 ×g for 10 min at 4°C, the protein content of the supernatant was quantified by a BCA assay using Pierce™ BCA Protein Assay Kit (Thermo Fisher Scientific, 23227) according to the manufacturer's protocol.…”

Role of Inflammasomes in HIV-1 and Drug Abuse Mediated Neuroinflammaging

“…It has been reported that cocaine self-administration in mice reduced uptake of NDEVs by the astrocytes primarily in the motor cortex, an effect that was effectively reversed by extinction training [ 205 ]. Drugs of abuse like cocaine, morphine, methamphetamine [ 206 , 207 , 208 ] can induce chronic low-level inflammation and can also potentiate inflammatory status in the context of HIV-1 [ 209 , 210 , 211 ], which together can contribute to the process of inflammaging. As discussed above presence of ApoE4 is highly prevalent in the aging HIV-1 population.…”