Dextromethorphan Dampens Neonatal Astrocyte Activation and Endoplasmic Reticulum Stress Induced by Prenatal Exposure to Buprenorphine

Abstract

Prenatal exposure to buprenorphine renders offspring vulnerable to cerebral impairments. In this study, our data demonstrate, for the first time, that prenatal exposure to buprenorphine escalates astrocyte activation concurrent with indications of endoplasmic reticulum (ER) stress in the hippocampi of neonates, and this can be prevented by the coadministration of dextromethorphan with buprenorphine. Furthermore, dextromethorphan can inhibit the accumulation of GPR37 in the hippocampus of newborns caused by buprenorphine and is accompanied by the proapoptotic ER stress response that involves the procaspase-3/CHOP pathway. Primary astrocyte cultures derived from the neonates of the buprenorphine group also displayed aberrant ER calcium mobilization and elevated basal levels of cyclooxygenase-2 (COX-2) at 14 days in vitro while showing sensitivity to lipopolysaccharide-activated expression of COX-2. Similarly, these long-lasting defects in the hippocampus and astrocytes were abolished by dextromethorphan. Our findings suggest that prenatal exposure to buprenorphine might instigate long-lasting effects on hippocampal and astrocytic functions. The beneficial effects of prenatal coadministration of dextromethorphan might be, at least in part, attributed to its properties in attenuating astrocyte activation and hippocampal ER stress in neonates.

Post-Injury Buprenorphine Administration Is Associated with Long-Term Region-Specific Glial Alterations in Rats

“…Bup treatment has also been shown to affect brain regions differently by other groups. Prenatal exposure to Bup resulted in higher GFAP levels specifically within the hippocampus [ 64 ]. Another group found a slight reduction in the percentage of GFAP+ area covered in the corpus callosum of mice days following Bup administration [ 42 ].…”

Post-injury Buprenorphine Administration Is Associated With Long-Term Region-Specific Glial Alterations in Rats

“…Bup treatment has also been shown to affect brain regions differently by other groups. Prenatal exposure to Bup resulted in higher GFAP levels specifically within the hippocampus 65 . Another group found a slight reduction in the percentage of GFAP+ area covered in the corpus callosum of mice days following Bup administration 42 .…”

Orphan G Protein-Coupled Receptor GPR37 as an Emerging Therapeutic Target

“…64 Conversely, exposure to buprenorphine was found to increase GPR37 accumulation, but coadministration with dextromethorphan inhibited this aggregation, thus mitigating the associated proapoptotic ER stress response. 65 These findings suggest the potential for treating neurodegenerative diseases and conditions that are characterized by protein misfolding and ER stress. Furthermore, the identification of peptides from the Nterminus-cleaved domain of GPR37 (ecto-GPR37) through mass spectrometry has revealed a notable increase in PD patients' cerebrospinal fluid (CSF) levels, with no significant changes observed in patients with Alzheimer's disease.…”

“…In cell culture models of PD with GPR37 overexpression, indole-3-propionic acid (IPA) effectively prevented β-amyloid aggregation and ER stress, resulting in reduced neuronal cell death . Conversely, exposure to buprenorphine was found to increase GPR37 accumulation, but coadministration with dextromethorphan inhibited this aggregation, thus mitigating the associated proapoptotic ER stress response . These findings suggest the potential for treating neurodegenerative diseases and conditions that are characterized by protein misfolding and ER stress.…”