Safety implications of concomitant administration of antidepressants and opioid analgesics in surgical patients.

BACKGROUND: Commonly prescribed antidepressants (paroxetine, fluoxetine, duloxetine, bupropion) inhibit bioconversion of several prodrug opioid medications to their active metabolite, potentially decreasing analgesic effect. There is a paucity of studies assessing the risk-benefit of concomitant administration of antidepressants and opioids. RESEARCH DESIGN AND METHODS: Observational study of adult patients taking antidepressants prior to scheduled surgery using 2017-2019 electronic medical record data to assess perioperative use of opioids and to determine the incidence and risk factors for developing postoperative delirium. We conducted a generalized linear regression with the Gamma log-link to assess the association between use of antidepressants and opioids and a logistic regression to assess the association between antidepressants use and the likelihood of developing postoperative delirium. RESULTS: After controlling for patient demographic and clinical characteristics, and postoperative pain, use of inhibiting antidepressants was associated with 1.67 times greater use of opioids per hospitalization day (p = 0.00154), a two-fold increase in the risk for developing postoperative delirium (p = 0.0224), and an estimated average of four additional days of hospitalization (p < 0.00001) compared to use of non-inhibiting antidepressants. CONCLUSIONS: Careful consideration to drug-drug interactions and risk of related adverse events remains critical in the safe and optimal management of postoperative pain in patients taking concomitantly antidepressants.

The Glu102 mutation disrupts higher-order oligomerization of the sigma 1 receptor.

The sigma 1 receptor (σ1R) is a unique endoplasmic reticulum membrane protein. Its ligands have been shown to possess therapeutic potential for neurological and substance use disorders among others. The E102Q mutation of σ1R has been found to elicit familial cases of amyotrophic lateral sclerosis (ALS). Despite reports of its downstream signaling consequences, the mechanistic details of the functional impact of E102Q at molecular level are not clear. Here, we investigate the molecular mechanism of the E102Q mutation with a spectrum of biochemical, biophysical, and pharmacological approaches. Our analysis of the interaction network of σ1R indicates that a set of residues near E102 is critical for the integrity of C-terminal ligand-binding domain. However, this integrity is not affected by the E102Q and E102A mutations, which is confirmed by the radioligand binding results. Instead, the E102 mutations disrupt the connection between the C-terminal domain and the N-terminal transmembrane helix (NT-helix). Results from bioluminescence resonance energy transfer and western blot assays demonstrate that these mutations destabilize higher-order σ1R oligomers, while our molecular dynamics simulations based on a σ1R crystal structure reveal a potential mechanism by which the mutations perturb the NT-helix dynamics. Thus, we propose that E102 is at a critical position in propagating the effects of ligand binding from the C-terminal domain to the NT-helix, while the latter may be involved in forming alternative oligomer interfaces, separate from the previously reported trimer interface. Together, these results provide the first account of the molecular mechanism of σ1R dysfunction caused by E102Q.

The Effects of Terminal Tagging on Homomeric Interactions of the Sigma 1 Receptor.

The sigma 1 receptor (σ1R) has been implicated in cancers, neurological disorders, and substance use disorders. Yet, its molecular and cellular functions have not been well-understood. Recent crystal structures of σ1R reveal a single N-terminal transmembrane segment and C-terminal ligand-binding domain, and a trimeric organization. Nevertheless, outstanding issues surrounding the functional or pharmacological relevance of σ1R oligomerization remain, such as the minimal protomeric unit and the differentially altered oligomerization states by different classes of ligands. Western blot (WB) assays have been widely used to investigate protein oligomerizations. However, the unique topology of σ1R renders several intertwined challenges in WB. Here we describe a WB protocol without temperature denaturization to study the ligand binding effects on the oligomerization state of σ1R. Using this approach, we observed unexpected ladder-like incremental migration pattern of σ1R, demonstrating preserved homomeric interactions in the detergent environment. We compared the migration patterns of intact σ1R construct and the C-terminally tagged σ1R constructs, and found similar trends in response to drug treatments. In contrast, N-terminally tagged σ1R constructs show opposite trends to that of the intact construct, suggesting distorted elicitation of the ligand binding effects on oligomerization. Together, our findings indicate that the N-terminus plays an important role in eliciting the impacts of bound ligands, whereas the C-terminus is amenable for modifications for biochemical studies.