As most opiate drugs preferentially act via MOR, a potential explanation for differential interactive effects of opioids in the context of neuroHIV is the phenomenon of selective or “biased agonism”, such that different agonists can trigger distinct signaling events at the same receptor (Hauser et al. 2012). For example, coupling of MOR to Gα, Gβγ, and/or β-arrestin have been noted to differ depending on the MOR agonists involved (McPherson et al. 2010; Thompson et al. 2015; Burgueno et al. 2017). Physiologic outcomes of MOR activation in any cell type are determined by a bias for specific signaling pathways, the initial step of which is activation of G proteins and/or β-arrestin (Williams et al. 2013b; Violin et al. 2014; Suomivuori et al. 2020). The subcellular organization of GPCR signaling transduced by heterotrimeric G proteins and β-arrestin has been recently reviewed in detail (Eichel and von Zastrow 2018).