Opioid Substitution Therapies and the Role of Selective/Biased Agonism in neuroHIV Pathogenesis
Although morphine, methadone, and buprenorphine all activate MOR, each can impart different signals through MOR, related to the nature and timing of their coupling to Gα, Gβγ, β-arrestin and/or regulators of G protein signaling (RGS), since each downstream effector couples into unique cell functions. Functional selectivity occurs at each opioid receptor type, and for most endogenous opioid peptides at all three receptor types (Gomes et al. 2020). Moreover, opioid receptors can be expressed on a subset of virtually every cell type in the CNS—with second messenger coupling to each opioid receptor type potentially being unique, cell-type specific, and context dependent. Thus, the “pluridimensional” (Galandrin and Bouvier 2006; Kenakin 2011; Costa-Neto et al. 2016) actions of any opiate at MOR are sufficiently complicated that it is not possible to predict whether, e.g., morphine, methadone or buprenorphine, would similarly effect any aspect of neuroHIV pathology without empirical testing. Despite their significant use as medication-assisted therapies for treating opioid addiction, few studies have directly compared commonly used opiate substitution therapies (Bell and Strang 2020), especially in relation to HIV (Khalsa et al. 2006; Choi et al. 2020).
Opioid substitution therapies significantly reduce the frequency of injection drug use (Kwiatkowski and Booth 2001; Pettes et al. 2010), decrease HIV transmission risk (MacArthur et al. 2012; Platt et al. 2016), and reduce drug-related mortality (Mathers et al. 2013) and the risk of opioid overdose (Volkow et al. 2014). Further, improved ARV outcomes among PWH have been reported with opioid substitution therapies, including the uptake and retention on ARV, medication adherence rates, and viral suppression (Low et al. 2016; Mukandavire et al. 2017). The two main medications used for opioid substitution therapy include methadone, a MOR full agonist, and buprenorphine, a MOR partial agonist and partial antagonist of KOR (Noble and Marie 2018). In comparison to methadone, buprenorphine has been shown to have fewer pharmacodynamic interactions with ARVs and causes less opioid withdrawal symptoms potentially due to its partial agonism on MOR, but also due to its high affinity and long duration of MOR binding (Walsh et al. 1994; McCance-Katz 2005; Whelan and Remski 2012). Further, differential proinflammatory and neurotoxic effects have been noted for various opioid treatments (Boland et al. 2014; Fitting et al. 2014b; Carvallo et al. 2015; Dutta and Roy 2015). In primary astrocytes, agonist-selective actions at MOR and KOR can be clearly demonstrated (Bohn et al. 2000; Belcheva et al. 2003; McLennan et al. 2008; Hahn et al. 2010), and we found that morphine, methadone, and buprenorphine differentially increase ROS and [Ca2+]i alone or following Tat co-exposure (Fitting et al. 2014b). Morphine can enhance HIV-1-induced production of cytokines and specifically chemokines (El-Hage et al. 2008a; Dave 2012; El-Hage et al. 2014), while other opioids including methadone, oxycodone, buprenorphine, and DAMGO can decrease inflammatory function and decrease monocyte migration (Boland et al. 2014; Carvallo et al. 2015; Jaureguiberry-Bravo et al. 2016; Chilunda et al. 2019).
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).
In the context of HIV, it has been shown that selective MOR agonists such as endomorphin-1, but not DAMGO or morphine, significantly increase HIV-1 replication in infected microglia (Peterson et al. 1999). This effect might be due to an apparent bias of endomorphin-1 towards arrestin recruitment and receptor phosphorylation, which was significantly correlated with agonist-induced internalization of MOR (McPherson et al. 2010). It is suggested that ligands that display bias towards G protein-mediated pathways and away from β-arrestin 2 recruitment may have improved therapeutic profiles against the development of tolerance and dependence/addiction (McPherson et al. 2010).