Overview

The Opioid Crisis
Opioid abuse in the United States (U.S.) has reached catastrophic levels. According to the latest World Drug Report, 53.4 million people worldwide used opioids in 2017, which is 56% higher than in the previous year (UNODC 2019a). North America remains the region with the highest non-medical use of opioids with a staggering 4% of the population aged 15–64 using opioids (UNODC 2019a, c). In 2017, the burden of opioid use in the U.S. had accounted for 42 million healthy years of life lost due to premature death and disability (Institute for Health Metrics and Evaluation 2017; UNODC 2019a). During 2017, there were 70,237 overdose related deaths, out of which 47,600 (67.8%) were caused by opioids, which was a 12% increase from 2016 (Scholl et al. 2018; UNODC 2019c). The Centers of Disease Control and Prevention (CDC) reports that on average 130 Americans die from an opioid overdose each day (CDC 2017). Due to the constant rise in deaths involving opioids, the U.S. Government declared the opioid crisis/epidemic a public health emergency in 2017 (U.S. Department of Health and Human Services 2017). Injection drug use increases the likelihood of contracting human immunodeficiency virus (HIV) and drug abuse and HIV have long been described as interrelated epidemics (Swan 1997; Leshner 1998; Nath et al. 1999, 2002). Despite this understanding, opioid use disorder (OUD) and HIV remain a huge public health concern (Strathdee and Beyrer 2015; Peters et al. 2016). In fact, the opioid crisis is seen as a major roadblock in several aspects of public health, including thwarting the goal of eliminating HIV within the next decade (Fauci et al. 2019; Lerner and Fauci 2019).
OUD is also likely to exacerbate many negative aspects of the COVID-19 pandemic (Alexander et al. 2020; Becker and Fiellin 2020; NIDA 2020; Wakeman et al. 2020). Not only are individuals with OUD more vulnerable to SARS-CoV-2 and liable to spread the infection, social-distancing practices create isolation, despair, and economic hardships, heightening opioid abuse (with inherent respiratory depression depending on the amount of tolerance developed) and the probability of overdose (Becker and Fiellin 2020; Wakeman et al. 2020). By virtue of its greater safety profile and decreased likelihood for abuse (Bell and Strang 2020), the use of buprenorphine via telemedicine has become advantageous for managing OUD during the COVID-19 pandemic (Leppla and Gross 2020; Samuels et al. 2020) but presents new challenges (Khatri and Perrone 2020).
The current opioid crisis did not happen quickly; in fact, it has been described as occurring in three phases. The first phase began in the late 1990s with an increase in the number of prescription opioids. This led to overdose deaths that were attributable to natural and semi-synthetic opioids, such as methadone (Kolodyny et al. 2015; CDC 2017). The second phase began in 2010 in which heroin took the lead as the principal cause of overdose deaths. The most recent, third wave, began in 2013 in which highly potent synthetic opioids, such as fentanyl and its analogs became the main cause of mortality (Kolodyny et al. 2015; CDC 2017). The entry of fentanyl and its analogs into the clandestine market has changed the dynamics of the opioid market in the U.S. The synthetic opioids, such as fentanyl, are several orders of magnitude more potent than morphine, easily smuggled, and frequently and inconsistently mixed with lower quality drugs increasing the probability of overdosing. According to the National Forensic Laboratory Information System of the U.S. Drug Enforcement Administration (DEA), fentanyl accounted for one-third of the illicit opioids seized in 2017 (UNODC 2019c) and has become a global problem (UNODC 2019b).

The Pathophysiology of Opioid Abuse
The effects of opioid abuse on the central nervous system (CNS) have been extensively examined. Immediate effects of opioids result in decreased levels of consciousness, sedation (Collett 1998; Thompson 2000; Indelicato and Portenoy 2002), drowsiness, and sleep disturbances (Moore and Dimsdale 2002; Bourne and Mills 2004; Qureshi and Lee-Chiong 2004). While acute opioid exposure can impair cognition in healthy subjects (Lawlor 2002; Ersek et al. 2004), enduring cognitive and psychomotor deficits occur with chronic opioid use (Sjogren et al. 2000; Dublin et al. 2015; Roberts et al. 2018; Wollman et al. 2019; Serafini et al. 2020), including altered pain perception (opioid-induced hyperalgesia), dysregulated reward/saliency processing, hyperkatifeia, and epigenetic changes, which can persist years following abstinence (Ersche et al. 2006; Browne et al. 2020). The behavioral changes seen with long-term opioid use are accompanied by lasting structural and epigenetic (e.g., altered DNA methylation and expression of non-coding RNAs) alterations in brain regions implicated in mood, reward, and motivation (Upadhyay et al. 2010; Dublin et al. 2015; Volkow and Morales 2015; Koob and Volkow 2016; Serafini et al. 2020).
Up to 90% of post-mortem tissues sampled from opiate abusers display brain edema (Buttner 2011), astrogliosis and microgliosis especially in the hippocampus (Oehmichen et al. 1996), white matter, and subcortical regions at autopsy (Tomlinson et al. 1999; Anthony et al. 2005; Buttner et al. 2006; Buttner and Weis 2006). The reactive gliosis is accompanied by increases in proinflammatory cytokines and inflammatory mediators, including TNF-α, IL-1β, and nitric oxide synthase (NOS) (Dyuizen and Lamash 2009). Opiates especially drive the enhanced activation of heme-oxygenase, NOS, and cyclic GMP-dependent-protein kinase (Liang and Clark 2004) and production of reactive nitrogen species (RNS) such as peroxynitrite (Salvemini 2009), and resultant nitrosative damage (Zou et al. 2011). Nitrosative damage is an important endpoint for opiate exposure (Pasternak et al. 1995; Liang and Clark 2004; Salvemini 2009) and key site of convergence for the oxidative stress accompanying HIV protein exposure (Hauser and Knapp 2014; McLane et al. 2018).
For delayed heroin overdose death after a survival period of 5 h or more, studies report neurovascular disorders, hypoxic ischemic leukoencephalopathy, and region-specific atrophy with neuronal losses that can include the hippocampal formation, the cerebellar Purkinje cell layer and olivary nucleus (Protass 1971; Ginsberg et al. 1976; Gosztonyi et al. 1993), as well as other areas (Buttner 2011; Cadet et al. 2014). Loss of neurons and synaptic connections is supported by postmortem reports of smaller mean relative volumes in various brain regions in individuals with OUD, including cortical areas (Danos et al. 1998; Pezawas et al. 1998), the basal ganglia (Muller et al. 2015, 2019), prefrontal cortex (Cadet et al. 2014), and hypothalamus (Muller et al. 2018). Interestingly, leukoencephalopathy, atrophy (Cadet et al. 2014), and increased hyperphosphorylated tau-containing neurofibrillary tangles are reported with chronic opiate abuse compared to age-matched controls (Ramage et al. 2005; Anthony et al. 2010; Kovacs et al. 2015). Glycogen synthase kinase 3 α or β (GSK-3α/β; the pan antibody used in this study does not discern α from β isoforms) and/or cyclin-dependent kinase-5 (Cdk-5) are increased in the frontal and temporal cortices, the locus coeruleus, and the hippocampus, respectively, and correlate with microgliosis (Anthony et al. 2010). Further, more prolonged use increases the risk of accelerated age-related and even Alzheimer’s-like pathological changes (Ramage et al. 2005; Anthony et al. 2010; Kovacs et al. 2015) and cognitive impairment (Gruber et al. 2007).
Moreover, heroin use is associated with symmetric T2 and fluid-attenuated inversion recovery (FLAIR) hyperintense white matter lesions of the CNS using magnetic resonance imaging (MRI), which coincide with increased microgliosis and inflammation at the same sites (Upadhyay et al. 2010; Bora et al. 2012; Qiu et al. 2013; Alaee et al. 2014; Li et al. 2016; Shrot et al. 2017). Although a few studies have started to examine opiate-HIV interactions in white matter (see below), we predict that the interactive effects on myelin dysregulation will significantly worsen CNS outcomes.
Preclinical studies indicate opioid-induced neuroimmune signaling alter the saliency of opioid reward and physical dependence (Narita et al. 2006; Hutchinson et al. 2008, 2009). Direct injections of astrocyte-conditioned medium containing cytokines into the nucleus accumbens (NAc) increase morphine conditioned place preference (Narita et al. 2006). Drugs reported to selectively attenuate glial inflammation block morphine conditioned place preference and attenuate symptoms of opioid withdrawal (Narita et al. 2006; Hutchinson et al. 2009; Liu et al. 2010). μ (MOR), δ (DOR), and κ (KOR) opioid receptors are expressed by subsets of astrocytes and microglia (Stiene-Martin and Hauser 1991; Eriksson et al. 1992; Stiene-Martin et al. 1993; Ruzicka et al. 1995; Gurwell et al. 1993; Hauser et al. 1996; Turchan-Cholewo et al. 2008; Maduna et al. 2018) and are involved in opioid tolerance and dependence to varying degrees (Kieffer and Gaveriaux-Ruff 2002; Berger and Whistler 2010; Morgan and Christie 2011). Despite some reports of morphine triggering immune activation via Toll-like receptor 4 (TLR4) (Terashvili et al. 2008; Hutchinson et al. 2010; Coller and Hutchinson 2012; Hutchinson et al. 2012; Theberge et al. 2013; Lacagnina et al. 2017) by binding to a myeloid differentiation protein-2 intermediary (Wang et al. 2012), this is contrary to the typical actions of opiates, which by themselves (and in the absence of a priming event such as HIV co-exposure) tend to suppress immune function (Eisenstein 2019). A vast majority of the immune, antinociceptive, and other physiological effects of opioids are mediated by opioid receptors per se and not TLR4 (Hu et al. 2011; Fukagawa et al. 2013; Stevens et al. 2013; Mattioli et al. 2014; Eisenstein 2019).
Overall, the findings indicate that immune signaling plays a critical role in the pathophysiology of OUD and associated physical dependence. How opioids effect neuroHIV, as well as how opioid abuse and dependence are altered by neuroHIV or whether opioid-HIV interactions result in a unique disease state are discussed.