Confronting the opioid crisis with basic research in neuropharmacology

1. Introduction

Opioid medications are widely prescribed to alleviate pain and suffering for millions of patients, but the utility of these drugs is limited by serious adverse effects including abuse liability, dependence, and overdose. At present, the non-medical (i.e., recreational) abuse of opioids is a worldwide public health threat. In the United States alone, more than 47,000 opioid-related overdose deaths occurred during 2017, and most of these fatalities were associated with synthetic opioids, especially fentanyl and its various analogs. Fentanyl is a muopioid receptor (MOP) agonist that is 50–100 times more potent than morphine as an analgesic agent. The origins of the current opioid crisis are complex, and effective solutions will require multidisciplinary cooperation among law enforcement personnel, first responders, treatment providers, policymakers, and scientists. To this end, basic research in pharmacology can provide critical information for addressing the opioid crisis. In this Special Issue of Neuropharmacology, entitled “New Vistas in Opioid Pharmacology”, we bring together an international panel of experts who report research findings related to three topics: 1] neuropharmacology of heroin, fentanyl and its analogs; 2] development of safer pain medications; and 3] novel pharmacotherapies for substance use disorders.

2. Neuropharmacology of heroin, fentanyl and its analogs

The current epidemic of opioid overdose deaths in being driven by fentanyl and its various analogs (Scholl et al., 2018). Fentanyl in recreational drug markets is not a diverted pharmaceutical product but is manufactured in clandestine laboratories and trafficked over the Internet (Prekupec et al., 2017). This illicitly manufactured fentanyl is encountered as a standalone product, an adulterant in heroin, or an ingredient in counterfeit pain pills. In the first section of the Special Issue, Kiyatkin (2019) compares the effects of morphine, heroin and fentanyl on respiratory depression and brain hypoxia, two factors contributing to opioid overdose death. Although all opioid drugs produce marked brain hypoxia in rats, the suppressive effect of heroin plus fentanyl is more sustained than the effect of either drug alone. These data may have implications for the current overdose epidemic where drug users are unknowingly consuming heroin mixed with fentanyl. Next, Towers et al. (2019) describe a preclinical model of heroin self-administration in which mice display escalation of drug intake under long-access conditions. Important sex differences are found, with females self-administering more heroin than males. Based on the availability of optogenetic and chemogenetic technologies in mice, this model will be useful for determining the neurobiological underpinnings of sex differences in heroin reinforcement. The study of Avvisati et al. (2019) reports that the principal heroin metabolite, 6-monoacetylmorphine (6-AM), supports robust self-administration behavior in rats, suggesting this compound may play a role in reinforcing effects of intravenous heroin. On the other hand, immunoneutralization of 6-AM does not affect ongoing heroin self-administration, so additional research on this intriguing topic is needed.

One of the more troubling aspects of the current opioid crisis is the emergence of novel synthetic opioids (NSO), which include fentanyl analogs and non-fentanyl compounds (Prekupec et al., 2017). NSO are presumed to act as MOP agonists, but little information is available about many of these compounds when they first appear in recreational drug markets. Varshneya et al. (2019) characterize the antinociceptive and locomotor effects of fentanyl analogs that are being confiscated by law enforcement. All of the fentanyl analogs tested exhibit pharmacological effects in mice that mimic the effects of morphine, but the compounds vary in potency by more than 500-fold, with isobutyrylfentanyl being most potent (ED₅₀ = 0.08 mg/kg) and benzodioxolefentanyl being least potent (ED₅₀ = 46.3 mg/kg). Likewise, Walentiny et al. (2019) demonstrate that fentanyl analogs engender oxycodone-like discriminative stimulus effects but vary widely in potency. The article by Bergh et al. (2019) examines the pharmacology of carfentanil, an ultrapotent fentanyl analog responsible for many overdose deaths. It is shown that carfentanil produces sustained catalepsy and hypothermia in rats given doses of 3 μg/kg or greater, and pharmacodynamic effects are accompanied by non-linear accumulation of the drug in plasma. Impaired carfentanil clearance could exacerbate its adverse effects and might also explain the phenomenon of re-narcotization after initial naloxone rescue in humans. The findings with these highly potent fentanyl analogs illustrate the inherent risk of overdose to drug users who are unaware of their exposure to NSO when taking adulterated heroin or counterfeit pain pills. The risk of overdose can also be increased by consumption of opioids in combination with other types of drugs. Afzal and Kiyatkin (2019) examine the interaction of benzodiazepines with heroin and show that the combination of midazolam plus heroin produces more severe brain hypoxia when compared to either drug alone.

3. Development of safer pain medications

A key long-term solution to the current opioid crisis is the development of pain medications that are safer and less addictive (Madras, 2018). In the second section of the Special Issue, Moerke and Negus (2019a) review the literature on intracranial self-stimulation (ICSS) in rats as a model for assessing the interactions between pain states and opioid reward. An advantage of the ICSS procedure is that abuse-related effects (i.e., ICSS facilitation) and abuse-limiting effects (i.e., ICSS depression) of drugs can be monitored during repeated drug exposures. Across a broad range of MOP agonists, initial exposure to the drugs produces only abuse-limiting effects, whereas repeated treatment promotes the emergence of abuse-related rewarding effects (Moerke and Negus, 2019b). Importantly, neither acute nor chronic pain models are protective against the enhancement of opioid reward after repeated drug administrations. These preclinical ICSS findings provide evidence for reward sensitization after repeated opioid exposures, even in the context of pain treatment, and highlight the need for new pain medications with reduced abuse liability.

To this end, several studies in this Special Issue address the potential therapeutic advantage of simultaneously targeting both MOPs and non-MOP receptor types to enhance MOP-mediated analgesia and/or to reduce MOP-mediated side effects. Three general strategies to achieve this goal are described. First, Li (2019) discusses the strategy of combining opioid agonists with non-opioid compounds for pain management. Ideally, such combination treatments will improve the therapeutic index for MOP agonists by enhancing antinociceptive effects while diminishing unwanted side-effects. As a specific example, the combination of a MOP agonist with an imidazoline I₂ receptor agonist reduces the dose of opioid needed for pain relief, along with a side-effects profile superior to opioid alone, in rat models of chronic pain.

Second, Cunningham et al. (2019) review the literature on “bi-functional” ligands as novel analgesics with improved safety. Bifunctional ligands achieve the same goal as medication combinations, but in this case, a single chemical entity satisfies the requirements for two pharmacophores and can interact with two different receptor systems simultaneously. A variety of bifunctional ligands are in preclinical development as pain medications, including MOP agonist/delta-opioid receptor (DOP) antagonists and MOP agonist/nociceptin opioid receptor (NOP) agonists. The buprenorphine analog, BU08028, is an example of a bifunctional MOP agonist/NOP agonist that exerts long-lasting antinociception with minimal abuse liability in monkeys. Similarly, Chao et al. (2019) report that BPR1M97 is a bifunctional MOP agonist/NOP agonist with potent antinociceptive effects in mice, but with less cardiovascular and gastrointestinal side-effects when compared to morphine.

A final strategy to simultaneously target MOP and non-MOP receptors focuses specifically on MOP-containing heteromers. Heteromers are multi-protein aggregates that contain two or more physically linked and adjacent receptors, and they may display different binding and signaling characteristics than their constituent receptors in isolation. One approach to targeting heteromers has been to synthesize “bivalent” ligands comprised of two distinct pharmacophores connected by a chemical linking group. For example, the bivalent ligand MCC22 targets MOP/chemokine receptor 5 (CCR5) heteromers by having one pharmacophore that acts as an agonist at the former site linked to a second pharmacophore that acts an antagonist at the latter site. Cataldo et al. (2019) show that MCC22 alleviates signs of neuropathic pain in mice more potently than morphine, without evidence of tolerance or reward. It is noteworthy that the length of the linking group between the two pharmacophores of MCC22 and other bivalent ligands is a critical determinant of biological activity, because the length of this linking group must be optimized for the distance between the drug-binding pockets in the adjacent heteromeric receptors. In an analogous manner, the bivalent ligand MMG22 targets MOP/metabotropic glutamate receptor 5 (mGluR5) heteromers to reduce signs of bone cancer pain in mice (Shueb et al., 2019). Jacobs et al. (2019) use the heteromer-specific ligand, 6′-GNTI, to demonstrate that DOP/kappa-opioid receptor (KOP) heteromers expressed in peripheral sensory neurons display unique signaling characteristics and functional regulation, suggesting these heteromers can serve as novel targets for medication development.

An exciting advance in the field of opioid pharmacology is the discovery that certain MOP ligands display preference, or bias, for G protein-dependent signaling pathways (e.g., cyclic AMP) as opposed to G protein-independent signaling pathways (e.g., β-arrestin) (Conibear and Kelly, 2019). The issue of MOP ligand bias has important clinical implications because evidence suggests that MOP-mediated antinociception is mediated via G protein recruitment whereas some adverse effects, like respiratory depression, are mediated via β-arrestin recruitment. Thus, the search for G protein-biased MOP agonists is an active area of research that led to the development of novel medications like TRV-130 (oliceridine). Pedersen et al. (2019) examine the time course of MOP binding and signaling for a number of clinically-relevant opioid medications to assess the role of kinetics in ligand bias. Their findings demonstrate that G protein-bias at MOP is not related to kinetics of binding or signaling, indicating the phenomenon is conformation-dependent rather than time-dependent. Interestingly, it is shown that the MOP partial agonist buprenorphine displays a high degree of G protein-bias, equivalent to newer compounds like oliceridine. Next, the study of Schwienteck et al. (2019) compares abuse-related (i.e., discriminative stimulus) and antinociceptive effects of MOP ligands in rats. The findings reveal that biased agonists like oliceridine display abuse-related effects similar to unbiased agonists, but the relative potency in drug discrimination versus antinociceptive tests is more favorable for biased agonists. These in vivo results in rats support the notion that G protein-biased MOP agonists are safer than traditional opioid analgesics like morphine.

4. Novel pharmacotherapies for substance use disorders

Clinical evidence shows that medication-assisted treatment of opioid use disorder is an effective therapeutic approach (Bell and Strang, 2020). Methadone and buprenorphine are MOP agonist medications with proven track records of success in managing opioid dependence, retaining patients in treatment, and preventing overdose. However, since both medications target MOP, they bear some risk for abuse and diversion. In the final section of the Special Issue, Jordan et al. (2019a) review the neurobiological rationale for the use of opioid agonist medications, then extend this logic to propose analogous strategies for treating cocaine use disorder. At present, there are no medications for cocaine use disorder that have been approved by the Food and Drug Administration. Next, Pravetoni and Comer (2019) review ongoing efforts to develop vaccines for treating opioid use disorder and reducing the incidence of overdose. Because vaccines are highly specific and long-lasting, they could complement existing behavioral and pharmacologic treatments for opioid use disorder. Furthermore, vaccines targeting fentanyl might be implemented as a harm reduction approach to protect against fentanyl overdose. The study of Jordan et al. (2019b) demonstrates that the selective dopamine D₃ receptor antagonist, R-VK4-40, reduces oxycodone self-administration in rats trained under fixed-ratio and progressive-ratio schedules of reinforcement. Such findings suggest that D₃ receptor antagonists may represent promising non-opioid pharmacotherapies for opioid use disorder. Finally, Atigari et al. (2019) report that the bifunctional KOP agonist/DOP agonist MP1104 reduces cocaine self-administration and cocaine-primed reinstatement of drug-seeking behavior in rats. It is noteworthy that the DOP-agonist properties of MP1104 serve to antagonize the aversive effects of KOP activation, which illustrates the utility of co-activating both receptors to optimize therapeutic effects.

5. Conclusions

The current opioid crisis seems overwhelming in scope and complexity, and there are no easy solutions. Nevertheless, basic research in neuropharmacology is an important component of the multipronged approach to dealing with the problem (Baumann et al., 2018). The articles published in this Special Issue of Neuropharmacology present viable strategies for addressing short- and long-term responses to the opioid crisis. In the short-term, the findings related to the pharmacology of heroin, opioid analgesics, and the proliferating number of NSO, serve to inform clinicians, policymakers, families, and individuals about the risks posed by these substances, especially when users are unknowingly exposed to potent MOP agonists via adulterated heroin or counterfeit pain pills. In the long-term, the findings related to medication discovery efforts provide clues for safer treatment of pain and addiction, including drug combinations, bifunctional/bivalent ligands, biased MOP agonists, and novel non-opioid compounds. It is hoped that the preclinical advances presented herein will be ultimately translated into efficacious clinical treatments to combat the scourge of opioid addiction and improve overall public health.