The isolation of morphine by Friedrich Serturner in 1804 unlocked the powerful essence of opium. There are now a plethora of natural, synthetic, and semi-synthetic opioid analgesics that are more potent than morphine and possess diverse pharmacokinetic and pharmacodynamic properties (Staahl et al., 2009). Opioid medications are a pharmacological cornerstone in pain management, but as their use shifted from primarily acute, palliative, and cancer pain to encompass chronic pain, so too did their broader societal impact (Rosenblum et al., 2008). The more liberal use of opioids in the 1990s resulted in patients receiving higher doses of opioid medications and for longer periods of time, increasing their risk of adverse effects. This change in opioid prescribing may have provided the push that contributed to a sharp rise in opioid prescribing in Canada and the United States. However, the long-term efficacy of opioids for alleviating pain is questionable and their utility in chronic pain management has ignited controversy, as reviewed in this Special Issue by Montgomery (2020). Within the context of the opioid crisis, this Special Issue highlights recent advances in the opioid field and explores the potential of novel therapeutic targets and strategies for improving the safety and utility of opioid pain medications.

Opioid receptors are classically divided into mu (µ), delta (δ), and kappa (κ) receptor subtypes, which are a superfamily of seven-transmembrane G protein–coupled receptors expressed at critical nodes along the pain pathway. Each receptor has been cloned and found to share approximately 50%–70% sequence homology (Knapp et al., 1995; Koch et al., 1998). While opioid receptors possess structural similarities, their 3D crystal structures reveal distinct ligand-binding domains that confer unique pharmacological properties (Granier et al., 2012; Manglik et al., 2012; Martinez-Mayorga et al., 2013; Wu et al., 2012). There may also be a greater diversity of opioid receptors than previously anticipated, as evidenced by reports of a variety of opioid receptor splice variants, notably within the µ receptor gene (OPRM1) (Pan et al., 2001; Shabalina et al., 2009). Huang et al. (2020) guide us through the evolution of opioid receptors in the Pacific Hagfish. Brown et al. (2020) describe altered expression patterns of µ receptor variants in the medial prefrontal cortex of people who abuse heroin and in rats that develop heroin-seeking behavior. Cooper et al. (2021) then report novel findings on the constitutive activity of µ receptors and its contribution to the transition of acute to chronic pain. In addition, Kimmey et al. (2020) provide a thoughtful and compelling discussion about deconstructing brain mechanisms to understand how endogenous opioid circuitry modulates not only the sensory, but also the affective and emotional components of pain.

Efforts to improve the utility of opioid pain therapy have also focused on δ receptors because they may possess a better side effect profile as compared with µ receptor-directed therapies (Quirion et al., 2020). Degrandmaison et al. (2021) review trafficking patterns of the δ receptor dictated by precise amino acid motifs (akin to cellular barcodes) that direct receptor transport, internalization, recycling, and degradation. This is complemented by an elegant study from Cahill et al. (2020) showing that changes in δ receptor ultrastructural localization and signaling critically modulates affective pain and modality-specific pain hypersensitivity in chronic neuropathic pain. Barker et al. (2021) describe synergistic interactions between δ and µ receptor signaling which augment fentanyl analgesia. Lorente et al. (2020) then turn our attention to the importance of κ receptors in modulating interactions between pain, stress, and alcohol addiction. Taylor et al. (2020) expand the focus on κ receptors with a study that reveals the sexual dimorphism of κ receptor-mediated antinociception is influenced by the number of X chromosomes.

The nociceptin/orphanin FQ peptide (NOP) receptor (a.k.a. opioid receptor like-1 receptor) and classical opioid receptors share considerable structural homology, convergent intracellular mechanisms, and similar receptor distribution within the brain and spinal cord. Despite these similarities, NOP receptors are naloxone insensitive and possess relatively little or no affinity for endogenous opioid peptides (β-endorphin, enkephalins, and dynorphin) and exogenous opioid agonists (Mollereau et al., 1994). Kiguchi et al. (2020) provide a detailed review of the NOP receptor system, highlighting the therapeutic potential of NOP and µ receptor coactivation for enhancing opioid analgesic efficacy and reducing opioid abuse liability.

Opioid receptors are expressed throughout the nervous, gastrointestinal, and immune systems (Brownstein, 1993). The impact of opioids on nervous and gastrointestinal function is well established, and it has long been recognized that opioids modulate peripheral immune cell activity (Bryant & Roudebush, 1990; Eisenstein & Hilburger, 1998; Sharp, 2006; Wybran et al., 1979). The new perspective is that opioids can also trigger a robust neuroimmune response within the central nervous system (Lacagnina et al., 2017; Zhang et al., 2020). A key feature of this neuroimmune response is increased reactivity of microglia, which are the resident innate immune cells of the central nervous system (Ferrini et al., 2013; Kierdorf & Prinz, 2013; Trang et al., 2012; Watkins et al., 2009; Wen et al., 2011). In an original article, Reiss et al. (2020) use a conditional µ receptor knockout mouse model to describe the sex-dependent contribution of microglial µ receptors in morphine tolerance, hyperalgesia, and dependence. In addition to microglia, opioids influence the activity of astrocytes, which are immunocompetent cells within the central nervous system (Dong & Benveniste, 2001; Machelska & Celik, 2020). Dozio et al. (2020) apply data-independent acquisition mass spectrometry to delve into how morphine treatment affects the proteome and phosphoproteome of human astrocytes. Bajic et al. (2021) then explore central glial reactivity in a model of chemotherapy-induced gut toxicity in the presence of opioid and nonopioid analgesics. These reports provide novel insights into the complex interplay between opioids and the immune system, with glia as a key neuroimmune interface for opioid-related side effects.

In addition to activating classical opioid receptors and modulating activity of various cell types, opioid drugs can engage nonopioid receptor signaling pathways and drive the release of a myriad of factors that modulate central and peripheral processes (Grace et al., 2016; Trang et al., 2015; Zhang et al., 2020). For example, morphine antinociception critically depends on adenosine release, such that disruptions in adenosine levels or impaired adenosine receptor signaling underlies adverse opioid effects including opioid tolerance, dependence, and withdrawal (Cahill et al., 1993; Doyle et al., 2020; Sweeney et al., 1987). In this issue, Leduc-Pessah et al. (2021) show that spinal A₃ adenosine receptor activation transiently restores morphine antinociception in opioid-tolerant rats. Adenosine is a molecular building block for ATP, a primary ligand for the P2X family of receptors which are implicated in a variety of chronic pain conditions (Inoue, 2021; Kohno & Tsuda, 2021; Mapplebeck et al., 2018) and adverse opioid outcomes (Ferrini et al., 2013; Ide et al., 2014; Leduc-Pessah et al., 2017). Green-Fulgham et al. (2020) report that blocking ATP-gated P2X7 receptors and toll-like receptor 4 (TLR4) in the presence of morphine improves voluntary wheel running in nerve-injured rats. The resumption of wheel running suggests that targeting P2X7R and TLR4 with morphine cotreatment ameliorates neuropathic pain. Interactions between opioid receptors and several other receptor systems are also highlighted in this Special Issue. Mohammadkhani and Borgland (2020) review the cellular and behavioral basis of cannabinoid and opioid interactions in opioid dependence and withdrawal. Grenier et al. (2019) present evidence that blocking dopamine D1 receptors disrupts morphine reward in pain naïve but not neuropathic rats. Finally, Piccin and Contarino (2020) establish a causal link between the activity of the corticotropin releasing factor (CRF1) receptor and social behavioral deficits associated with opioid use disorder.

Concerns about opioid-related side effects and abuse liability are major limitations of opioid pain therapy. The short-term side effects of opioids may include drowsiness, nausea, constipation, euphoria, and respiratory depression which can result in opioid-related death. Stevens (2020) provides a mechanistic overview of opioid respiratory depression and proposes an intriguing opioid receptor-centric solution to address opioid overdose deaths. Long-term opioid use is further mired by the risk of analgesic tolerance, opioid-induced hyperalgesia, and dependence (Burma et al., 2017). Blomqvist et al. (2020) report that peripheral antagonism of opioid receptors is not sufficient to prevent morphine tolerance, implicating central rather than peripheral mechanisms in opioid tolerance. Lewter et al. (2020) then tackle the problem of opioid physical dependence by developing an innovative nanoparticle approach for sustained release of naloxone; they find that slow release reduces the severity of withdrawal in morphine-dependent mice.

Some people with opioid physical dependence may also struggle with opioid use disorder. An estimated 17 million people worldwide (United Nations Office on Drugs and Crime, 2021) are affected by opioid use disorder, which is defined by impaired control of opioid use, compulsiveness, cravings, and continued use despite harm (DSM-5, 2013). In a retrospective study, Agrawal et al. (2020) report that subjective responses to initial opioid exposure differ between people who progress to developing opioid use disorder and those who do not. This inter-individual variability in opioid responses and addiction liability has a significant genetic component (Glatt et al., 2007; Goldman et al., 2005; Levran et al., 2021; Reed & Kreek, 2021). Indeed, several genes have been associated with altered opioid response, including those that encode for opioid receptors, metabolizing enzymes, drug transporters, and proteins involved in other modulating systems such as descending adrenergic and serotonergic inputs (Klepstad et al., 2005; Nielsen et al., 2015; Stamer et al., 2005). Notably, a single nucleotide polymorphism in the µ receptor (A118G) has been found to have significant genetic association with opioid analgesia and addiction (Taqi et al., 2019; Walter et al., 2013). In this issue, Sumitani et al. (2020) review the genetic implications of opioid treatment in a group of patients treated for palliative cancer pain.

Among opioid users are women of childbearing age and pregnant women, increasing the incidence of perinatal exposure to opioids at an alarming rate. Mothers who use prescription or illicit opioids during pregnancy may have babies suffering from neonatal opioid withdrawal. The American Academy of Pediatrics estimates that every 25 min a baby is born experiencing symptoms of opioid withdrawal. In this issue, Isaac et al. (2021) review the clinical presentation and management of neonatal opioid withdrawal. Boggess and Risher (2020) also provide a complementary and detailed review on the long-term impact of prenatal opioid exposure on brain development.

As the opioid crisis continues to claim lives and affect families and communities, there is an urgency to improve the safety of opioid pain medications and a strong push to find solutions for curbing opioid addiction. Despite significant concerns surrounding opioid use, they remain the most potent analgesics at our disposal. Now, more than ever, there is a need for effective nonopioid alternatives to treat chronic pain conditions. This Special Issue brings together diverse clinical and mechanistic perspectives to highlight some of the recent exciting advances in the opioid field. These include fundamental discoveries that are unraveling the hidden secrets of opioid receptors and deciphering how opioids hijack circuitry that control pain, mood, and addiction. There is also a notable shift in responsible opioid prescribing, a realization of the importance of proper pain management for patients, and increased awareness of the close links between chronic pain, mental health, addiction, and socioeconomics. Momentum is building and much work remains, but our collective efforts will end the opioid crisis.

CONFLICT OF INTEREST

Dr. Trang is co-founder of AphioTx Inc., which is developing pannexin-1 channel targeted therapies.