Neuropeptide and cytokine regulation of pain in the context of substance use disorders

Abstract

Substance use disorders (SUDs) are frequently accompanied by affective symptoms that promote negative reinforcement mechanisms contributing to SUD maintenance or progression. Despite their widespread use as analgesics, chronic or excessive exposure to alcohol, opioids, and nicotine produces heightened nociceptive sensitivity, termed hyperalgesia. This review focuses on the contributions of neuropeptide (CRF, melanocortin, opioid peptide) and cytokine (IL-1β, TNF-α, chemokine) systems in the development and maintenance of substance-induced hyperalgesia. Few effective therapies exist for either chronic pain or SUD, and the common interaction of these disease states likely complicates their effective treatment. Here we highlight promising new discoveries as well as identify gaps in research that could lead to more effective and even simultaneous treatment of SUDs and co-morbid hyperalgesia symptoms.

1. Substance use disorders and pain as negative reinforcement

Substance use disorders (SUDs) are defined by a loss of control over substance use and the emergence of negative affective symptoms (e.g., anxiety, pain) during withdrawal (Edwards and Koob, 2010). Such co-morbid symptoms may promote negative reinforcement mechanisms that drive continued or escalated substance use. SUDs are often life-long psychiatric diseases based on the emergence of craving symptoms and high propensity for relapse during attempted abstinence (Koob and Volkow, 2010). Thus, SUDs can be conceptualized as chronic diseases characterized by a three-stage cycle: binge/intoxication, withdrawal/negative affect, and pre-occupation/anticipation (Koob, 2013; Pahng et al., 2017a). This cycle can worsen over time and impacts over 21 million people in the United States who suffer from SUDs (Koob, 2013; McCance-Katz et al., 2017). Other mental health conditions appear to interact closely with SUD, with over 8.5 million people suffering both an SUD along with an accompanying affective disorder (McCance-Katz et al., 2017).

Based on its intimate association with negative affect, the experience of chronic, unrelieved pain is a key factor likely contributing to the maintenance of SUDs via a host of neurobiological and psychosocial mechanisms (LeBlanc et al., 2015; Ditre et al., 2019). Chronic pain affects approximately 20% of adults worldwide (Goldberg and McGee, 2011), a number that will likely increase over the next several decades given the aging global population. In the United States alone, over 50 million individuals report chronic pain at a cost of over $600 billion in healthcare expenses and lost productivity (IOM, 2011; Dahlhamer, MMWR, 2018). This review will focus on three commonly abused substances (alcohol, opioids, and nicotine) that function as potent analgesics, likely contributing to negative reinforcement processes at the intersection of pain relief and SUD liability (Edwards, 2016). While the majority of pain research has focused on spinal and peripheral mechanisms, this abundance of data has produced few effective analgesic therapies and alternatives to opioids. Recently, more progressive conceptual and research efforts have attempted to incorporate the contributions of pain-related negative affect and central nociceptive and motivational circuitry in chronic pain and its potentially crucial relationship to a variety of SUDs (Elman et al., 2013; Navratilova et al., 2013; Thompson and Neugebauer, 2019; Serafini et al., 2020).

Human clinical evidence and preclinical animal models have demonstrated that nociceptive hypersensitivity (or hyperalgesia) is produced alongside escalated intake of multiple abused substances including alcohol, opioids, and nicotine (Parkerson et al., 2013; Elman and Boorsook, 2016; Massaly and Moron, 2019; Edwards et al., 2020). We hypothesize that hyperalgesia may drive both continuous substance use and relapse propensity as a powerful negative reinforcement mechanism based on its persistent negative affective valence. Dysregulation of multiple neuropeptide and cytokine systems appears to be involved in this process (Caputi et al., 2019; Gonçalves Dos Santos et al., 2020), while targeting these systems may represent a viable therapeutic strategy for the treatment of pain in the context of SUDs. This review will describe the contributions of select major neuropeptide and cytokine systems to the development and maintenance of SUD-associated hyperalgesia, with the hope of promoting new therapeutic avenues for the treatment of both SUD and pain (Shurman et al., 2010; Egli et al., 2012).

1.1. Alcohol use disorder and pain

Alcohol use disorder (AUD) affects roughly 13.9% of the population in the United States (Grant et al., 2015). Alcohol has long been used for its stress-reducing and analgesic efficacy (Wolff et al., 1942; Egli et al., 2012; Thompson et al., 2017). Self-reports of alcohol use specifically for pain management are common (e.g., Riley and King, 2009). Problem drinkers at risk for AUD not only report more severe pain symptoms compared to non-drinkers, but also report a higher incidence of using alcohol to manage their pain (Brennan et al., 2005). Chronic or excessive alcohol exposure often results in increased pain sensitivity in both humans and animal models as part of a broader alcohol withdrawal syndrome (Gatch and Lal, 1999; Dina et al., 2000; Jochum et al., 2010; Edwards et al., 2012; Fu et al., 2015). Such data suggest that frequent drinking in individuals suffering from AUD may be motivated in part by a desire to alleviate hyperalgesia symptoms (Zale et al., 2015) as a negative reinforcement process that facilitates AUD progression. At the preclinical level, partial evidence for this relationship comes from a recent study where hyperalgesia symptoms in rats made dependent via chronic and passive alcohol inhalation were attenuated following either experimenter-administered alcohol or volitional alcohol self-administration (Roltsch Hellard et al., 2017). AUD has been hypothesized to stem from functional alterations in the neurobiological substrates of supraspinal pain processing (Egli et al., 2012), including a key contribution from the central amygdala (CeA; Neugebauer, 2015). Stimulation of the CeA produces an analgesic effect in animals, whereas CeA inhibition results in hyperalgesia symptoms (Itoga et al., 2016). Consistent with this, chronic alcohol exposure and withdrawal produces increases in inhibitory GABAergic transmission in the CeA (Roberto et al., 2004), likely contributing to the manifestation of AUD-associated hyperalgesia symptoms. Alcohol also disrupts the activity of CeA projections to the periaqueductal gray (PAG), a region that is critically involved in endogenous analgesic mechanisms (Avegno et al., 2018).

Additional neurobiological changes across both hypothalamic and extra-hypothalamic stress systems have been observed in preclinical AUD animal models and people living with AUD that parallel their transition from recreational to uncontrolled alcohol consumption (Edwards et al., 2015; Vendruscolo et al., 2015). For example, both alcohol and alcohol withdrawal elevate systemic glucocorticoid levels due to activation of the endocrine HPA axis (Rivier, 2014). Glucocorticoid receptor (GR) activity transcriptionally regulates multiple signaling networks within the brain, including stress-related neuropeptide systems within the CeA that are hypothesized to become potentiated in the context of AUD (Makino et al., 1994; Shepard et al., 2000; Lachize et al., 2009; Gilpin and Roberto, 2012; Myers et al., 2014; Edwards et al., 2015; Gilpin et al., 2015). These neuroadaptations may promote both escalation of alcohol drinking and hyperalgesia in the context of AUD as well as explain the therapeutic efficacy of the GR antagonist mifepristone to reduce alcohol intake and craving symptoms in both preclinical animals and humans (Simms et al., 2012; Vendruscolo et al., 2015). Importantly, mifepristone also alleviates hyperalgesia symptoms in an animal model of alcoholic neuropathy (Dina et al., 2008).

Neuroinflammation is another likely contributor to alcohol reinforcement, alcohol-related pain, and associated negative affect (Blednov et al., 2012; Liu et al., 2019; Woelfer et al., 2019). Acute and chronic alcohol exposure influences both circulating and central nervous system (CNS) pro-inflammatory cytokine production (Doremus-Fitzwater et al., 2014; Erickson et al., 2019) and shares a common behavioral phenotype with depression (Anton et al., 2017) and sickness-related symptoms (e.g., fever, anhedonia, reduced activity, and reduced social behavior; Richey et al., 2012). Importantly, the relationship between alcohol and neuroimmune activity appears to be modified further by recent stress history. For example, Deak and colleagues demonstrated that animals receiving a footshock 24 h prior to an alcohol challenge exhibited a greater increase in hippocampal levels of the pro-inflammatory cytokine interleukin-6 (IL-6) compared to unstressed controls (Doremus-Fitzwater et al., 2018). In addition to its ability to reduce alcohol drinking and hyperalgesia as mentioned above, the GR antagonist mifepristone also attenuates depression-like behaviors induced by chronic CNS administration of the pro-inflammatory cytokine interleukin-1β (IL-1β) (Zhang et al., 2018). Consequently, interactions of stress and neuroinflammation likely promote negative affective symptoms (Walker et al., 2014) experienced as a consequence of chronic alcohol exposure. Similar relationships also likely contribute directly to an exacerbation of somatic and/or affective pain-related symptoms associated with AUD (Egli et al., 2012; Walker et al., 2013). These results indicate a multi-faceted and complex neurobiology regulating both excessive alcohol use and subsequent hyperalgesia, but also indicating that both conditions may be treated simultaneously. For a recent translational overview of medication strategies for AUD and pain interactions, see Edwards et al. (2020).

1.2. Opioid use disorder and pain

Both illicit and prescription opioids represent potent anti-nociceptive (analgesic and/or anti-hyperalgesic) medications used extensively for the management of acute and chronic pain (Trang et al., 2015). Unfortunately, opioids are commonly prescribed to treat certain chronic pain conditions (such as neuropathies) that are largely unresponsive to their beneficial analgesic effects (Volkow et al., 2018; Manion et al., 2019; Martinez-Navarro et al., 2019). Even when opioids are effective, chronic administration often leads to the development of analgesic tolerance and hyperalgesia, motivating patients to escalate the dose used to overcome pain symptoms (Angst and Clark, 2006; Pahng et al., 2017b). Opioid over-utilization and escalation of opioid use may also drive neuroadaptations in central pain and reinforcement centers to promote the establishment or progression of opioid use disorder (OUD) in vulnerable populations (Shurman et al., 2010; Edwards, 2016).

Importantly, hyperalgesia can persist for years in formerly opioid-dependent individuals, while negative affective experiences from pain or other sources can exacerbate pain symptoms in patients (Carcoba et al., 2011; Tsui et al., 2016; Wachholtz et al., 2019). Nociceptive hypersensitivity can also act as a factor that drives opioid craving after protracted abstinence. For example, formerly opioid-dependent individuals exhibit reduced pain tolerance even after several months of abstinence, a time when opioid cue-induced craving is correlated with hyperalgesia symptoms (Ren et al., 2009). Moreover, this pain hypersensitivity is based not on pain perception but on pain-induced negative affect, indicating the critical role of the negative affective dimension of pain in long-term relapse propensity as opposed to the sensory dimension of nociception itself (LeBlanc et al., 2015). Additional recent comprehensive reviews of opioid-induced tolerance and hyperalgesia from a clinical perspective are available (Martyn et al., 2019; Colvin et al., 2019). An important direction for future animal work will be to better model the endurance of hyperalgesia symptoms into protracted withdrawal and how these symptoms interact to facilitate reinstatement to opioid-seeking behavior using operant models.

The neurobiological mechanisms of opioid-induced hyperalgesia include contributions from a number of factors within both peripheral and central nervous systems, including enhancement of excitatory neurotransmission, neuropeptide release, glial cell activation, and the subsequent release of pro-inflammatory cytokines (Lee et al., 2011; Roeckel et al., 2016; Cahill and Taylor, 2017). While opioid-mediated analgesia is believed to result primarily from direct actions on opioid receptors, the phenomenon of hyperalgesia is thought by some to occur upon opioid-induced activation of glial cells via toll-like receptor 4 (TLR4) signaling (Watkins et al., 2009). Another hypothesis behind opioid-induced hyperalgesia is the “two-hit hypothesis”, which posits that microglia are primed for pain following nerve injury, then re-activated following the subsequent administration of opioids, thus leading to an exaggerated inflammatory response and enduring hyperalgesia (Grace et al., 2016). Similar to AUD, dysregulation of central stress and reinforcement circuitry (including contributions from the CeA) is hypothesized to facilitate OUD-associated hyperalgesia mechanisms as well as an enhancement of negative emotional states related to pain, termed hyperkatifeia (Shurman et al., 2010; Koob, 2020). Interestingly, animals exhibit hyperalgesia symptoms during withdrawal that directly correlate with recent levels of opioid self-administration (Edwards et al., 2012). Opioid-dependent animals also exhibit significantly greater pain-avoidance behavior during withdrawal compared to non-dependent animals (Pahng et al., 2017).

Opioids primarily work through four major receptors in the brain: mu-opioid (MOR), delta-opioid (DOR), kappa-opioid (KOR), and the non-classical nociceptin (NOR) receptors. These G-protein coupled receptors are also activated by endogenous neuropeptides including endorphins, dynorphins, enkephalins, and nociceptin (Le Merrer et al., 2009; Koob and Volkow, 2010; Bodnar, 2013). Opium-derived substances like morphine and codeine, as well as synthetic and semi-synthetic opioids like fentanyl, methadone, and oxycodone, can also bind to these receptors (Bodnar, 2013; Pathan and Williams, 2012). Opioid receptors are widely expressed throughout the nervous system, including high levels in the limbic system and higher pain-related cortical areas such as the CeA and anterior cingulate cortex (Bodnar, 2013; Le Merrer et al., 2009). As a consequence, this system also contributes to affective pain regulation and reinforcement processes, making it a key target for treating OUD and other SUDs (Koob and Volkow, 2016). In addition, opioid regulation of non-neuronal cells and immune system processes likely represents another important mechanistic locus in both the exacerbation and treatment of pain and OUD (Jacobsen et al., 2014; Varrassi et al., 2018; Eisenstein, 2019). Finally, it is important to mention that opioid receptor signaling appears critical for alcohol reward processes, including important contributions from MOR (Roberts et al., 2000; Contet et al., 2004), DOR (Alongkronrusmee et al., 2018), and KOR (Walker et al., 2012; Anderson and Becker, 2017; Karkhanis et al., 2017) systems. These interactions likely play a key role the combined efficacy and frequent co-use of opioids and alcohol for pain management (Witkiewitz and Vowles, 2018).

1.3. Nicotine use disorder and pain

Compared to alcohol and opioids, nicotine produces modest analgesic effects that can be difficult to detect in human laboratory settings (Ditre et al., 2016). Nicotine exerts its analgesic effects via binding to nicotinic acetylcholine receptor channels (nAchRs) and subsequent modulation of spinal and supra-spinal cholinergic neurotransmission (Naser and Kuner, 2018) and immune cell function (Kiguchi et al., 2012). Chronic nicotine use is a serious medical problem in the United States as health-related complications associated with nicotine use disorders (NUDs) account for over half a million deaths per year and costs upwards of $289 billion (National Center for Chronic Disease Prevention and Health Promotion Office on Smoking and Health, 2014). Nicotine is most commonly used in the form of cigarettes and vapor-related devices. Emerging electronic cigarette and vaping technologies now affect roughly 6.9 million users, with that number on the rise, especially in teenagers (Kohut, 2017; Wang et al., 2018). Nicotine use is also highly correlated with alcohol drinking (Funk et al., 2006; Leão et al., 2015; McGinn et al., 2016) along with use of other analgesic substances such as opioids and cannabis (Kohut, 2017). Similar to alcohol and opioids, chronic nicotine use facilitates the development of negative affective states (including hyperalgesia) that most notably manifest during abstinence periods (O’Dell et al., 2014; Cohen et al., 2015; Jackson et al., 2015; Bruijnzeel, 2017; LaRowe et al., 2018; Ditre et al., 2018). These symptoms are hypothesized to drive negative reinforcement mechanisms that promote a high rate of relapse following attempts to quit (Pang et al., 2014; George and Koob, 2017).

Despite its modest analgesic efficacy, substantial research has shown important links between the subjective experience of pain and nicotine cravings (Ditre et al., 2011) as well as pain promoting the co-use of nicotine and alcohol together (LaRowe et al., 2020). In addition to direct alterations in nAChR function (Bagdas et al., 2018; Naser and Kuner, 2018), other neurobiological changes in both cortical and sub-cortical stress-related circuitry (as seen in AUD and OUD) likely contribute to nicotine withdrawal symptoms, including hyperalgesia (Mihov and Hurlemann, 2012; Li et al., 2014; Cohen and George, 2013; Leao et al., 2015). For example, increased corticotropin-releasing factor (CRF) activity in the CeA has been linked to enhanced anxiety- and pain-related symptoms during nicotine withdrawal (Cohen et al., 2015). In humans, increased capsaicin-induced pain intensity ratings, neurogenic inflammation, and mechanical hyperalgesia is evident following 12–24 h of abstinence from nicotine use (Ditre et al., 2018), while other aversive aspects of nicotine withdrawal may persist for weeks (McLaughlin et al., 2015). Finally, reciprocal analgesic interactions between cholinergic and opioid systems are under-studied but may represent an important mechanism and treatment opportunity for NUD-related pain (Naser and Kuner, 2018).

2. Neuropeptide systems contributing to SUD-Associated hyperalgesia

Neuropeptides are short-chain polypeptides that mediate a wide range of neurophysiological functions, including analgesia, reward and reinforcement, social behaviors, and memory processes (Hokfelt et al., 2003). Perhaps the most obvious peptidergic system involved in pain and SUD is the endogenous opioid system, although other neuropeptides have been discovered to substantially contribute to somatic and/or affective components of nociception. The generation of small molecule ligands acting at neuropeptide receptors has contributed to our mechanistic understanding of these processes as well as provided novel future therapeutics for the treatment of pain in the context of SUD.

2.1. Corticotropin-releasing factor system

Corticotropin-releasing factor (CRF) is a 41-amino acid polypeptide that regulates hormonal, sympathetic, and behavioral responses to stressors (Heinrichs and Koob, 2004; Logrip et al., 2011). Within the brain, substantial CRF immunoreactivity and corresponding CRF1 and CRF2 receptor densities are present throughout the neocortex, amygdala, medial septum, hypothalamus, and autonomic midbrain and hindbrain nuclei (Charlton et al., 1987). In addition to its adaptive hormonal role in stress responsiveness within the HPA axis (Bale and Vale, 2004), substantial preclinical evidence has accumulated for CRF systems in the regulation of negative affect and negative reinforcement mechanisms in the context of SUDs (Edwards and Koob, 2010; Schreiber and Gilpin, 2018). A more complicated role for CRF in nociception has also emerged. CRF interacts with opioid receptor signaling throughout ascending and descending pain circuitry (Mousa et al., 2007). CRF can also directly activate immune cells that have accumulated at damaged peripheral nerves to facilitate opioid-mediated anti-nociception (Schafer et al., 1997; Labuz et al., 2006, 2010). Peripheral actions of CRF are likely mediated via both CRF1 and CRF2 receptors (Mousa et al., 2003; Yarushkina and Filaretova, 2018). Early research described a similar anti-nociceptive role of CRF in the context of inflammation and stress-induced analgesia (Lariviere and Melzack, 2000), although CRF was also demonstrated to facilitate visceral hypersensitivity (Tache et al., 2005). Additional research helped reconcile these seeming contradictions. Lariviere et al. (2011) described opposite effects of centrally administered CRF in the formalin test that depended upon the precise behavioral nociceptive response measured. Additionally, with the implementation of selective pharmacological tools for distinguishing CRF receptor-subtype function, additional work suggested that the central anti-nociceptive effects of CRF are most likely mediated through CRF2 receptors (Ji and Neugebauer, 2008). In contrast, CRF1 receptors facilitate the pro-nociceptive effects of this neuropeptide, and this relationship is mediated at least partly via the CeA (Ji and Neugebauer, 2007; Fu and Neugebauer, 2008). Importantly, CRF1 receptors also appear to drive pain-related anxiety-like behavior (Ji et al., 2007). Accordingly, the effects of CRF1R antagonists to alleviate pain-related behaviors have been demonstrated across multiple chronic pain models, although this drug category does not affect pain-related readouts (e.g., audible or ultrasonic vocalizations, paw withdrawal thresholds) in naïve (non-injured) animals (e.g., McNally and Akil, 2002; Fu and Neugebauer, 2008; Edwards et al., 2012), indicating an anti-hyperalgesic mechanism as opposed to an analgesic effect.

A wealth of research has also delineated a role for CRF in promoting hyperalgesia during withdrawal from alcohol, opioids, and nicotine. A role for amygdala CRF receptor signaling in regulating thermal hyperalgesia following precipitated opioid withdrawal was first demonstrated by McNally and Akil (2002). In this study, rats were made dependent via morphine pellet and withdrawal was precipitated by naloxone. Under these conditions, dependent rats exhibited a reduced tail flick latency compared to sham-pelleted, naltrexone-treated animals, and this thermal hyperalgesia was alleviated by microinjection of a non-selective CRF receptor antagonist (alpha-helical CRF) into the CeA. Importantly, intra-CeA administration of a CRF receptor antagonist also reduces opioid withdrawal-induced conditioned place aversion, suggesting possible links among negative affect, hyperalgesia, and CRF signaling after chronic opioid exposure (Heinrichs et al., 1995). Subsequent studies using operant opioid self-administration procedures discovered that individual levels of opioid intake in animals given extended access to heroin correlated with severity of mechanical hyperalgesia measured during subsequent withdrawal periods (Edwards et al., 2012). The authors speculated that attempts to alleviate somatic and/or motivational withdrawal states may in part underlie compulsive opioid seeking, while tolerance to the anti-nociceptive effects of opioids may in part drive the need to escalate opioid use over time. Mechanical hyperalgesia in the context of either alcohol or opioid dependence was significantly attenuated via systemic administration of the CRF1R-selective antagonist MPZP (Edwards et al., 2012), and a follow-up study further discovered that chronic, prophylactic treatment with MPZP was capable of reducing both heroin intake escalation and development of hyperalgesia symptoms over time (Park et al., 2015). Indeed, additional studies suggest that blockade of CRF1Rs may alleviate hyperalgesia symptoms associated with a host of psychiatric disorders, including nicotine use disorder (Cohen et al., 2015) and post-traumatic stress disorder (Itoga et al., 2016), with the CeA representing the critical neuroanatomical mediator. These convergent data suggest that CRF systems represent highly viable targets for treating multiple conditions that are co-morbid with SUD. Indeed, future SUD medication strategies may need to be guided by the effective treatment of co-morbid stress-related conditions unique to each patient, including hyperalgesia (Cannella et al., 2019).

2.2. Melanocortin receptor system

The melanocortins, including adrenocorticotropic hormone (ACTH) and the various melanocyte-stimulating hormones (MSHs), are products of proopiomelanocortin (POMC) processing (with the other major product being the endogenous opioid beta-endorphin). POMC is synthesized in the anterior and intermediate lobes of the pituitary and in neurons of the arcuate nucleus of the hypothalamus and nucleus of the solitary tract (Cawley et al., 2016). Melanocortin peptide actions are mediated via five G protein-coupled receptors (MC1R-MC5R; Dores et al., 2016). The brain primarily contains a high expression of MC3 and MC4 melanocortin receptors (Mountjoy, 2010) that may also activate MAPK-family signaling (Mountjoy, 2015). Their primary endogenous ligand is alpha-MSH, while agouti-related peptide (AgRP) acts as an endogenous inverse agonist based on the substantial constitutive activity of melanocortin receptors (Tao, 2014). Melanocortin activity is involved in both stress- and pain-related signaling. Specifically, MC4R has emerged as an intriguing target for the treatment of pain in the context of SUD based on work demonstrating that systemic MC4R blockade with HS014 reduces both tolerance to opioid analgesia as well as hyperalgesia symptoms during opioid withdrawal (Kalange et al., 2007). This promising finding was extended recently in alcohol-dependent animals, wherein both intracerebroventricular (ICV) and intranasal administration of HS014 alleviated hyperalgesia symptoms observed during withdrawal (Roltsch Hellard et al., 2017). The chosen routes of administration in this study highlighted not only a novel and highly tractable route of administration, but further evidence that supra-spinal neuropeptide activity could be targeted for the treatment of pain. Gilpin and colleagues went on to discover contributions of MC4Rs in the CeA to the regulation of pain sensitivity, with intra-CeA alpha-MSH administration capable of producing thermal hyperalgesia in otherwise naïve animals, and intra-CeA HS014 able to alleviate hyperalgesia symptoms in alcohol-dependent animals (Avegno et al., 2018). Interestingly, facilitation of hyperalgesia by CeA MC4Rs was prevented by infusion of the MOR agonist DAMGO into the periaqueductal gray (PAG), thereby functionally connecting these two important supraspinal pain-regulatory areas. Thus, blocking melanocortin activity may represent a viable therapeutic strategy for facilitating descending analgesic opioid mechanisms (described below) in the context of SUD-related hyperalgesia.

2.3. Mu-opioid receptor system

The mu-opioid receptor (MOR) system mediates a central role in endogenous opioid-mediated antinociception based on its actions within the descending pain modulatory system, which is comprised of the PAG, rostral ventromedial medulla (RVM), and spinal cord (Basbaum and Fields, 1984). MORs are also located throughout several additional peripheral and central nervous system areas, including supra-spinal nociceptive centers (e.g., CeA and anterior cingulate cortex) and also on peripheral immune cells such as leukocytes (Machelska and Celik, 2020). Contributions of MOR endocytosis to opioid analgesic tolerance has been the subject of intense debate (Finn and Whistler, 2001), in addition to intracellular signaling mechanisms downstream of MORs that may promote effective and sustained analgesia versus analgesic tolerance. MORs activate at least two signal transduction pathways (G_i/o protein and beta-arrestin-2 systems) with MOR-mediated G_i/o protein signaling thought to confer (at least) the primary analgesic actions (Bohn et al., 2000; Raehal et al., 2005). Such information has been used in the search for more effective opioid analgesics with fewer side effects (Manglik et al., 2016). Indeed, much interest has been generated at the potential for developing “biased” MOR ligands that selectively activate G_i/o-protein over beta-arrestin signaling pathways (Grim et al., 2020). However, the biased MOR agonism strategy has recently been challenged, as beta-arrestin-2 knockout mice still develop opioid-induced respiratory depression (Kliewer et al., 2020). Somewhat surprisingly, the importance of MOR contributions to opioid-induced hyperalgesia relative to toll like receptor-4 (TLR4) activity remains a matter of intense debate (Hutchinson et al., 2011). However, morphine-induced thermal and mechanical hyperalgesia are absent in both male and female MOR knockout mice (Anne Roeckel et al., 2017), while opioid-induced hyperalgesia still occurs in TLR4-mutant mice (Mattioli et al., 2014). Thus, in addition to the mechanisms described here, additional research to delineate novel MOR-dependent signaling mechanisms (Befort et al., 2008) that are driven by excessive exposure to opioids and other abused substances may help shed light on the development and treatment of SUD-associated hyperalgesia.

2.4. Delta-opioid receptor system

Delta-opioid receptors (DORs) and their primary endogenous ligands (enkephalins) are highly expressed in forebrain regions, including the striatum and cortex (Mansour et al., 1993). Importantly, the analgesic effects of DOR stimulation appear more pronounced in the context of chronic pain when DOR levels are up-regulated (Cahill et al., 2007; Pradhan et al., 2011). DORs also represent a potentially valuable therapeutic target at the intersection of pain and emotional dysregulation in the context of SUDs, as DOR activity appears to reduce both nociception and negative affect (Lutz and Kieffer, 2013). DOR knockout mice display enhanced nociception (Martin et al., 2003; Nadal et al., 2006), as well as increased anxiety- and depression-like behaviors (Filliol et al., 2000). Consistent with their role in endogenous analgesia mechanisms (Gendron et al., 2016), DORs also appear to play a protective role against hyperalgesia during alcohol withdrawal (Alongkronrusmee et al., 2016). Hyperalgesia symptoms in mice chronically gavaged with 3 g/kg ethanol were worsened and prolonged in DOR knockout mice and following administration of the DOR antagonist naltrindole. In contrast, intrathecal administration of the DOR agonist TAN-67 produced antinociception in alcohol self-administering mice. Importantly, DOR agonism is also efficacious in other chronic pain models (Kabli and Cahill, 2007), and may reduce hyperalgesia mechanisms in part via blockade of TLR4 activity (Madera-Salcedo et al., 2013). As DOR agonism is effective against multiple AUD-related symptoms, including excessive drinking and other components of withdrawal, they would appear to be a very attractive translational target for AUD (van Rijn et al., 2010). In contrast to preclinical studies of alcohol withdrawal hyperalgesia, the role of DORs in opioid-induced hyperalgesia appears to be altogether different. The DOR antagonist naltrindole reduces tolerance to morphine analgesia (Abdelhamid et al., 1991), and subsequent work discovered a likely contribution of the type 2 DOR (Beaudry et al., 2015). Naltrindole also reduces remifentanil-induced hyperalgesia (Wang et al., 2015; Liu et al., 2018), indicating that DOR activity facilitates opioid-induced hyperalgesia. Consequently, DOR-based therapies for SUD-associated hyperalgesia may need to account for the substance(s) being abused by the patient and/or DOR receptor subtype targeted.

2.5. Kappa-opioid receptor system

Kappa-opioid receptors (KORs) and their major endogenous ligands, the dynorphins, are expressed throughout the central nervous system and at relatively high levels in brain areas including the nucleus accumbens, hippocampus, hypothalamus, bed nucleus of the stria terminalis, and amygdala (Chavkin et al., 1982; Fallon and Leslie, 1986; Schwarzer, 2009). KORs signal through G_i/o-proteins and can also activate G protein-coupled receptor kinases (GRKs) as well as members of the mitogen-activated protein kinase (MAPK) family (Bruchas and Chavkin, 2010). Recent investigations into KOR signaling have discovered conditions where hyperalgesia and other components of negative affect associated with SUD appear to be dissociable. For example, KOR antagonism with norbinaltorphimine (nor-BNI) reduces escalated heroin self-administration in animals given extended access (12 h/day) to the drug, but does not alleviate the somatic hyperalgesia symptoms that manifest during heroin withdrawal (Schlosburg et al., 2013). In fact, nor-BNI administration produced hyperalgesia in animals given limited (1 h/day) access to heroin, consistent with other reports of pro-nociceptive actions of nor-BNI (Obara et al., 2003). Consequently, KOR antagonism would be expected to promote somatic hyperalgesia mechanisms and has indeed been demonstrated to enhance and prolong antinociceptive tolerance and exacerbate other somatic indices of withdrawal (Suzuki et al., 1992). In comparison to somatic indices of pain, more recent studies have discovered that KOR antagonism can reduce pain-related negative affect (Liu et al., 2019; Massaly et al., 2019), revealing contributions of mesolimbic KOR activity and dopamine depletion in this process. KORs are located on ventral tegmental area dopamine neurons terminating in the nucleus accumbens, where they act to inhibit dopamine release (Di Chiara and Imperato, 1988). As dopamine deficits occur in the context of both chronic pain and SUDs, KOR antagonism might be expected to treat both conditions simultaneously (Jarcho et al., 2012; Taylor et al., 2015, 2016). Given the possible dissociable effects of KOR activity on distinct pain constructs (reducing somatic pain but facilitating the aversive nature of pain), the translational promise of this approach remains to be determined (Cahill et al., 2014). However, many have argued that the affective components of pain may come to predominate in cases of pain chronification and overall reduction in the quality of life in human subjects (Shurman et al., 2010). Indeed, this mechanism may explain the effectiveness of buprenorphine (a partial MOR agonist and KOR antagonist) in alleviating pain experiences and improving the quality of life in pain and OUD patients (Uberall and Muller-Schwefe, 2013; Worley et al., 2015). Similar to MOR-based strategies described above, there is hope that biased KOR agonism toward specific intracellular signaling pathways may facilitate better therapeutic strategies that can treat pain in the absence of other undesirable KOR-mediated effects such as dysphoria and hallucinations (Bruchas and Chavkin, 2010; Dogra and Yadav, 2015), although the translational efficacy of such approaches remains to be determined.

2.6. Nociceptin receptor system

Nociceptin (also known as orphanin FQ) and the nociceptin receptor (NOR, previously known as opioid receptor-like-1) are widely expressed throughout the peripheral and central nervous systems, including in the spinal cord and within key supraspinal nociceptive centers such as the CeA and anterior cingulate cortex (Letchworth et al., 2000; Kiguchi et al., 2020). Nociceptin is also expressed in immune cells (Peluso et al., 1998). Interestingly, nociceptin does not bind to classical opioid receptors, and is therefore selective for NOR binding due to some unique structural features of the receptor (Thompson et al., 2012), which is a G_i/o protein-coupled receptor (Hawes et al., 2000). True to its name, nociceptin has long been associated with pain regulation (Kolesnikov and Pasternak, 1999), and the peptide shares considerable homology to other endogenous opioids (Toll et al., 2016). However, early work described both analgesic and hyperalgesic actions for nociceptin (Yamamoto et al., 1999), with these effects being driven in part by distinct cellular mechanisms within the rostral ventral medulla (RVM) depending on the behavioral state of animals. Acting in a homeostatic fashion, nociceptin appeared to block the analgesic actions of exogenously applied opioids, but also facilitated analgesia in the context of opioid withdrawal. Nociceptin is also capable of reducing stress-induced analgesia that is typically driven by endogenous opioid mechanisms (Mogil et al., 1996). Important sex differences may also exist in the regulation of stress-induced hyperalgesia by nociceptin, a phenomenon that is absent in male (but preserved in female) NOR knockout rats (Zhang et al., 2019). Interestingly, systemic nociceptin administration is effective in alleviating hyperalgesia symptoms exhibited in an alcoholic pancreatitis model that combined administration of a Lieber-DeCarli alcohol (6%) diet regimen along with a high-fat diet (McIlwrath and Westlund, 2015). Another recent study incorporating an animal model of oxycodone dependence found that increased levels of oxycodone self-administration corresponded to reductions in CeA nociceptin levels (Kallupi et al., 2020). In line with this neuroadaptation, intra-CeA administration of nociceptin reduced oxycodone use, but did not significantly affect hyperalgesia symptoms that emerged during withdrawal. Altogether, these findings indicate that the efficacy of potential nociceptin-based therapies to treat pain in the context of SUDs could likely be dependent on sex as well as the substance abused, with mechanistic sites of action remaining to be determined.

3. Cytokine systems contributing to SUD-Associated hyperalgesia

Cytokines represent a broad category of non-hormonal peptide factors (e.g. interleukins, chemokines, and interferons) released by cells in response to external signals, and play a specialized role in immunomodulation. Cytokines also activate nociceptive sensory neurons and contribute to the development of hyperalgesia and allodynia via inflammation and sensitization processes (Zhang and An, 2007; Gonçalves Dos Santos, 2019). Alterations in cytokine function has recently been linked to opioid-induced hyperalgesia (Chang et al., 2018a, 2018b), including contributions from the classic pro-inflammatory cytokines interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α). Interestingly, atypical chemokines have also been linked to failure of resolution of substance-induced hyperalgesia, most-notably fractalkine and chemokine (C–C motif) ligands (Johnston et al., 2004; Li et al., 2016).

3.1. Interleukin-1β (IL-1β)

IL-1β is a pain-mediating cytokine and one of the archetypal pro-inflammatory cytokines (Hayward and Lee, 2014; Lawrence and Gilroy, 2007). Chronic intrathecal morphine administration triggers the release of IL-1β from microglia in the dorsal spinal cord and cerebrospinal fluid, indicating that activated glial cells may play a role in the development of opioid-induced hyperalgesia (OIH; Johnson et al., 2004). This led to the discovery that blocking glial cell activation via cytokine antagonists prevents the development of hyperalgesia (Johnston et al., 2004; Raghavendra et al., 2002). As humans and mice with diabetes have both decreased sensitivity to morphine and elevated levels of interleukin-1, it has previously been hypothesized that diabetic mice are less sensitive to opioid analgesia due to elevated IL-1β activity. In support of this, after administering IL-1β intracerebroventricularly, researchers were able to abolish morphine analgesia (Gul et al., 2000). Watkins and colleagues have demonstrated a role for morphine in prolonging neuropathic pain via NLRP3 inflammasome/IL-1β signaling (Grace et al., 2016). Alcohol also increases IL-1β secretion from microglia via a purinergic receptor-mediated mechanism (Asatryan et al., 2018). Moreover, adolescent binge alcohol exposure in rats potentiates IL-1β-induced hyperalgesia behaviors observed during adulthood (de Oliveira et al., 2017). The analgesic effects of nicotine appear to mediated in part by macrophage inhibition and reduction of IL-1β expression (Kiguchi et al., 2010). Additional studies are warranted to examine these changes in more robust animal models of SUD, as well as determine whether therapeutic administration of IL-1β antagonists could prevent the development of hyperalgesia in the context of SUDs.

3.2. Tumor necrosis factor-α (TNF-α)

Tumor necrosis factor-α (TNF-α) is produced by macrophages and brain glial cells in response to pathological challenges such as ischemia, trauma, and infections. Importantly, TNF-α activity results in the recruitment of other pro-inflammatory peripheral cells into the central nervous system (Delery and MacLean, 2019; Feuerstein et al., 1994). Along with interleukin-1β, TNF-α is referred to as a pain-mediating inflammatory cytokine (Hayward and Lee, 2014). TNF-α can directly activate neurons of the central nervous system and produce nociception and central sensitization, making it critical in conditions such as neuropathic pain (Yang et al., 2013). Increased TNF-α expression is also found in the cerebrospinal fluid of rats after intraplantar complete Freund’s adjuvant (CFA) administration to mimic inflammatory hyperalgesia (Bianchi et al., 2007). The two TNF cell surface receptors responsible for mediating thermal and mechanical hyperalgesia are TNFR1 and TNFR2 (Yang et al., 2013). It is believed that they modulate spinal synaptic transmission, and possibly trigger the transduction of excitatory amino acids linked to chronic neuropathic pain. TNF-α also induces toll-like receptor TLR2 expression in astrocytes (Phulwani et al., 2008). Since TLR2 hypersensitivity exists in astrocytes in response to previous inflammatory challenges, this supports the “two-hit hypothesis” that cells are primed via the first inflammatory challenge, which subsequently leads to a greater cellular activation in response to a second challenge (Grace et al., 2016; Henn et al., 2011), such as exposure to alcohol, opioids, or nicotine. One example of this may come from prenatal alcohol exposure (PAE), which engenders a risk for chronic pain development following subsequent injury in adulthood in association with elevated TNF-α production (Sanchez et al., 2017; Noor et al., 2017). Another example presages the risk of excessive opioid treatment of pain, where it was shown that surgical incision injury along with perioperative fentanyl administration elevated hyperalgesia behaviors along with TNF-α and IL-1β levels to a greater extent than what was observed with either insult alone (Chang et al., 2018). Opioid tolerance has also been shown to be promoted by TNF-α activity in the PAG, a key pain-modulatory region (Eidson et al., 2017). These preliminary findings indicate that future studies are warranted to examine the effects of co-administration of pro-inflammatory cytokine antagonists with opioids, as well as incorporating animal models of SUDs to examine the potential of treating hyperalgesia by blocking pro-inflammatory cytokine production or signaling.

As described above, negative affective co-morbidities such as major depressive disorder are commonly linked to SUDs. Human studies of pain and depression have indicated higher plasma levels of TNF-α in patients with major depressive disorder and that this was correlated with increased pain sensitivity in women (Burke et al., 2015). Since women are also more susceptible to the effects of stress hormones, it is possible that there is an intimate relationship between TNF-α and glucocorticoids that mediate this phenomenon (Kamal et al., 2014; Randesi et al., 2018). Further studies need to be performed to elucidate sex differences in TNF-α expression in relation to SUDs and associated hyperalgesia.

3.3. Other cytokines and chemokines of interest

Fractalkine is a large cytokine in the CX3C chemokine family that is constitutively expressed in primary nociceptive neurons, including sensory neurons in the dorsal root ganglion (Souza et al., 2013). Fractalkine has been identified as a key cytokine in the manifestation of neuropathic pain, and has also been hypothesized to play a role in substance-induced hyperalgesia (Clark and Malcangio, 2014; Milligan et al., 2008; Souza et al., 2013). Satellite glial cells are found in the dorsal root ganglion where they protect sensory neurons by reacting to inflammatory damage by activating, proliferating, and releasing pro-inflammatory cytokines (Souza et al., 2013). Fractalkine is expressed on sensory neuron cell bodies, while its receptor CX3CR1 is found on the satellite glial cells (Souza et al., 2013). Importantly, research indicates an intimate biofeedback between pro-inflammatory cytokines and fractalkine. When satellite glial cells are activated, they release pro-inflammatory cytokines such as IL-1β and TNF-α, which in turn activates fractalkine to enhance nociception. This exaggerated nociceptive response may trigger the release of even more pro-inflammatory cytokines, leading to a positive feedback loop of cellular excitation and activation that maximizes inflammatory pain (Souza et al., 2013). Such hypernociceptive processes can also induce transcriptional and post-translational changes to induce central sensitization and potentiation of supra-spinal nociceptive circuits, indicating aberrant neurobiological changes that could contribute to substance-induced hyperalgesia. Indeed, chronic nicotine exposure that produces hyperalgesia symptoms is associated with increases in spinal fractalkine CXCR1 receptors, while neutralizing antibodies targeting CXCR1s significantly alleviates the observed hyperalgesia (Ding et al., 2015).

While chemokine (c-c motif) ligands 3 and 5 (CCL3 and CCL5) are more commonly associated with HIV infection and other viral challenges, they may actually play an additional role in the neurobiology of SUD (Fischer-Smith and Rappaport, 2005; Klein et al., 1999; Zhou et al., 2008). CCL3 and its primary receptor, CCR5, exhibit increased glial expression in the dorsal root ganglion of rats administered the opioid remifentanil (Li et al., 2016). Interestingly, when rats were given either a CCL3-neutralizing antibody or the CCR5 antagonist maraviroc, opioid-induced hyperalgesia was attenuated (Li et al., 2016). Another study demonstrated the pro-nociceptive effect of CCL5 following both systemic and intra-PAG administration (Szabo et al., 2002). CCL5 significantly reduces analgesia when injected systemically and prevents opioid analgesia entirely when injected into the PAG (Adler et al., 2008; Szabo et al., 2002), effects that be partially due to a rapid heterologous desensitization of MORs and DORs (Chen et al., 2007). These findings suggest that both opioid-induced tolerance and hyperalgesia mechanisms may result from a positive feedback loop leading to greater expression of pro-inflammatory cytokines with each priming and subsequent challenge between opioid exposures (Johnston et al., 2004; Hutchinson et al., 2008; Delery and MacLean, 2019).

3.4. Current limitations and future directions

Our review highlights some initial avenues into the therapeutic potential of targeting neuropeptide and cytokine systems for the relief of pain associated with SUDs. The vast majority of research has focused on opioid-induced hyperalgesia, leaving considerable gaps in our understanding of how chronic exposure to other substances such as alcohol and nicotine regulate hyperalgesia symptoms. A greater understanding of substance-induced hyperalgesia and its interactions with other negative affective symptoms linked to SUDs will greatly accelerate our mechanistic insight and treatment of both SUDs and chronic pain.

3.5. Additional therapeutic strategies for treating pain in the context of SUD

While our review has focused on pro-inflammatory cytokine/chemokine signaling mechanisms, strategies aimed at boosting anti-inflammatory mechanisms represent another viable therapeutic strategy for pain in the context of SUD (Vanderwall and Milligan, 2019). These include boosting activity of pro-resolving mediators such as neuroprotectin D1 (Bang et al., 2018) and cytokines such as IL-10 (Chen et al., 2019). Interestingly, early environmental enrichment decreases IL-1β and TLR2 expression while increasing anti-inflammatory IL-10 levels. This intervention also reduces opioid self-administration in adult animals, an effect that was recapitulated via boosting IL-10 levels in the nucleus accumbens (Lacagnina et al., 2018). Several authorities and laboratories are currently interested in the hypothesis that individuals suffering from chronic pain or pain in the context of OUD may be effectively treated with medicinal cannabis or other cannabinoid-based strategies. Exploiting the anti-inflammatory properties of exogenous and endogenous cannabinoids would indeed seem to be a potentially valuable translational pipeline (Bouchet and Ingram, 2020).

Based on the findings reviewed here, another strategy for tackling pain is taking a hybrid or combinatorial approach that targets multiple opioid receptors (Gunther et al., 2018). These include approaches combing MOR agonists with NOR antagonists (Lagard et al., 2017), MOR agonists with NOR agonists (Ding et al., 2018), MOR agonists and DOR antagonists (Gendron et al., 2016) and agents that selectively target MOR-DOR heteromeric dimers (Tiwari et al., 2019). Exploration of additional endogenous opioid systems is another viable avenue. For example, MOR-selective endomorphin analogs have recently been developed (Zadina et al., 2016) that exhibit potent analgesia and anti-hyperalgesia across several pain conditions (Feehan et al., 2017) with limited side effects characteristic of traditional opioids (including tolerance, respiratory depression, and abuse liability). It will be important to examine such agents in animal models of SUD and SUD-associated hyperalgesia.

Finally, proteomic approaches that focus on peptidomics can also be used to generate a wealth of novel therapeutic candidates and perhaps more quickly compare neuroadaptations shared among disease models. One recent investigation analyzed over 1500 peptide alterations across several pain-related areas between mouse models of migraine vs. opioid-induced hyperalgesia (Anapindi et al., 2019). They identified sixteen neuropeptides altered between the two conditions, including pituitary adenylate cyclase-activating polypeptide (PACAP) in the PAG. Follow-up experiments demonstrated that systemic administration of the PACAP receptor (PAC1 receptor) inhibitor M65 significantly alleviated periorbital hyperalgesia induced in both migrane and opioid-induced hyperalgesia models. As PAC1 receptor ligands are already being tested in clinical trials for migraine (Vollesen et al., 2018), this study represents the value of bridging the preclinical research fields of chronic pain and SUD.

3.6. Supra-spinal circuit-based mechanisms of hyperalgesia

Several studies highlighted above indicate a central role for periaqueductal gray (PAG) activity in substance-induced hyperalgesia. Opioids exert their analgesic action in part via disinhibiting projections from the PAG to the rostral ventromedial medulla (RVM), leading to suppression of pain signals at the spinal cord level. Recent work has substantially added to this classical descending analgesia pathway by understanding how the PAG communicates with other supra-spinal brain regions. For example, recent work by Kash and colleagues has demonstrated a role for PAG dopamine neuron projections to the bed nucleus of the stria terminialis (BNST) as a mediator of supra-spinal opioid analgesia (Li et al., 2016). Importantly, PAG dopamine neurons appear to mediate antinociception without regulating anxiety-like behavior (Taylor et al., 2019), further evidence that these two negative affective components are dissociable. Comparatively, projections from the PAG to the ventral tegmental area (VTA) were shown to facilitate pain-avoidance behavior, while inactivation of this circuit elicited reward-like place preference behavior only in animals experiencing pain (Waung et al., 2019). As neuropeptide activity in the BNST (Minami and Ide, 2015) and cytokine signaling in the VTA (Wang et al., 2018) facilitate pain-related behaviors, additional studies targeting this circuit could provide valuable evidence demonstrating how these systems contribute to interactions between substance use and pain sensitivity.

The CeA represents a key neuroanatomical locus linking pain, negative reinforcement, and SUD (Thompson and Neugebauer, 2017). While CeA projections to the PAG are well known to contribute to the phenomenon of stress-induced analgesia (Rizvi et al., 1991; Butler and Finn, 2009; Ferdousi and Finn, 2018), as described above, alcohol dependence and withdrawal appears to disrupt this circuit via reduction of GABAergic signaling from CeA terminals onto PAG neurons (Avegno et al., 2018), an effect under the control of melanocortins and MC4Rs in the CeA. Other unresolved questions are how these circuits and hyperalgesia symptoms are differentially modified in the context of passive exposure to, versus active self-administration of, abused substances, as well as how long circuit adaptations might last into withdrawal periods to regulate nociceptive sensitivity. The continued adoption of chemogenetic and optogenetic methods to explore neuropeptide and cytokine function within specific nociceptive circuits is warranted for the generation of more targeted therapeutic interventions that can match distinct aspects of negative affective symptoms experienced in SUDs.

3.7. Interactions of substance withdrawal, negative affect, and pain coping

Individuals suffering from SUDs are often exposed to numerous sources of stress, including stigma and socioeconomic pressures, in addition to the experience of substance withdrawal itself. Stress is a crucial yet complex mediator of pain sensitivity, as both stress-induced hyperalgesia and analgesia can occur, depending on individual differences, sex, and contextual factors (Girdler et al., 2005; Al’Absi et al., 2013; Nakajima and Al’Absi, 2014; Geva and Defrin, 2018; Timmers et al., 2018; Timmers et al., 2019). Controlled human studies have indicated that negative affective stimuli increase hyperalgesia symptoms in opioid-dependent individuals undergoing withdrawal (Carcoba et al., 2011). To gain better mechanistic insights into the inter-relatedness of negative affect (including stress associated with substance withdrawal) and pain-related outcomes, better preclinical constructs of these phenomena are needed. However, a particular challenge for animal modeling (Edwards and Koob, 2012) is how to distinguish among the various forms of negative affective-like behaviors that can concurrently manifest during withdrawal (e.g., stress, nociceptive hypersensitivity, anxiety-like behavior, and anhedonia).

At the clinical level, how individuals cope with unrelieved pain is another critical variable (Menendez and Ring, 2016), especially as persistent pain symptoms can lead to pain-related catastrophizing (an exaggerated negative emotional response to pain) that hampers the resolution and treatment of pain-related health outcomes (Schutze et al., 2018; Miller and Kaiser, 2018; McHugh et al., 2019). Moreover, in individuals with co-morbid SUD and pain, catastrophizing symptoms are specifically associated with higher levels of substance craving (Martel et al., 2014; Kneeland et al., 2019), a phenomenon that likely competes with more adaptive pain-coping strategies (Ditre et al., 2010). Past abuse of analgesic substances increases the morbidity and mortality of individuals experiencing future elective painful events, such as surgery (Menendez et al., 2015). Patients who continue to use opioid pain medications one to two months after surgery for musculoskeletal trauma also exhibit more negative affect, catastrophic thinking, and have fewer effective coping strategies, regardless of original injury severity (Helmerhorst et al., 2014).

In a recent review, Zale et al. (2015) described the pain-coping utility of alcohol that parallels the well-established strategy of drinking to manage stress (Holahan et al., 2001). They present evidence for a curvilinear relationship between alcohol use and pain, whereby limited alcohol use is actually linked to positive pain-related outcomes (e.g., greater quality of life). In contrast, excessive drinking and AUD is associated with more negative pain-related outcomes, such as overall pain intensity. Since additional negative affective symptoms commonly emerge as AUD becomes more severe, these could all additively interfere with natural pain-coping strategies (e.g., relaxation techniques) and motivate further and/or escalated alcohol consumption for attempted analgesic or anti-hyperalgesic benefits (Lawton and Simpson, 2009).

Studies have also examined the motivational links between chronic nicotine use, withdrawal, and pain coping. In regular smokers, extended nicotine deprivation (12–24 h) increases capsaicin-induced pain intensity ratings, neurogenic inflammation, and mechanical hyperalgesia compared to individuals allowed to continue smoking (Ditre et al., 2018). The relationship between pain and increased nicotine craving symptoms is mediated by pain-induced negative affect (Ditre and Brandon, 2008), with individual differences in pain-related anxiety hypothesized to promote the development and progression of NUDs (Ditre et al., 2013). A new questionnaire (the 9-item Pain and Smoking Inventory) was recently developed to better understand patient perceptions of interrelations between pain and nicotine use (Ditre et al., 2017). The future utilization of such measures will help assist our understanding of how withdrawal phenomena moderate hyperalgesia symptoms, as well as how patient self-medication with abused substances interferes with more adaptive pain-coping strategies such as biofeedback training and Cognitive Behavioral Therapy (Wachholtz et al., 2015).

4. Conclusions

Few effective therapies exist for either chronic pain or SUD, and the common interaction of these disease states (due to powerful negative reinforcement processes) likely complicates their effective treatment. The rapid growth in neuropeptide and cytokine/chemokine research in these areas has revealed novel mechanisms and treatment avenues aimed at this intersection (Fig. 1). Neuropeptide signaling has been shown to mediate both somatic and affective aspects of pain, and many therapies targeting these systems have demonstrated efficacy in reducing the motivation for substance use in preclinical models. Several findings also suggest that SUDs and hyperalgesia might even be treated with the same medication category. Following excessive exposure to alcohol, opioids, and nicotine, a cyclical loop of immune priming and glial cell activation leads to sustained pro-inflammatory cytokine production, which in turn leads to chronic neuroinflammation. To halt this process, substance-induced hyperalgesia may be effectively attenuated via pro-inflammatory cytokine receptor antagonism to attenuate neuroinflammation and glial cell activation in order to prevent subsequent pain sensitization mechanisms. Future studies should focus more on the examination of anti-inflammatory mediators (including cannabinoid-based mechanisms) for treating pain and SUD, as well as bridge gaps in our understanding of how various substances of abuse interact within nociceptive circuitry to promote somatic and affective hyperalgesia symptoms that may promote or sustain SUD.

Fig. 1.

Alcohol, opioids, and nicotine exert their analgesic effects within spinal and supra-spinal nociceptive centers. Excessive use of these substances facilitates the development of somatic hyperalgesia and affective pain symptoms, which in turn may drive increased motivation for continued or escalated substance use in attempts to treat pain. Neurobiological mechanisms promoting hyperalgesia development in the context of SUD represent viable candidates for therapeutic intervention, with some strategies possibly capable of reducing both excessive substance use as well as pain symptoms simultaneously.

HIGHLIGHTS.

• Pain is a major negative affective component of substance use disorder (SUD).

• Neuropeptide and cytokine signaling regulates pain-related SUD symptoms.

• Treatments for SUD-associated pain are limited and a critical research priority.