Abstract
Opioid overdoses recently became the leading cause of accidental death in the US, marking an increase in the severity of the opioid use disorder (OUD) epidemic that is impacting global health. Current treatment protocols for OUD are limited to opioid medications, including methadone, buprenorphine, and naltrexone. While these medications are effective in many cases, new treatments are required to more effectively address the rising societal and interpersonal costs associated with OUD. In this article, we review the opioid and cholinergic systems, and examine the potential of acetylcholine (ACh) as a treatment target for OUD. The cholinergic system includes enzymes that synthesize and degrade ACh and receptors that mediate the effects of ACh. ACh is involved in many central nervous system functions that are critical to the development and maintenance of OUD, such as reward and cognition. Medications that target the cholinergic system have been approved for the treatment of Alzheimer’s disease, tobacco use disorder, and nausea. Clinical and preclinical studies suggest that medications such as cholinesterase inhibitors and scopolamine, which target components of the cholinergic system, show promise for the treatment of OUD and further investigations are warranted.
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Opioid use disorder (OUD) is increasing in the population and new medications could help reduce the negative impact to global health. |
Medications that target the brain cholinergic system show promise in clinical and preclinical studies of OUD. |
Further studies on cholinergic medications for OUD are warranted. |
1 Introduction
The US is currently facing an opioid use disorder (OUD) epidemic, which started with large increases in opioid prescriptions in 1990 and expanded by the widespread availability of heroin and synthetic opioids [1, 2]. In addition to affecting the US, OUD is problematic in several other countries and significantly contributes to global disease burden [3]. The current epidemic has resulted in an estimated 2.1 million individuals in the US with OUD in 2016 [4, 5]. In 2016, over 42,000 people died from opioid overdose, making it the leading cause of accidental death in the US [6]. Medication-assisted treatment (MAT), including methadone, buprenorphine, and naltrexone, is effective in reducing opioid use, rate of OUD-associated infections, and psychosocial consequences of OUD [7,8,9]. However, high rates of attrition limit the effectiveness of MAT, underscoring the need to develop novel primary or adjunct treatments for OUD [7, 8].
As discussed in this review, among potential treatment targets for OUD, the brain cholinergic system shows a particular promise. Acetylcholine (ACh) participates in a wide range of central nervous system (CNS) functions that are thought to be critical in the development and maintenance of OUD, including reward, motivation, attention, mood, nociception, stress response, and neuroimmune functions [10,11,12,13,14,15]. Accumulating evidence from many studies support a close functional coupling between ACh and endogenous opioids. Furthermore, preclinical and clinical studies suggest that medications targeting the cholinergic system may have utility for OUD treatment. This paper synthesizes studies that have examined the potential role of the cholinergic system as a treatment target for OUD. We first summarize clinical aspects of OUD, followed by current treatment approaches and clinical challenges. Next, we overview the neurobiology, pharmacology, and genetics of endogenous opioid and cholinergic systems for CNS functions that are relevant for OUD. We then review preclinical and clinical studies that have examined the use of cholinergic medications for outcomes relevant for OUD. We conclude with a discussion of research gaps and future directions.
2 Overview of Opioid Use Disorder (OUD)
OUD is a chronic relapsing disorder characterized by compulsive and uncontrollable opioid use, most commonly heroin or prescription opioids. OUD increases the mortality rate of affected individuals 6–20 times over the general population, primarily due to overdose deaths [16]. Opioid overdose deaths are mainly due to respiratory depression; the risk of overdose is accentuated by concurrent benzodiazepine use [17]. Typically, first exposure to opioids is through prescription opioids, followed by nonprescription opioid use and eventually heroin use [18]. Following initial exposure, individual vulnerability factors to develop OUD include depression, post-traumatic stress disorder (PTSD), presence of an additional substance use disorder, and adolescence [19]. In addition, multiple genetic variations have been associated with the risk of developing OUD [20,21,22]. OUD is highly comorbid, with many psychiatric and medical problems, such as depression, anxiety disorders, PTSD, chronic pain, and infections, including the human immunodeficiency virus and hepatitis C virus [23,24,25].
3 Pharmacological Treatment of OUD
The primary pharmacological approach for OUD is referred to as MAT, comprising methadone, buprenorphine, and naltrexone. MAT reduces or eliminates opioid use, prevents overdose deaths, and reduces the risk of contracting infections [26]. The principal limitation of MAT is high dropout rates and subsequent relapse to opioid use. For buprenorphine and methadone maintenance treatments, retention rates at 1 year are typically < 50% [7, 8]. Retention rates for injectable sustained-release naltrexone are even lower [27,28,29,30]. In addition, long-term treatment with opioid medication is associated with adverse effects, including cognitive deficits, endocrine disturbances, decreased libido, and increased pain sensitivity or hyperalgesia [31,32,33,34]. Thus, there is a great need to identify novel non-opioid medications for OUD treatment, including those that could be used alone or in combination with MAT.
4 Overview of the Opioid System
Endogenous opioids and their receptors are widely distributed in the CNS and peripheral tissues, reflecting their participation in multiple functions, including reward, pain, emotion, cognition, and immune response. The endogenous opioid system includes four opioid receptors, i.e. mu (MOR), delta (DOR), kappa (KOR), and NOP, and four families of opioid peptides, i.e. β-endorphin, enkephalins, dynorphins and prepronociception (PNOC) [35]. Opioid receptors belong to the G-protein-coupled receptor superfamily and their activation leads to inhibition of cyclic adenosine monophosphate production and voltage-gated calcium channels, and activation of inwardly rectifying K+ channels and mitogen-activated protein kinase activity [36, 37]. These effects result in presynaptic inhibition of neurotransmitter release and inhibition of neuronal excitability. In the brain reward circuitry, the MOR increases dopamine (DA) release by disinhibition, i.e. inhibiting γ-aminobutyric acid (GABA)ergic interneurons that inhibit DA neurons [38].
4.1 Endogenous Opioid Peptides
The endogenous opioid peptides are derived from four large precursor proteins (Table 1): (1) proopiomelanocortin (POMC), the precursor for β-endorphin; (2) preproenkephalin (PENK), the precursor for leucine (Leu)- and methionine (Met) enkephalins; (3) preprodynorphin (PDYN), the precursor of dynorphins A and B, and neoendorphins [39,40,41]; and (4) PNOC, the precursor of nociceptin or orphanin FQ (N/OFQ) [42]. The POMC synthesizing neurons are located in the arcuate nucleus of the hypothalamus and the nucleus tractus solitarius in the dorsal medulla. The arcuate nucleus POMC neurons project to the cortical and limbic regions, including the amygdala, hypothalamus, nucleus accumbens, periaqueductal gray and ventral tegmental area. In contrast, the POMC neurons located in the nucleus tractus solitarius project mainly to the spinal cord and brainstem. PENK and PDYN are synthesized locally in neurons in multiple regions of the CNS, including the cortex, hippocampus, basal ganglia, thalamus, hypothalamus, periaqueductal gray area, ventral tegmental area, rostral ventromedial medulla, and the dorsal horn of the spinal cord. PNOC is expressed in multiple areas in the CNS, including the amygdala, thalamus, subthalamic nuclei, hypothalamus, and basal ganglia [42]. β-endorphin, N/OFQ, and enkephalins are released in response to a multitude of painful or stressful stimuli [43]. Analgesia induced by physical and mental stressors is cross-tolerant with morphine and blocked by naloxone [44]. Overall, endogenous opioids have anti-stress effects mediated by MOR, DOR, and KOR activation.
4.2 Opioid Receptors
Opioid receptors are widely distributed in the central and peripheral neurons, and neuroendocrine and immune cells [45]. In the CNS, opioid receptors are found in the ventral tegmental area, nucleus accumbens, hypothalamus, prefrontal cortex, and amygdala. This distribution pattern is consistent with their participation in analgesia, reward, cognitive, and emotional functions. The MOR, DOR, and KOR have differential sensitivity to endogenous opioid peptides. While β-endorphin has a high affinity to the MOR and DOR, enkephalins and dynorphins have high affinity for the DOR and KOR, respectively.
4.2.1 Mu Opioid Receptor
The MOR is the main target for the rewarding, analgesic, and addictive effects of opioids such as morphine, heroin, fentanyl, and oxycodone. For example, unlike wild-type mice, MOR gene knockout mice do not show preference for morphine in a conditioned place preference task, do not self-administer morphine or heroin, and do not show signs of opioid withdrawal following chronic opioid exposure [46, 47]. The MOR also has a key role in mediating rewarding effects from non-opioid drugs of abuse, including alcohol, cocaine, nicotine, and tetrahydrocannabinol. MOR knockout mice are less sensitive than wild-type mice to rewarding effects of these drugs of abuse [48,49,50]. These effects are mediated mainly by MORs that are located on GABAergic inhibitory cells in the ventral tegmental area, which provides tonic inhibition to ventral tegmental area DA neurons. The inhibition of GABAergic cells by the MOR (i.e. disinhibition) results in increased DA release in the nucleus accumbens [51]. In humans, naltrexone, an antagonist at the MOR and, to a lesser extent, KOR and DOR, attenuates reward from food [52], physical activity [53], music [54], and drugs of abuse, including cocaine [55], alcohol, and nicotine [56].
4.2.2 Delta Opioid Receptor
The DOR does not seem to be essential for the rewarding effects of opioids as morphine self-administration in DOR knockout mice is similar to wild-type mice [57]. However, DOR knockout mice show enhanced depressive-like behavior and DOR agonists show antidepressant effects in animal models of depression, suggesting that the DOR may be related to the mood-regulating effects of opioids [58].
4.2.3 Kappa Opioid Receptor
Dynorphin A is the main endogenous KOR agonist. Dynorphin, through KOR activation, counteracts the rewarding effects of MOR in the ventral tegmental area and reduces DA release in the nucleus accumbens [59]. As a result, activation of KOR induces dysphoric effects and blocks rewarding effects from drugs of abuse, including nicotine, alcohol, cocaine, and tetrahydrocannabinol [60,61,62].
4.2.4 Nociception Opioid Peptide
The NOP (also known as ORL1) is not blocked by opioid antagonists, naloxone, or naltrexone. The main endogenous ligand for NOP is a peptide named N/OFQ [35]. Similar to other opioid receptors, when activated, NOP inhibits adenylate cyclase, increases potassium conductance, and reduces calcium conductance [63]. These inhibitory effects result in reduced neuronal activity and neurotransmitter release [64]. N/OFQ has complex effects on pain: it blocks morphine-induced antinociception and conditioned place preference when administered supraspinally [65], but has analgesic effects at the spinal cord in mice [66].
4.3 Molecular Mechanisms of Opioid Effects
Exposure to opioids leads to upregulation and desensitization of the opioid receptors [67]. Desensitization is a likely mechanism for the development of opioid tolerance and includes several processes, including receptor phosphorylation, uncoupling of receptors to G proteins, and internalization of receptors [67]. Phosphorylation of opioid receptors by G-protein-coupled receptor kinases increases their affinity for intracellular β-arrestin molecules. β-arrestin-opioid receptor complex formation results in uncoupling of G-proteins and facilitates opioid receptor internalization [68]. The internalization process disrupts the heterodimer between the MOR and DOR, resulting in reduced function of opioid receptors. Opioid agonists differ in their ability to induce internalization, resulting in different levels of tolerance in response to chronic exposure [69].
4.4 Adaptations to Chronic Opioid Exposure
Chronic exposure to opioids leads to tolerance and withdrawal as the main components of physical dependence to opioids [68]. Multiple mechanisms for the development of opioid tolerance have been discussed, including uncoupling of the MOR to co-effectors such as G-proteins [70] and changes in secondary signaling cascades (e.g. upregulation of cyclic adenosine monophosphate-dependent signaling) [71]. Tolerance development leads to dose increases by individuals in order to receive the desired effects from opioids (e.g. pain relief or euphoria). In the presence of physical dependence, abstinence (or a significant reduction in opioid intake) leads to opioid withdrawal syndrome, which includes both physical and affective components [72]. Physical signs and symptoms include abdominal pain, diarrhea, vomiting, nasal discharge, enlarged pupils, pain, and chills. Affective symptoms include dysphoria, anhedonia, anxiety/irritability, and craving. Depending on the elimination half-life of the particular opioid drug, physical components of opioid withdrawal syndrome subside within 1–2 weeks [73].
4.5 Insights into the Opioid System from Human Genetics Studies
Genetic variation in genes that encode opioid receptors and endogenous opioid peptides has received much attention. The genes that encode the MOR, DOR, KOR, and NOP in humans are OPRM1, OPRD1, OPRK1, and OPRL1, respectively. Genetic studies can be useful for understanding how certain genes function in humans, for prioritizing molecules as therapeutic targets, and for stratifying patients for precision medicine approaches. Genome-wide association studies (GWAS), which interrogate most common variants in the genome without bias, are the current ‘gold standard’ method for conducting genetic association studies [74]. GWAS and other genetic studies of OUD and OUD treatment have been more extensively reviewed elsewhere by Jensen [75], and more recently by Crist et al. [76] and Berrettini [77]. Among these genetic studies are several that highlight an important role of opioid receptors for OUD (Table 2). As discussed in prior sections, opioid receptors are important for several processes, such as reward, pain, emotion, cognition, and immune response. The MOR, in particular, is essential for the rewarding effects of drugs of abuse, including opioids and genetic variation in OPRM1, the gene encoding MOR, has been studied intensely. A nonsynonymous single nucleotide polymorphism (SNP), rs1799971, which causes an asparagine to aspartic acid substitution (Asn40Asp) in the MOR, has been widely studied due to its possible effects on MOR function, although some in vitro studies suggest that effects on protein function are modest [78, 79] and might involve alternative mechanisms, such as effects on OPRM1 messenger RNA (mRNA) expression [80]. Moreover, genetic association studies of rs1799971 to OUD have yielded conflicting results, indicating that research on other variations encoded within OPRM1, and elsewhere in the genome, is warranted. For example, a recent study of heroin dependence that focused on 103 OPRM1 cis-eQTLs (i.e. SNPs associated with OPRM1 mRNA expression in brain tissue) identified a robust association (p = 4.3 × 10−8) with rs3778150, a SNP in the first intron of OPRM1 [81]. This association was based on a meta-analysis that included 16,729 subjects, and it was noted that rs1799971 was not associated with heroin dependence in any cohort or in the meta-analysis [81]. In a GWAS of methadone dose requirements by Smith et al., the most statistically robust association (p = 2.8 × 10−8) identified was for SNP 5′, the OPRM1 transcription start site in an African American sample (n = 383) with OUD [82]. The SNP was also associated with morphine dose in a separate sample of opioid-naive African American pediatric subjects (n =241) [82]. Crist et al. tested the association of several OPRM1 haplotypes to OUD treatment response and identified an SNP, rs10485058, in the OPRM1 3′ untranslated region that was associated with response to methadone in two European ancestor samples of OUD [83]. In an important extension of this work, Crist et al. found that the SNP modified microRNA regulation of gene expression in a cell culture system [83]. In a separate study of variation in OPRD1, the gene encoding DOR, Crist et al. tested the association of OUD treatment response to an OPRD1 SNP, rs678849, which had been previously linked to opioid dependence risk. They observed an association to treatment response in an African American sample with OUD that differed in terms of the effect direction based on the medication group (methadone or buprenorphine) [84]. Many association signals have emerged for GWAS of OUD-related phenotypes (e.g. OUD symptom count, sensitivity to opioids) that have implicated genes with no clear link to opioid signaling, and functional studies to elucidate the biological mechanisms are required [20,21,22, 85].
5 Overview of Acetylcholine (ACh)
ACh, the first neurotransmitter discovered, contributes to multiple CNS functions, including sensory and motor processing, sleep, nociception, mood, stress response, attention, arousal, memory, motivation, and reward [10,11,12,13,14]. A large body of evidence also supports the role of ACh in initiation and maintenance of addictive processes. It has been suggested that the DA/ACh balance in the nucleus accumbens may affect the reward and aversion spectrum, such that an increased ratio facilitates reward and a decreased ratio generates an aversive state [86]. For example, drugs that increase ACh levels reduce self-administration of drugs of abuse, including stimulants and opioids [87, 88]. Conversely, drug withdrawal states for opioids, cocaine, and nicotine are associated with reduced DA and increased ACh levels [89,90,91].
5.1 Endogenous Cholinergic System in the Central Nervous System (CNS)
In the cytoplasm of cholinergic neurons, ACh is synthesized from acetyl-coenzyme A and choline by choline acetyltransferase (ChAT) [92]. Following its release into the synaptic cleft, ACh signals through two classes of receptor: nicotinic (nAChR) or muscarinic (mAChR) type cholinergic receptors, which are both described in more detail below. ACh is rapidly inactivated by an enzyme, acetylcholinesterase (AChE), which is also inhibited by a range of toxins and medications [93].
5.2 ACh Biosynthesis and Distribution in the CNS
Cholinergic neurons consist of two types: cholinergic interneurons and cholinergic projection neurons [94]. Cholinergic interneurons are located mainly in the striatum and modulate output from the basal ganglia. A subgroup of these neurons, the tonically-active striatal cholinergic interneurons, has important roles in stimulus salience and orienting functions [95].
The cholinergic projection neurons are located in the brainstem and the basal forebrain. The brainstem cholinergic neurons are located in the pedunculopontine tegmental and laterodorsal tegmental nuclei, and project to the ventral tegmental area and thalamus [94]. These neurons modulate the sleep/wake cycle [96]. The basal forebrain cholinergic neurons are located in the nucleus basalis of Meynert, medial septal nucleus and vertical and horizontal limb nuclei of Broca [97]. These cholinergic neurons project to the hippocampus, amygdala, and cerebral cortex, and modulate memory and attention functions [98].
5.3 Muscarinic Receptors
mAChRs are ACh receptors (AChRs) that are activated by muscarine. There are five types of muscarinic receptors, which are classified into two groups: M1, M3, and M5 vs. M2 and M4 [99, 100]. Among these, M1, M2, and M4 are the main mAChRs expressed in the CNS. M1, M3, and M5 mAChRs are Gq-coupled and largely postsynaptic. They activate phospholipase C, intracellular calcium, inositol triphosphatase, and mitogen-activated protein kinase [100]. M1 mAChRs, the predominant mAChRs in the CNS, are implicated in learning and memory processes. Consistent with their functions, they are distributed in the cerebral cortex, hippocampus, and striatum [101]. M3 mAChRs are sparsely distributed in the CNS and their functions are not well-known [102], while M5 receptors, expressed on the DA neurons in the ventral tegmental area and substantia nigra, facilitate DA release in the nucleus accumbens [103].
M2 and M4 mAChRs are usually presynaptic and inhibit adenylyl cyclase and voltage-operated calcium channels and activate mitogen-activated protein kinases, and G-protein-activated inwardly rectifying potassium channels M2 receptors are expressed in the brainstem, thalamus, cortex, hippocampus, and striatum and inhibit ACh and DA release [101, 102, 104]. M4 mAChRs are found in the midbrain, cortex, hippocampus, and striatum [101, 102]. Stimulation of M4 mAChRs inhibits ventral tegmental area DA neurons, leading to reduced DA release in the nucleus accumbens [105].
The net effect of mAChR signaling is to reduce the number of synaptic inputs that neurons receive, resulting in increased responsivity for the remaining synaptic inputs [106]. This is achieved by increased membrane resistance and input sensitivity, through activation of M1, M3, and M5 receptors, and reduced neurotransmitter release, through activation of M2 and M4 mAChRs. These effects are consistent with enhanced specificity of neuronal communication and memory encoding function of mAChRs [107, 108].
5.4 Nicotinic Receptors
nAChRs are AChRs that are activated by nicotine. nAChRs are ligand-gated ion channels arranged around a central pore, which is permeable to sodium, potassium, and calcium ions. nAChRs are comprised of pentameric combinations of α subunits (α2–α10) and β subunits (β2–β4) [109,110,111]. They can be either homomeric nAChRs that consist of one type of α subunits (e.g. α6 or α7) or heteromeric nAChRs that consist of a combination of α and β subunits (e.g. α4β2, α3β4). α4β2 and α7 subtypes represent the majority of nAChRs in the brain [109,110,111]. Most nAChRs in the brain are located presynaptically and increase the release of ACh, DA, serotonin, glutamate, GABA, and norepinephrine [112,113,114,115]. Stimulation of α4β2 nAChRs located on the DA cell bodies in the ventral tegmental area shifts these cells from tonic to phasic firing mode, which results in increased DA release in both the nucleus accumbens and the prefrontal cortex. β2-containing receptors are critical for the addictive as well as cognitive performance-enhancing properties of nicotine [116, 117]. Nicotine withdrawal has been shown to reduce brain reward function in rats, which may also be mediated by α4, β2, and α7 subunits [118].
5.5 Insights into the Cholinergic System from Human Genetics Studies
GWAS have highlighted some important functions for certain genes within the cholinergic system. There are five genes within the human genome that encode mAChRs (abbreviated as CHRM1, CHRM2, CHRM3, CHRM4, and CHRM5), and 16 genes that encode nAChRs, including multiple α and β subunits (abbreviated as CHRNA1-7,9,10, CHRNB1-4, CHRNE, CHRND, CHRNG). AChE is encoded by the Acetylcholinesterase gene (abbreviated as AChE) and ChAT is encoded by the Choline O-acetyltransferase gene (abbreviated as CHAT). Among the most robust and well-characterized associations based on GWAS is genetic variation within the CHRNA5-A3-B4 gene cluster on chromosome 15, and measures of nicotine intake, such as the number of cigarettes smoked per day and cotinine levels [119, 120]. However, it is unclear whether genetic variation encoded within these genes is related to substance use disorder phenotypes such as OUD. It is important to note that sample sizes for genetic studies of OUD have been smaller than many genetic studies of medical traits that have yielded highly informative genetic associations. This likely limits the statistical power that is required to detect genetic effects associated with OUD. In addition, whether genetic variants in the cholinergic system, (including SNPs with strong statistical links to clinically relevant traits) affect the response to medication is a topic of ongoing research.
6 Interactions between Opioids and ACh
Several lines of evidence suggest a close functional coupling between ACh and opioid transmission. An earlier study demonstrated that morphine administration in mice increased ACh concentration in striatum that coincided with the time-course of the analgesic effects of morphine [121]. Similar increases in ACh levels have also been observed in the spinal cord following morphine administration in monkeys [122]. In another study conducted in rats, ACh administration increased the release of β-endorphin, Leu-enkephalin, and dynorphin in the spinal cord [123]. Consistent with these findings, an increase in ACh level in the CNS produced by systemic administration of AChE inhibitors enhanced the analgesic effects of opioids (see next section for details). In contrast to the actions of MOR agonists on ACh release, N/OFQ reduced ACh release in cortical and hippocampal slices and NOP knockout mice showed increased ACh release in hippocampus [124, 125]. These findings support the possible role of NOP receptors in hippocampal cholinergic function.
In a recent study, chronic morphine treatment increased ACh transmission in the laterodorsal tegmental nucleus (LDTg)/pedunculopontine tegmentum, which provide stimulatory cholinergic inputs to the ventral tegmental area DA cells [126]. This effect may represent one potential mechanism by which ACh transmission modulates neuroadaptation to chronic morphine exposure. On the other hand, chronic nicotine exposure attenuated the analgesic effects of opioids, suggesting a cross-tolerance between opioids and nicotine. In humans, opioids and nicotine products (e.g. tobacco cigarettes) are commonly abused together, and smoking status is an important predictor for using higher doses of prescription opioids and misuse of prescription opioids [127, 128]. Together, these studies suggest that ACh and opioids may play an important role in modulating the pharmacological effects of each other, as well as impact ongoing use and addiction to opioids and nicotine. The role of nAChRs and mAChRs in mediating the analgesic and rewarding effects of opioids remains controversial, partly due to the lack of pharmacological specificity of currently available drugs targeting these receptors [126, 129]. The neural circuits mediating the effects of ACh on opioid analgesia, reward, withdrawal, and behavioral sensitization remain to be elucidated.
7 ACh as a Treatment Target for OUD: Current Evidence
We performed a PubMed search between January and March 2018 to identify preclinical and clinical publications relevant to clarifying the role of the cholinergic system as a potential treatment target for OUD. The search was limited to English-language articles. Preclinical studies were included if they (1) included outcomes related to OUD, including opioid self-administration, conditioned place preference, opioid sensitization, opioid withdrawal, and opioid analgesia; and (2) used a cholinergic medication. Clinical studies were included if they examined opioid use, opioid withdrawal, and opioid adverse effects. We included studies published between 1999 and 2018 as previous studies have been reviewed elsewhere [130, 131].
Preclinical and clinical studies examining the effects of cholinergic compounds on opioid-related outcomes are summarized in Table 3. The highlights from the table are described below. The majority of studies are preclinical. Regarding opioid reward, morphine self-administration was decreased by arecoline (AREC), a non-selective partial mAChR agonist, and scopolamine, an mAChR antagonist [132, 133]. Morphine-induced conditioned place preference was inhibited by donepezil or rivastigmine, which are both AChE inhibitors, and by scopolamine [134,135,136]. Morphine-induced sensitization to locomotor effects was attenuated by mecamylamine, an nAChR antagonist [126], while morphine-induced behavioral sensitization was attenuated by huperzine A, an AChE inhibitor [137]. AREC also reduced reinstatement of drug seeking for morphine [133]. Regarding effects on analgesia, both donepezil and rivastigmine increased the acute analgesic effects of morphine [138]. Donepezil, rivastigmine, and scopolamine each attenuated the development of tolerance to the analgesic effects of morphine [134, 138, 139]. In contrast, mecamylamine did not affect tolerance to the analgesic effects of morphine [126].
Naloxone-induced opioid withdrawal symptoms were attenuated by diisopropylfluorophosphate (DFP; an AChE inhibitor that acts both centrally and peripherally), echothiophate (a selective peripherally-acting AChE inhibitor), or AREC [140] or scopolamine [141]. Nicotine and the nAChR antagonist lobeline attenuated opioid withdrawal symptoms induced by naloxone, but mecamylamine was not effective [142].
In human studies, donepezil reduced opioid-induced sedation without affecting analgesia in a sample of cancer patients (n = 6) who were receiving high doses of opioids [143]. In another study of inpatients undergoing opioid taper, varenicline was well-tolerated. In one clinical study, a non-significant trend for decreased opioid withdrawal symptoms compared with placebo was noted [144]. In a separate clinical study, scopolamine was tested in 91 opioid-dependent patients undergoing opioid taper. Compared with placebo, scopolamine reduced anxiety, depression, craving, and prolonged time to relapse [145]. Overall, very limited clinical data are currently available to support a role of cholinergic agents in treating OUD.
8 Future Directions for Medication Development
The preclinical and clinical studies summarized above support the promise of medications targeting the cholinergic system for the treatment of OUD, including AChE inhibitors and medications targeting nAChRs and mAChRs. The adverse effects of opioid agonists (i.e. methadone or buprenorphine) include nausea, vomiting, constipation, endocrine disturbances, decreased libido, and increased pain sensitivity or hyperalgesia, as well as possible cognitive deficits [31,32,33,34]. The adverse effects of naltrexone include nausea, headaches, insomnia, injection site pain (injectable form), elevation of transaminases, hypertension, nasopharyngitis, and influenza, as well as possible depression or anhedonia [146, 147]. The most common adverse effects of AChE inhibitors include nausea, vomiting, diarrhea, loss of appetite, headache, and dizziness [148]. For intravenous scopolamine, common adverse effects include reduced sweating, dry skin, dry mouth, amnesia, somnolence, and, less commonly, hallucinations and confusion [149]. Overall, cholinesterase inhibitors have a long-established safety profile and their use for OUD is feasible. The more serious adverse effects of scopolamine (e.g. confusion or hallucinations) require closed monitoring of the adverse effects at the time of and after infusion. Recent technological advances, such as in genomics, can facilitate the development of new medications by identifying and prioritizing drug targets, helping improve outcomes for established treatments (i.e. by patient stratification), and capturing in-depth treatment responses (e.g. biomarkers) to assist in evaluating efficacy [150, 151]. As such, it is a promising time to develop and evaluate new medications for OUD treatment.
8.1 Medications Targeting Acetylcholinesterase
The AChE inhibitors rivastigmine, donepezil, and galantamine are marketed for the treatment of dementia [93, 152, 153]. AChE inhibitors differ in their pharmacological profiles, although their efficacy for the treatment of dementia is comparable [154]. Galantamine is a positive allosteric modulator of nAChRs, resulting in increased synaptic DA and glutamate levels [155, 156]. Donepezil and rivastigmine are more potent AChE inhibitors than galantamine [157, 158]. Rivastigmine may also modulate a glutamatergic transporter [159]. In contrast to donepezil and rivastigmine, galantamine also increases the activity of nAChR via allosteric effects [155]. As summarized in Table 3, in preclinical studies AChE inhibitors attenuated opioid reinforcement, enhanced the analgesic effects of opioids, reduced tolerance to opioid analgesia, and attenuated opioid withdrawal. In human studies, galantamine showed promising results as a treatment for alcohol or tobacco use disorder [160, 161]. In a recent randomized clinical trial, galantamine, compared with placebo, reduced cocaine use among cocaine- and opioid-addictive individuals who were stabilized on methadone [162]. AChE inhibitors have not been examined for the treatment of OUD in humans, and clinical trials testing the potential efficacy of AChE inhibitors on OUD are warranted.
8.2 Medications Targeting Nicotinic ACh Receptors (AChRs)
Although there is some evidence that medications targeting nAChRs have efficacy for treating substance use disorders, the evidence specifically for OUD is mixed. In preclinical studies, the nAChR antagonists lobeline and mecamylamine did not show consistent efficacy across outcomes [126, 136, 138, 142]. Varenicline, a partial agonist at the α4β2 nAChR, is marketed for smoking cessation and has also shown promise for alcohol use disorder [163,164,165]. Varenicline also reduced rates of smoking in opioid-addicted individuals maintained on methadone, however there was no effect on opioid use [166]. Functional genetic variation encoded in nAChRs, such as the well-characterized and common variants in the CHRNA5-A3-B4 gene cluster, might affect the response to some medications. For smoking cessation, reports on differential responses to varenicline based on CHRNA5-A3-B4 gene cluster variants have been mixed [167,168,169]. As noted above, other nicotinic receptor genes encode variants with strong trait associations (e.g. CHRNA4) that might affect nACHR function and response to treatment. As research in this area progresses, it will be important to consider these known genetic effects and how they might shape the response to medication that targets nAChRs.
8.3 Medications Targeting Muscarinic AChRs
As outlined in Table 3, in preclinical studies, both mAChR agonists (e.g. AREC) and the mAChR antagonist scopolamine showed promising effects. AREC reduced both opioid self-administration and reinstatement of opioid self-administration, and blocked naloxone-induced opioid withdrawal [133]. Scopolamine also prevented development of tolerance to morphine and attenuated naloxone-induced opioid withdrawal [138]. These findings seem to be contradictory as both an antagonist and agonist of mAChR have similar effects. It is important to note that AREC is a non-selective partial mAChR agonist, which also has significant agonist effects in multiple nAChR subtypes [170]. Similarly, scopolamine influences nAChRs and N-methyl-d-aspartate (NMDA) receptors in addition to its mAChR antagonist effects [171]. Several mAChR agonists, including AREC, carbachol, and cevimeline have been examined in clinical trials, although not for OUD [172]. Development of these compounds have been abandoned due to their adverse effects, such as nausea and diarrhea, which are likely mediated by the drug acting at peripheral M2 and M3 mAChRs. However, scopolamine is currently used for postoperative nausea and motion sickness. It has rapid antidepressant effects, with some reports showing efficacy for treating major depressive disorder [173]. It is noteworthy that the study by Liu et al. reported that, compared with methadone treatment, scopolamine reduced depression and anxiety during opioid tapering [145]. Depression is elevated among those seeking treatment for substance use disorders [174] and common in that population, with 40% of an individual’s risk for depression attributed to their genetics [175]. Scopolamine could be most effective for those who are at increased risk for depression during detoxification, either based on their genetics or a pre-existing condition (e.g. major depressive disorder or bipolar disorder). Further studies testing the efficacy of scopolamine for OUD are warranted.
9 Conclusions
New strategies are needed to meet the challenges associated with the current OUD epidemic facing the US and other countries. MAT, using opioid-based pharmacotherapies (methadone, buprenorphine, and naltrexone), are the only current US FDA-approved treatments for OUD. MAT effectiveness is limited by high dropout rates and the adverse effects associated with long-term treatment with opioid medications, such as cognitive deficits, endocrine disturbances, decreased libido, and increased pain sensitivity or hyperalgesia. The cholinergic system shows promise as a treatment target for OUD. The cholinergic and opioid systems are tightly linked, with ACh involved in CNS functions that are relevant to the development and maintenance of OUD. Several cholinergic medications show promise in clinical and preclinical studies, and further studies testing the efficacy of cholinergic medication for OUD are warranted.
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This work was supported by the U.S. Department of Veterans Affairs, Veterans Administration (VA) Mental Illness Research, Education and Clinical Center (MIRECC), and National Institute of Health Grants P50 DA-009241 and K01 DA039299.
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Kevin P. Jensen, Elise E. DeVito, Sarah Yip, Kathleen M. Carroll and Mehmet Sofuoglu declare no conflicts of interest.
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Jensen, K.P., DeVito, E.E., Yip, S. et al. The Cholinergic System as a Treatment Target for Opioid Use Disorder. CNS Drugs 32, 981–996 (2018). https://doi.org/10.1007/s40263-018-0572-y
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DOI: https://doi.org/10.1007/s40263-018-0572-y