• The brain contains a complex system of endogenous opioid peptides.
• These peptides are called endorphins, encephalins, and dynorphin.
• Endorphins preferentially bind to the mu opioid receptor (mOR).
• Encephalins preferentially bind to the delta receptor (dOR).
• Dynorphin preferentially binds to the kappa receptor (kOR).
• Opiates, such as heroin and morphine, also stimulate the mOR.
• The mOR is upregulated in substance addiction.
• Genetic polymorphisms at the mOR influence subjective responses to alcohol.
The opioid system of the brain is the major target for opiate drugs, such as morphine and heroin, and has been implicated in processes, such as pain, stress, and reward. Recent findings from human brain imaging research, however, are beginning to suggest that substance addiction per se may be associated with alterations in this system. These alterations may influence the craving, distress, and dysphoria found in early alcohol and drug abstinence.
In this chapter, we will discuss the brain opioid system and its neuropharmacology and specifically examine the effects of substance abuse on the endorphin system. The implications for treatment will also be discussed.
10.1 The opioid system
Opiate substances of addiction, such as heroin, reduce anxiety and decrease sensitivity to stimuli while inducing euphoria and sedation. They mimic the effects of endogenous substances on a variety of opioid receptor subtypes in the brain. These are the mu, kappa, and delta opioid receptor (mOR/kOR/dOR) subtypes. These are G-protein receptors that are negatively coupled to adenylyl cyclase. Their stimulation, therefore, results in reduced neuronal intracellular signalling.
There are a number of endogenous substances which produce different effects at these receptors. The endogenous opioid peptide β-endorphin preferentially binds with the mOR. Opiate substances of abuse also act at the mOR subtype, and this underlies their reinforcing effects and abuse potential. For example, antagonists, such as naltrexone, block heroin reinforcement, with mOR ‘knock-out’ mice unwilling to self-administer heroin. The mOR is located in a variety of brain regions, including the orbitofrontal cortex (OFC), thalamus, hippocampus, locus coeruleus, midbrain ventral tegmental area (VTA), nucleus accumbens (NAcc)/ventral striatum (VS), and amygdala.
Opiates mediate their reinforcing effects directly in the NAcc at the mOR. Opiates also produce their reinforcing effects indirectly. This indirect mechanism of action is through mOR inhibition of GABA functioning in the VTA. The binding of opiates to the mOR disinhibits dopamine VTA projections to the NAcc (see Figure 10.1).
The endogenous opioid system, and particularly the mOR, interfaces with environmental events, both positive (e.g. relevant emotional stimuli) and negative (e.g. stressors). Significantly, research has demonstrated that individuals reporting high impulsiveness have significantly higher regional mOR concentrations in a number of brain regions, including the OFC, NAcc, and amygdala. This may suggest that higher mOR numbers, in brain regions complicit in motivation and reward learning, bestow a greater vulnerability for impulsive/risky behaviours, such as substance abuse.
Encephalin peptides (i.e. met and leu encephalin) preferentially bind to the dOR. The dOR subtype is located at its highest densities in the NAcc, caudate, putamen, and cerebral cortex. They are located on presynaptic nerve terminals where they inhibit the release of other neurotransmitters (e.g. dopamine).
The dynorphin peptide preferentially binds to the kOR. The kOR is located in the hypothalamus and striatum (i.e. NAcc, caudate, and putamen). The binding of opiates or dynorphin to the kOR is thought to induce the dysphoric effects of these substances. This may be due to kOR ligands inhibiting the release of dopamine in the striatum. Interestingly, substances of abuse have been shown to increase the release of dynorphin in this region. This may implicate the dynorphin system in the reported dysphoria many substance abusers report following chronic consumption.
10.2 Substance addiction
Several studies to-date appear to suggest that the brain opioid system is activated by substances of abuse. For example, a high dose of amphetamine (i.e. indirect dopamine agonist) has been shown to reduce carfentanil (mOR agonist) binding in a number of regions, including the frontal cortex, putamen, and insula (see Figure 10.2). This effect is due to amphetamine-induced release of endorphins that displace the PET radioligand 11C-carfentanil. This effect has also been shown for alcohol in the OFC and NAcc of both control subjects and heavy drinkers (see Figure 10.3).
Also, the administration of naltrexone, an opioid receptor antagonist, in healthy human volunteers has been shown to attenuate the acute, positive effects of substances of abuse, such as amphetamine and alcohol, that do not directly act at the mOR. These results suggest that there are robust interactions between dopamine and opioid mechanisms in the brain. This further indicates that the chronic use and abuse of addictive substances is likely to have enduring effects on the opioid system.
Research suggests that the early stages of abstinence may be associated with alterations to the endorphin system in substance addiction. The OFC is involved in the processes of motivation and drive for rewards and the attribution of salience to reinforcing stimuli. Increased mOR binding in this region has been shown to predict time to relapse in cocaine addicts (Gorelick et al. 2008). The upregulation of the mOR in the OFC may enhance the motivation to use cocaine during abstinence—it may be a biomarker of relapse risk in substance addiction.
The endogenous opioid system may also play a significant role in alcohol dependence. In early abstinent alcoholics, there are elevated mOR numbers (indexed by increased carfentanil binding), compared to healthy controls in several regions implicated in addiction, including the striatum and amygdala (Weers et al. 2011). This suggests a possible upregulation of the mOR and/or a reduction in endogenous opioid peptide release following chronic alcohol use.
Projections from the VTA to VS are, in part, responsible for initiating the motivation for rewards. The initial weeks of alcohol abstinence have provided evidence for greater mOR availability in the VS compared to healthy controls. The higher availability of the mOR in this region is also significantly correlated with the intensity of alcohol craving (Heinz et al. 2005). This may suggest that greater mOR numbers in this region predict a greater vulnerability for relapse in early alcohol abstinence.
Striatal dopamine is involved in substance reward, and alcohol has been shown to induce dopamine release in this region in humans. Humans vary substantially in their responses to alcohol, however. This variability may be related to a genetic susceptibility for alcohol-use disorders—genetics are thought to account for more than half the disease risk in this condition. Importantly, a functional variation in the mOR may contribute to this variation by modulating alcohol-induced dopamine release.
Significantly, it has been shown that a functional OPRM1 A118G polymorphism influences striatal dopamine responses to alcohol in social drinkers (see Figure 10.4). The A118G polymorphism of the OPRM1 gene has been shown to confer functional differences to the mOR, such that the G variant binds β-endorphin three times more strongly than the A variant. It has also been shown that individuals with the G allele report higher subjective feelings of intoxication, stimulation, sedation, and happiness in response to alcohol, compared to individuals with the A allele.
Clinical trials have focussed on mOR blockade with naltrexone in substance dependence. Naltrexone, acamprosate (NMDA antagonist and GABAA agonist), and their combination appear significantly more effective than placebo in preventing alcohol relapse (Kiefer et al. 2003). Naltrexone has also shown some promise for the treatment of amphetamine dependence. Reduced craving levels and the consumption of amphetamine have been shown during naltrexone, compared to placebo. Depot injections of naltrexone have also been found to increase treatment retention in heroin addiction.
Both naltrexone and nalmefene (an mOR antagonist and a partial kOR agonist) have been shown to reduce alcohol use in alcoholics. This has been shown using a choice consumption paradigm following a standard ‘priming’ alcohol dose in a bar-laboratory setting (see Figure 10.5).
The efficacy of naltrexone in the treatment and management of alcoholism may also be moderated by genetics. The A118G polymorphism of the OPRM1 gene has been shown to confer differences in how people respond to the efficacy of naltrexone in attenuating the reinforcing effects of alcohol. In individuals with, at least, one copy of the G allele, effects of naltrexone on blunting alcohol-induced ‘high’ were significantly stronger (Ray and Hutchison 2007).
There is strong evidence for dopamine–endorphin interactions in the brain. The mOR findings in addiction may endorse this neuroadaptation as an important neural biomarker of early abstinence and relapse risk. There is also evidence for the effects of genetic polymorphisms at the mOR—effects that confer a greater dopamine response to the reinforcing effects of alcohol. There is evidence for the potential efficacy of mOR antagonists in reducing relapse, increasing treatment retention, and attenuating the subjective effects of substances of abuse. The effects of antagonists at the mOR may also be genetically moderated, suggesting that only some individuals will show a clinical response to these compounds. Medications with partial agonist activity at the kOR, such as nalmefene, may confer an additional clinical advantage—reduce binging following relapse in substance dependence.
References and Further Reading
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Comer SD, Sullivan MA, Yu E, et al. (2006). Injectable, sustained-release naltrexone for the treatment of opioid dependence: a randomized, placebo-controlled trial. Archives of General Psychiatry, 63, 210–18.Find this resource:
Drobes DJ, Anton RF, Thomas SE, et al. (2003). A clinical laboratory paradigm for evaluating medication effects on alcohol consumption: naltrexone and nalmefene. Neuropsychopharmacology, 28, 755–64.Find this resource:
Gianoulakis C (2009). Endogenous opioids and addiction to alcohol and other drugs of abuse. Current Topics in Medicinal Chemistry, 9(11), 999–1015.Find this resource:
Gorelick DA, Kim YK, Bencherif B, et al. (2008). Brain mu opioid receptor binding: relationship to relapse to cocaine use after monitored abstinence. Psychopharmacology (Berl), 200, 475–86.Find this resource:
Heinz A, Reimold M, Wrase J, et al. (2005). Correlation of stable elevations in striatal mu opioid receptor availability in detoxified alcoholic patients with alcohol craving: a positron emission tomography study using carbon 11-labeled carfentanil. Archives of General Psychiatry, 62, 57–64.Find this resource:
Jayaram-Lindstrom N, Hammarberg A, Beck O, et al. (2008). Naltrexone for the treatment of amphetamine dependence: a randomized, placebo-controlled trial. American Journal of Psychiatry, 165, 1442–8.Find this resource:
Jayaram-Lindstrom N, Konstenius M, Eksborg S, et al. (2008). Naltrexone attenuates the subjective effects of amphetamine in patients with amphetamine dependence. Neuropsychopharmacology, 33, 1856–63.Find this resource:
Karhuvaara S, Simojoki K, Virta A, et al. (2007). Targeted nalmefene with simple medical management in the treatment of heavy drinkers: a randomized double-blind placebo-controlled multicenter study. Alcoholism: Clinical and Experimental Research, 31(7), 1179–87.Find this resource:
Kiefer F, Jahn H, Tarnaske T, et al. (2003). Comparing and combining naltrexone and acamprosate in relapse prevention of alcoholism: a double-blind, placebo-controlled study. Archives of General Psychiatry, 60(1), 92–9.Find this resource:
Love TM, Stohler CS, and Zubieta JK (2009). Positron emission tomography measures of endogenous opioid neurotransmission and impulsiveness traits in humans. Archives of General Psychiatry, 66, 1124–34.Find this resource:
Mitchell JM, O’Neil JP, Janabi M, et al. (2012). Alcohol consumption induces endogenous opioid release in the human orbitofrontal cortex and nucleus accumbens. Science Translational Medicine, 4, 116ra116.Find this resource:
Ramchandani VA, Umhau J, Pavon FJ, et al. (2010). A genetic determinant of the striatal dopamine response to alcohol in men. Molecular Psychiatry, 16, 809–17.Find this resource:
Ray LA and Hutchison KE (2007). Effects of naltrexone on alcohol sensitivity and genetic moderators of medication response: a double-blind placebo-controlled study. Archives of General Psychiatry, 64, 1069–77.Find this resource:
Weerts EM, Wand GS, Kuwabara H, et al. (2011). Positron emission tomography imaging of mu and delta opioid receptor binding in alcohol-dependent and healthy control subjects. Alcoholism: Clinical and Experimental Research, 35, 2162–73.Find this resource: