Understanding opioid reward

doi:10.1016/j.tins.2015.01.002

Trends in Neurosciences

Volume 38, Issue 4, April 2015, Pages 217-225

https://doi.org/10.1016/j.tins.2015.01.002 Get rights and content

Opioids are the most potent analgesics in clinical use; however, their powerful rewarding properties can lead to addiction. The scientific challenge is to retain analgesic potency while limiting the development of tolerance, dependence, and addiction. Both rewarding and analgesic actions of opioids depend upon actions at the mu opioid (MOP) receptor. Systemic opioid reward requires MOP receptor function in the midbrain ventral tegmental area (VTA) which contains dopaminergic neurons. VTA dopaminergic neurons are implicated in various aspects of reward including reward prediction error, working memory, and incentive salience. It is now clear that subsets of VTA neurons have different pharmacological properties and participate in separate circuits. The degree to which MOP receptor agonists act on different VTA circuits depends upon the behavioral state of the animal, which can be altered by manipulations such as food deprivation or prior exposure to MOP receptor agonists.

Section snippets

Mu opioid receptors: function and dysfunction

Opioids are currently the most effective pain-relieving pharmaceuticals. However, they are also rewarding and their repeated use can lead to dependence and addiction. In fact, addiction to opioid analgesics is a growing socioeconomic and health problem with potentially serious consequences, documented by a rise in deaths due to overdose 1, 2. A critical CNS locus for opioid reward is the VTA (see Glossary). Recent work indicates that there is great anatomical and pharmacological heterogeneity

The VTA is a critical site for MOP receptor-mediated reward

The most consistent and robust rewarding effects of opioids require a functional MOP receptor [13]. The significance of the VTA for MOP reward has been established by several lines of evidence. Specifically, conditioned place preference (CPP) produced by systemically administered MOP receptor agonists can be blocked by intra-VTA MOP receptor selective antagonists or genetic knockdown of the MOP receptor 14, 15. Microinjecting a MOP receptor antagonist into the VTA also accelerates intravenous

Heterogeneity of VTA neurons: different neurotransmitters, distinct projection targets, and afferent inputs

Early studies of VTA contributions to reward focused on the dopaminergic projection to the ventral striatum. However, different subsets of VTA dopamine neurons project to other CNS targets implicated in reward-relevant functions, including: the amygdala, hippocampus, ventral pallidum, periaqueductal gray, bed nucleus of the stria terminalis, olfactory tubercle, locus coeruleus, and lateral habenula 26, 27, 28, 29, 30, 31. Furthermore, the properties of dopamine neurons vary based on their CNS

Dopamine neuron firing can encode positive outcomes and produce positive reinforcement

Although some pharmacological manipulations that increase dopamine in the ventral striatum do not produce reward (Box 1), there is a body of evidence implicating dopamine in positive reinforcement. In vivo single unit recordings in both primate and rodents show that midbrain dopamine neurons encode beneficial outcomes (e.g., 7, 58). More specifically, many dopaminergic neurons encode a signal consistent with the proposal that their firing reflects a reward prediction error. An encoded positive

Alternative circuits for MOP reward: dopamine and nondopamine

The canonical model of opioid reward asserts that the critical dopaminergic terminal region is the ventral striatum. Indeed, dopamine D1 receptor antagonists microinjected into the NAc can reduce MOP receptor agonist reinforcement [89]. However, recent evidence suggests that dopamine can be released in the striatum independent of increases in VTA dopamine neuron activity: first, VTA GABA neurons that project to the NAc synapse onto cholinergic interneurons [39]; second, cholinergic interneuron

Can inhibition of dopamine neurons produce reinforcement?

Another robust MOP receptor effect on a subset of VTA dopamine neurons is direct postsynaptic inhibition 32, 88, 94, 95. In fact, nearly half of all confirmed VTA dopamine neurons are inhibited by MOP activation ex vivo in the rat [88]. The heterogeneity of MOP receptor-mediated actions on VTA dopamine neurons, in particular the ubiquity of the direct inhibitory effect, undermines a critical simplifying assumption underpinning the two neuron model, that is, that dopamine neurons in the VTA form

Concluding remarks

While it is clear that direct synaptic actions in the VTA are required for MOP receptor-mediated reward, the goal of identifying the relevant mechanisms and sites of action is elusive for several reasons. For example, the process of reward itself comprises multiple elements dissociable in time and likely involving different circuits. This functional diversity may be reflected in the distinct connectivity and function of different subsets of VTA neurons. Despite this heterogeneity, a large

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Opioid use disorder (OUD) is a worldwide public health crisis with few effective treatment options. Traditional genetics and neuroscience approaches have provided knowledge about biological mechanisms that contribute to OUD-related phenotypes, but the complexity and magnitude of effects in the brain and body remain poorly understood. The gut-brain axis has emerged as a promising target for future therapeutics for several psychiatric conditions, so characterizing the relationship between host genetics and the gut microbiome in the context of OUD will be essential for development of novel treatments. In this review, we describe evidence that interactions between host genetics, the gut microbiome, and immune signaling likely play a key role in mediating opioid-related phenotypes. Studies in humans and model organisms consistently demonstrated that genetic background is a major determinant of gut microbiome composition. Furthermore, the gut microbiome is susceptible to environmental influences such as opioid exposure. Additional work focused on gene by microbiome interactions will be necessary to gain improved understanding of their effects on OUD-related behaviors.
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Neuropathic pain is a debilitating pathological condition that presents significant therapeutic challenges in clinical practice. Unfortunately, current pharmacological treatments for neuropathic pain lack clinical efficacy and often lead to harmful adverse reactions. As G protein-coupled receptors (GPCRs) are widely distributed throughout the body, including the pain transmission pathway and descending inhibition pathway, the development of novel neuropathic pain treatments based on GPCRs allosteric modulation theory is gaining momentum. Extensive research has shown that allosteric modulators targeting GPCRs on the pain pathway can effectively alleviate symptoms of neuropathic pain while reducing or eliminating adverse effects. This review aims to provide a comprehensive summary of the progress made in GPCRs allosteric modulators in the treatment of neuropathic pain, and discuss the potential benefits and adverse factors of this treatment. We will also concentrate on the development of biased agonists of GPCRs, and based on important examples of biased agonist development in recent years, we will describe universal strategies for designing structure-based biased agonists. It is foreseeable that, with the continuous improvement of GPCRs allosteric modulation and biased agonist theory, effective GPCRs allosteric drugs will eventually be available for the treatment of neuropathic pain with acceptable safety.
Mu Opioid Receptor–Expressing Neurons in the Dorsal Raphe Nucleus Are Involved in Reward Processing and Affective Behaviors
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Mu opioid receptors (MORs) are key for reward processing, mostly studied in dopaminergic pathways. MORs are also expressed in the dorsal raphe nucleus (DRN), which is central for the modulation of reward and mood, but MOR function in the DRN remains underexplored. Here, we investigated whether MOR-expressing neurons of the DRN (DRN-MOR neurons) participate in reward and emotional responses.
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Trends in Neurosciences

Feature ReviewUnderstanding opioid reward

Section snippets

Mu opioid receptors: function and dysfunction

The VTA is a critical site for MOP receptor-mediated reward

Heterogeneity of VTA neurons: different neurotransmitters, distinct projection targets, and afferent inputs

Dopamine neuron firing can encode positive outcomes and produce positive reinforcement

Alternative circuits for MOP reward: dopamine and nondopamine

Can inhibition of dopamine neurons produce reinforcement?

Concluding remarks

Neuron

Neuron

Pharmacol. Biochem. Behav.

Neuron

Curr. Opin. Neurobiol.

Trends Pharmacol. Sci.

Neuroscience

Brain Res.

Life Sci.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Neuroscience

Brain Res.

Brain Res. Bull.

Neuron

Neuron

Brain Res.

Brain Res.

Prog. Neuropsychopharmacol. Biol. Psychiatry

Neuroscience

Neuroscience

Behav. Brain Res.

Neuron

Neuron

Neuron

Neuroscience

Brain Res.

Cell Rep.

Neuron

Neuroscience

Trends Neurosci.

Patterns of abuse among unintentional pharmaceutical overdose fatalities

JAMA

The role of catechol-O-methyltransferase in reward processing and addiction

CNS Neurol. Disord. Drug Targets

The neurobiology of opiate motivation

Cold Spring Harb. Perspect. Med.

Reward processing by the opioid system in the brain

Physiol. Rev.

The nucleus accumbens as part of a basal ganglia action selection circuit

Psychopharmacology

Dopamine system: manager of neural pathways

Front. Hum. Neurosci.

Dopaminergic neurons promote hippocampal reactivation and spatial memory persistence

Nat. Neurosci.

The development of a conditioned place preference to morphine: effects of microinjections into various CNS sites

Behav. Neurosci.

Rewarding and psychomotor stimulant effects of endomorphin-1: anteroposterior differences within the ventral tegmental area and lack of effect in nucleus accumbens

J. Neurosci.

Anatomical and pharmacological specificity of the rewarding effect elicited by microinjections of morphine into the nucleus accumbens of mice

Psychopharmacology

Anatomically distinct opiate receptor fields mediate reward and physical dependence

Science

Neuroanatomical sites mediating the motivational effects of opioids as mapped by the conditioned place preference paradigm in rats

J. Pharmacol. Exp. Ther.

Deprivation state switches the neurobiological substrates mediating opiate reward in the ventral tegmental area

J. Neurosci.

Opioid hedonic hotspot in nucleus accumbens shell: mu, delta, and kappa maps for enhancement of sweetness ‘liking’ and ‘wanting’

J. Neurosci.

Ventral tegmental area neurons in learned appetitive behavior and positive reinforcement

Annu. Rev. Neurosci.

Biochemical and radioautographic evidence for dopaminergic afferents of the locus coeruleus originating in the ventral tegmental area

J. Neural Transm.

Collateralization of monoamine neurons: mesotelencephalic dopamine projections to caudate, septum, and frontal cortex

J. Neurosci.

Properties and opioid inhibition of mesolimbic dopamine neurons vary according to target location

J. Neurosci.

Kappa opioids selectively control dopaminergic neurons projecting to the prefrontal cortex

Proc. Natl. Acad. Sci. U.S.A.

Feature Review
Understanding opioid reward