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Review
. 2015 Apr;38(4):217-25.
doi: 10.1016/j.tins.2015.01.002. Epub 2015 Jan 29.

Understanding opioid reward

Howard L Fields  1 , Elyssa B Margolis  2
Affiliations
Review

Understanding opioid reward

Howard L Fields et al. Trends Neurosci. 2015 Apr.

Abstract

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.

Keywords: VTA; addiction; midbrain; morphine; mu opioid receptor.

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Figures

Figure 1
Figure 1
Deconstruction of reward. Reward can be conceptualized as a teaching signal that promotes future actions that have been experienced as beneficial at specific times and places. The teaching signal includes several processes occurring at different times. Animals are subject to a variety of motivations for specific outcomes that improve their survival and reproductive success. Along with motivation, detection of contextual cues inform the animal about the current value (and cost) of actions. This information leads to a predicted outcome and an action is selected. The outcome of that action is then evaluated and compared to the predicted utility. If the outcome is better than predicted, i.e. a positive reward prediction error, subsequent utility predictions are greater and the likelihood of the action taken is increased in future under similar circumstances. Working memory is involved in two ways: first, to compare the predicted and actual outcome and second, to reinforce the actions and contextual cues leading to the outcome.
Figure 2
Figure 2
Distinct circuits course through the VTA. A variety of studies demonstrate that the VTA receives inputs from and projects to many brain regions (see [26, 124] for review); researchers have determined only a small number of exact circuit connections to date. These studies have revealed that inputs to VTA neurons differ based on their neurotransmitter content and projection target. At least four distinct circuits have so far been identified: A) A laterodorsal tegmental (LDT) glutamate input to VTA dopamine neurons projecting to NAc neurons, including medium spiny neurons (MSNs) [125]. B) A VTA GABA neuron projection specifically to NAc cholinergic interneurons (CIN) [39]. These VTA neurons receive inputs from mPFC and LDT [125, 126]. There is also evidence that these CINs can evoke release from NAc dopamine terminals via a presynaptic nicotinic cholinergic receptor [90]. C) A VTA dopamine neuron projection to mPFC receives glutamate inputs from mPFC and LDT and GABA inputs from the LDT [125]. It is unknown if these inputs converge onto all mPFC-projecting dopamine neurons. D) A VTA GABAergic projection to mPFC receives both glutamate and GABA inputs from LDT [125]. It is important to point out that this figure underestimates the number of circuits running through the VTA. Importantly, it It does not illustrate the VTA glutamate neurons, which have a distinct pattern of projection targets, nor does it illustrate several other major targets of dopamine and GABA neurons (e.g. amygdala, hippocampus, BNST, olfactory tubercle, ventral pallidum and hypothalamus).
Figure 3
Figure 3
Identified sites where MOP receptor action could disinhibit VTA neurons. MOP receptor agonists have been shown to directly hyperpolarize GABA neurons in the ventral pallidum (VP), rostromedial tegmental nucleus (RMTg) and within the VTA. In addition, MOR agonists inhibit release from the terminals of these three neuron groups.
Figure 4
Figure 4
Major pre- and postsynaptic mechanisms underlying MOP receptor (blue icon) control of VTA neurons. MOP receptor control of VTA neurons can have a net excitatory effect (directly by increasing Ca++ channel (yellow icon) conductance or indirectly by inhibiting GABA release) or a net inhibitory effect (directly by activating K+ channels (gray icon) or indirectly by inhibiting glutamate release).
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