UCSF UC San Francisco Previously Published Works Title Understanding opioid reward. Permalink https://escholarship.org/uc/item/99g2s2d3 Journal Trends in neurosciences, 38(4) ISSN 0166-2236 Authors Fields, Howard L Margolis, Elyssa B Publication Date 2015-04-01 DOI 10.1016/j.tins.2015.01.002 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Feature Review Understanding opioid reward Howard L. Fields and Elyssa B. Margolis Department of Neurology, The Wheeler Center for the Neurobiology of Addiction, Alcoholism and Addiction Research Group, University of California, San Francisco, CA, USA Opioids are the most potent analgesics in clinical use; it typically is used to denote a CNS process that increases however, their powerful rewarding properties can lead to the future probability of a behavioral response that has addiction. The scientific challenge is to retain analgesic produced a beneficial outcome; a more precise term for potency while limiting the development of tolerance, this process is ‘positive reinforcement’. In this review, we dependence, and addiction. Both rewarding and analge- focus on how the actions of mu opioid (MOP) receptor sic actions of opioids depend upon actions at the mu agonists in the VTA can produce positive reinforcement, opioid (MOP) receptor. Systemic opioid reward requires a critical initial step leading to opioid addiction. MOP receptor function in the midbrain ventral tegmental Positive reinforcement is not an elementary process; it area (VTA) which contains dopaminergic neurons. VTA comprises several inter-related processes occurring at dif- dopaminergic neurons are implicated in various aspects ferent times (Figure 1) and each process is likely to require of reward including reward prediction error, working activation of a distinct and partially independent neural memory, and incentive salience. It is now clear that subsets of VTA neurons have different pharmacological Glossary properties and participate in separate circuits. The degree to which MOP receptor agonists act on different VTA Channelrhodopsin (ChR): a light-activated channel natively expressed in green algae that is now commonly artificially expressed in neurons to enable acute, circuits depends upon the behavioral state of the animal, time-locked experimenter control of neural activity. When open, the channels which can be altered by manipulations such as food + + + 2+ nonselectively pass cations, including H , Na , K , and Ca . deprivation or prior exposure to MOP receptor agonists. Conditioned place preference (CPP): in this paradigm, a three-chamber apparatus is most commonly used, where each chamber has unique contextual cues. During training, drugs are administered and the animal is Mu opioid receptors: function and dysfunction then confined for a period in one of the end chambers. In alternate training Opioids are currently the most effective pain-relieving periods, vehicle is administered before placing the rat in a different chamber. Animals are later tested in a drug-free state by allowing them to roam freely pharmaceuticals. However, they are also rewarding and with access to all chambers of the apparatus. If animals spend more time in the their repeated use can lead to dependence and addiction. In drug-associated chamber, we say that the drug produces a CPP. fact, addiction to opioid analgesics is a growing socioeco- Drug self-administration: in this paradigm, animals are required to perform an operant action (typically a lever press or nose poke) to receive an infusion of nomic and health problem with potentially serious conse- drug. If rats emit more operant actions for the drug than for vehicle, it is quences, documented by a rise in deaths due to overdose evidence that the drug has a positively reinforcing action. [1,2]. A critical CNS locus for opioid reward is the VTA Mu opioid peptide (MOP) receptor: a member of the opioid family of seven transmembrane domain G protein-coupled receptors (GPCRs) classified in part (see Glossary). Recent work indicates that there is great by their high amino acid sequence homology. Other members of the family anatomical and pharmacological heterogeneity in VTA include the delta, kappa, and orphanin receptors. MOP receptors are widely neurons and that there are numerous opioid synaptic distributed throughout the peripheral and central nervous systems. MOP receptors can signal through a variety of downstream pathways but typically actions within the VTA. Here, we review the role of VTA their actions are inhibitory [e.g., to inhibit glutamate or GABA release from neurons in opioid reward and reinforcement, and the terminals or to hyperpolarize neurons through a G-protein activated inwardly rectifying potassium channel (GIRK)] [70]. synaptic and neural circuit mechanisms by which opioids Reinforcement: a process that leads to an increase in the probability of an action control VTA neuronal activity. that was previously followed by a beneficial outcome. Negative reinforcement refers specifically to removing an unpleasant stimulus or state (e.g., pain relief). Positive reinforcement occurs when the benefit does not require relief of an How are we using the term ‘reward’? unpleasant state. Punishment refers to the process whereby a harmful outcome Although there is broad consensus that addicting drugs reduces the probability of the action preceding the outcome. produce ‘reward’, inconsistency in the use of the term is an Ventral tegmental area (VTA): a region in the midbrain that includes dopaminergic neurons of the A10 cell group [99]. It is immediately ventral to impediment to progress in understanding how these drugs the red nucleus, caudal to the hypothalamus, and medial to and contiguous with influence behavior [3]. The word ‘reward’ can be used as a the substantia nigra (SN) [100]. The VTA has been divided into five subdivisions noun (‘rats will work for a reward’), a verb (‘he intends to (see Figure 3 in [101]). There are three midline nuclei: the interfascicular, rostral linear, and caudal linear. The two lateral divisions are the parabrachial pigmented reward the winner’), or an adjective (a rewarding flavor). and paranigral nuclei, which extend laterally from these midline nuclei to the Furthermore, even when used as a noun, it has several medial lemniscus and the medial edge of the SN. The original description of the distinct meanings: it can refer to the rewarding agent VTA by Tsai did not include the midline nuclei (e.g., [101]); however, there is general agreement that the catecholaminergic A10 group as originally defined by itself (e.g., a food or drug reward) or to the subjective Dahlstroem and Fuxe [99] includes dopamine neurons in all five of these hedonic feeling (i.e., pleasure). In behavioral psychology, subnuclei. At the time of writing, there was no evidence that the cytoarchitecto- nically described subdivisions of the VTA differ functionally. VTA neurons in each Corresponding author: Fields, H.L. ([email protected]). of the subnuclei project widely to several limbic areas implicated in motivation Keywords: midbrain; VTA; mu opioid receptor; morphine; addiction. and positive reinforcement [21,26,102,103] (see Figure 3 in [100]) and the weight of current evidence supports the idea that the critical organizational principal for 0166-2236/ grouping VTA neurons is their projection target and neurotransmitter content ß 2015 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tins.2015.01.002 rather than location within the VTA. Trends in Neurosciences, April 2015, Vol. 38, No. 4 217 Feature Review Trends in Neurosciences April 2015, Vol. 38, No. 4 projections to the nucleus accumbens (NAc) contribute to encoding incentive salience, while projections to the hip- Movaon pocampus promote spatial memory formation [12]. Given that the neuronal mechanisms underlying the actions of opioids and dopamine may differ in each of these circuits, a Context Predicted complete understanding of their contributions to ‘reward’ Acon and cues ulity requires disentangling these functions and defining the circuits relevant to each. Working The VTA is a critical site for MOP receptor-mediated memory reward Reinforcement The most consistent and robust rewarding effects of opioids Predicon Outcome or require a functional MOP receptor [13]. The significance of error evaluaon exncon the VTA for MOP reward has been established by several lines of evidence. Specifically, conditioned place preference TRENDS in Neurosciences (CPP) produced by systemically administered MOP recep- tor agonists can be blocked by intra-VTA MOP receptor Figure 1. Deconstruction of reward. Reward can be conceptualized as a teaching signal that promotes future actions that have been experienced as beneficial at selective antagonists or genetic knockdown of the MOP specific times and places. The teaching signal includes several processes occurring receptor [14,15]. Microinjecting a MOP receptor antagonist at different times. Animals are subject to a variety of motivations for specific into the VTA also accelerates intravenous (IV) heroin self- outcomes that improve their survival and reproductive success. Along with motivation, detection of contextual cues informs the animal about the current administration [16]. These observations do not prove that value (and cost) of actions. This information leads to a predicted outcome and an the systemic drug itself acts directly on receptors in the action is selected. The outcome of that action is then evaluated and compared