Reward Processing by the Opioid System in the Brain

Reward Processing by the Opioid System in the Brain – free full-text PMC article – Physiol Rev. 2009 Oct;

The opioid system consists of three receptors, mu, delta, and kappa, which are activated by endogenous opioid peptides processed from three protein precursors, proopiomelanocortin, proenkephalin, and prodynorphin.

Opioid receptors are recruited in response to natural rewarding stimuli and drugs of abuse, and both endogenous opioids and their receptors are modified as addiction develops.

Mechanisms whereby aberrant activation and modifications of the opioid system contribute to drug craving and relapse remain to be clarified. 

This review summarizes our present knowledge on brain sites where the endogenous opioid system controls hedonic responses and is modified in response to drugs of abuse in the rodent brain.

We review

  1. the latest data on the anatomy of the opioid system,
  2. the consequences of local intracerebral pharmacological manipulation of the opioid system on reinforced behaviors,
  3. the consequences of gene knockout on reinforced behaviors and drug dependence, and
  4. the consequences of chronic exposure to drugs of abuse on expression levels of opioid system genes.

Opioid peptides and receptors are broadly expressed throughout peripheral and central nervous systems and have been the subject of intense investigations for several decades. The opioid system plays a central role in nociception and analgesia, and the main aspects of opioid-regulated pain mechanisms have been reviewed recently

The opioid system also regulates numerous physiological functions, including responses to stress, respiration, gastrointestinal transit, as well as endocrine and immune functions.

Importantly, this system also plays a key role in modulating mood and well-being, as well as addictive behaviors.

Here we review current knowledge of the role of the opioid system in hedonic control and of genetic regulations of the system following drug exposure, with a specific emphasis on recent data from rodent models and a focus on the neurocircuitry and behavioral aspects of opioid function.


Opioid receptors and peptides are both broadly expressed throughout the brain. Figure 1Anatomical distribution of opioid receptors (A) and peptides (B)

Opioid receptors are expressed primarily in the cortex, limbic system, and brain stem. Binding sites for the three opioid receptors overlap in most structures, but some structures exhibit higher expression of one receptor over the others.


Positive emotions, such as pleasure, hedonism, or reward, when associated with the ability to learn from experience, can act to increase the probability of the occurrence of a particular behavior, a phenomenon called positive reinforcement.

Opioid peptides and receptors are expressed throughout the reinforcement network, placing the opioid system in a key position to modulate this circuit. Experimental data have accumulated over nearly 50 years showing that the opioid system is involved with reinforcement processes.

Globally, systemic mu and, to a lesser extent, delta agonists produce positive reinforcement, whereas kappa agonists induce aversion, hallucinations, and malaise.

Conversely, mu and delta antagonists suppress the positive reinforcing properties of natural rewards and opiate or nonopioid drugs, whereas kappa antagonists facilitate these effects

The Endogenous Opioid System and Drugs of Abuse

Drug addiction is a chronic disorder that builds up from initial recreational drug use and progresses towards compulsive drug seeking and intake. The reinforcing properties of abused drugs are thought to be responsible, in interaction with various environmental factors, for the initiation of drug taking.

Once repeated drug use is established, complex neuroadaptative mechanisms develop that lead to dependence, craving, and relapse and contribute to the maintenance of repeated drug intoxication

A current hypothesis in the field of drug addiction is that drugs of abuse abnormally recruit neuronal pathways and transmitter systems responding to natural reinforcement and progressively alter their function.

Drug reinforcement

Dependence reflects the development of complex neuronal adaptations in response to repeated and/or prolonged drug administration.

Note that this is true of all kinds of drugs, not just opioids, including antidepressants, alcohol, and caffeine.

Dependence is revealed, when drug use ceases, by a complex withdrawal syndrome associating physical (or somatic) signs with an intensely aversive emotional state also called motivational withdrawal.


Data reviewed in the present section, together with previously published results, demonstrate that the endogenous opioid system plays a key role in drug reinforcement.

Drug reinforcement

The mesolimbic dopaminergic system has long been considered the major neurobiological substrate mediating opiate reinforcement.

Numerous brain regions, which express opioid receptors, have been identified as directly supporting the reinforcing effects of opioids. Most of these regions also contribute to systemic opioid or nonopioid drug reinforcement.


Drugs of abuse produce reinforcement after a single or limited drug exposure.

This process does NOT necessarily lead to the development of addictive behaviors and is therefore considered a necessary, although not sufficient, step towards drug abuse.

In contrast, chronic exposure to drugs of abuse, particularly repeated exposure-withdrawal cycles, produces broad long-term and likely irreversible modifications within reinforcement networks, as well as in associated circuits controlling cognitive and emotional behaviors.

These modifications, in turn, contribute to the transition from recreational drug use to compulsive drug taking and abuse.

A vast amount of literature now indicates that the opioid system is altered following chronic drug exposure, and at many brain sites, and data are reviewed in this section with a focus on adaptations at the transcriptional level.

If this is true, then why don’t pain patient’s become addicted?

The statements here insist that any person exposed to opioids will become addicted.

This is where PROP found support for their contention that any opioid use is addiction.

Yet, we know this is not true in the presence of high pain.

These studies are all missing something critical by not explaining how opioids can be used non-addictively when extreme pain is present.

In the present review, we have focused on genes encoding opioid receptors and peptides….

The article then includes a long and detailed explanation of this process.


Altogether, the analysis of knockout mice clarified the role of each opioid receptor in a large number of behavioral responses and has identified highly distinct activity patterns for each receptor.

Relevant to drug intake, genetic data demonstrate that

  • mu receptors contribute to the reinforcing properties of most drugs of abuse,
  • whereas kappa receptors induce dysphoria and counteract mu receptors in regulating hedonic homeostasis.

With regard to other aspects of addictive behaviors, the data show a role for 

  1. mu receptors in drug dependence,
  2. kappa receptors in stress-induced drug intake, and
  3. delta receptors in emotional control.

Gene expression studies have revealed adaptive modifications of the opioid system in response to repeated drug treatments and following cessation of drug treatment.

Data from withdrawn animals are variable, likely due to the diversity of withdrawal conditions and the dynamic nature of the process.

In contrast, a picture emerges from studies of animals under chronic drug treatment.

Both repeated morphine and alcohol administration produce consistent downregulation of opioid peptides in many brain areas, whereas chronic psychostimulants upregulate those genes.

This observation reflects the possibility that distinct classes of drugs of abuse produce opposing neuroadaptations of endogenous opioids.

Chronic narcotic (opioids) or sedative (ethanol) drugs may repress the endogenous opioid tone as a result of repeated activation of this system,

whereas psychostimulants may activate the opioid system as a feedback mechanism counteracting the stimulant properties of the drugs.

#And then, after thousands of words of technical explanations of various system changes, they admit that:

This is, however, highly speculative, and more data are needed to substantiate this hypothesis.

Perspectives: Adaptations of Opioidergic Systems, Significance, and Implications

The significance of opioid system regulations to drug addiction remains an open question.

Natural genetic variations have been proposed to modulate susceptibility to addiction.

Variation in expression levels of opioid receptors and peptides across individuals may also play a role. Some genetic studies support this view (note that this entire research field was not reviewed here).

The data show changes in the expression of both receptors and peptides in drug-dependent and withdrawn animals.

However, the causal relationship between those changes and the development of addictive behaviors is presently unclear.


Genetic inactivation of the six genes encoding opioid receptors and peptides has produced a large variety of reward-relevant behavioral phenotypes.

Although these data are suggestive of a role for gene regulation in the development of addiction, the correlative nature of this approach does not examine the causal link between changes in gene expression and behavioral adaptations to drugs of abuse.

Even though they state that the data only show correlation, the whole article is written from the perspective on causation.

Opiates have been used for thousands of years and abused for almost two centuries.

I question whether they can so unequivocally state that they’ve been abused for 2,000 years. Where would such data be found?

This is typical of the whole article, as it makes the assumption of causation even while stating there is only correlation.

Rodent-based approaches will further the development of testable hypotheses…

No, they will not.

Rodents are not humans, and lack the innumerable psychological and sociological factors relevant to human pain and addiction.

Relying on rodent studies to illustrate the process of addiction ignores topics that have long been shown to be relevant to addiction, like poverty, lack of education, and income inequality.


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