Opioids and Mood: A First Take From Animal Research

The endogenous opioids—endorphins, enkephalins, and dynorphins—are found in many areas of the brain. In addition to their roles in pain and addiction, their actions correlate with changes in mood. Since there is now some evidence for a role for opioid-based medication in treating depression, a look at the role of opioids in brain systems related to mood is in order. This turns out to be an area of great complexity, with rapidly advancing research spurred in part by the need for more effective treatments. New endogenous opioids and receptors are being discovered, and their distributions and functions are beginning to be mapped.

In the mid-1970’s Solomon Snyder electrified a McLean Hospital audience with his group’s discovery of opioid receptors in brain tissue. Since then, three classes of opioid receptors have been identified. The originally-discovered mu- receptors occur in several forms and bind endorphins and enkephalins. Delta-receptors also bind enkephalins, while kappa-receptors bind dynorphins. Another neuropeptide, nociceptin, and its receptor share opioid amino acid sequences with the opioid system, but their receptor activities do not overlap. Nevertheless, nociceptin activity is associated with pain, anxiety, depression, reward, learning, and memory. Yet another set of endogenous opioid peptides, the endomorphins, has been identified, but their generation and function have not been elucidated. There is eveb some evidence that the morphine and codeine molecules themselves are produced in the brain. Since most research to date has looked at the mu- and, to a lesser extent, the delta- and kappa- systems, I will focus on them, but the nociceptin, endomorphin, and possibly other systems may also contribute to mood.

Mu- receptors are found in the periaqueductal gray, olfactory bulb, amygdala, nucleus of the solitary tract, and cortex. Physicians are familiar morphine’s effects on pain, gastrointestinal motility, and respiration; their neurobiology has been studied most in pain and addiction. Beta-endorphin is one of the cleavage products of a large precursor protein synthesized in the pituitary, hypothalamus, brainstem, and skin, which is processed in various tissues to yield at least ten biologically active peptides, including adrenocorticotropic hormone (ACTH.)

For technical reasons, the enkephalins and their delta- receptors have been studied much less than the mu- system. The distribution of delta- receptors varies from species to species; in humans they are found in the basal ganglia and cortex. They are involved in pain and mood regulation and possibly in impulse control, addiction, and the neural response to inflammation.

Kappa- receptors are widely distributed in the nervous system, including the hypothalamus, periaqueductal gray, and claustrum. Dynorphin/kappa circuits are related to mood, motivation, and cognition and have been implicated in mood disorders, addiction, and schizophrenia.

Psychiatrists are familiar with several drugs which act on opioid receptors. Morphine and its congeners produce their analgesia, respiratory depression, reduced gastrointestinal motility, and addiction through mu-opioid agonism. The opioid antagonist naltrexone, used to treat opioid addiction and alcoholism, is strong mu-blocker, a weaker kappa-blocker, and a very weak delta-blocker. The anti-overdose drug naloxone is a mu-inverse agonist, which means it binds to mu-receptors and produces effects opposite to those of morphine, and a weaker kappa- and delta-blocker. Buprenorphine, which is used in the treatment of opioid addiction, is a mu- partial agonist which binds tightly to the mu- receptor and exerts some agonist activity while blocking the action of other mu-opioids such as heroin. Buprenorphine is also a kappa-opioid antagonist, which may be important in understanding its effects on depression.

These opioid systems have a number of actions in many areas of the nervous system, influencing a diverse range of processes. They appear to be examples of evolution’s repurposing molecules, receptors, and circuits which evolved for one reason to meet other needs as well.

Much of what we know about the neurobiology of opioids comes from animal research. Pierre-Eric Lutz and Brigitte Kieffer of the University of Strasbourg in France have reviewed their function in animals, including rodent models of depression such as learned helplessness, forced swim, and tail suspension.

Knockout mice genetically engineered with inactive mu-opioid receptors show decreased anxiety and depressive-like behaviors, decreased conditioning responses to addictive drugs, reduced motivation to eat, and reduced maternal attachment, suggesting roles for the mu-system in mood and reward. On the other hand, delta- knockout mice show increased anxiety and depressive-like behaviors and inconsistent changes in preferences for addictive drugs. Kappa- knockout animals how no change in mood-related behaviors and inconsistent responses to addictive drugs.

In animal models of depression, mu- agonists have antidepressant-like effects. This appears to be inconsistent with the decreased dysphoria-like behaviors in the mu- knockout mice and suggests that something more complex is taking place. The opioid antagonist naloxone is depressant in animal models, but depression is not usually a problematic side effect when it is used to treat human patients with addiction. Delta- agonists have antidepressant-like effects. In contrast, kappa- agonists are depressant in animal models, and kappa- antagonists are antidepressant.

Lutz and Kieffer note that in addition to these more direct effects on mood, opioid receptors regulate the hypothalamus-pituitary-adrenal (HPA) axis and its stress hormones, which tend to be overactive in depression.

Animal pharmacological studies, using techniques such as local infusion of drugs into the nucleus accumbens, have found that the mu-, delta-, and kappa- systems are all involved in regulation of the dopamine reward system. In addition, they affect serotonin systems--in animals, the effects of antidepressant medication are augmented by low doses of codeine, a weak mu- agonist, and antagonized by naloxone. Further evidence of the interplay between opioid and serotonergic systems comes from studies involving injection of a mu- agonist into the dorsal raphe nucleus, which increases serotonin in various limbic regions. Kappa-opioid agonists, on the other hand, may increase serotonin reuptake, which according to the monoamine hypothesis would produce depression. Although acute administration of mu-opioids is antidepressant, chronic administration, on the other hand, appears to reduce serotonin responsiveness, and depressive-like behaviors appear on withdrawal from chronic mu-opioid administration.

There is also some evidence for involvement of mu-opioids in the regulation of noradrenergic activity. Acute morphine injection increases dopamine and serotonin release but reduces norepinephrine release in the forebrain. Withdrawal from chronic opioid administration produces noradrenergic hyperactivity, particularly in the bed nucleus of the stria terminalis (BNST.)

Chronic mu- signaling also decreases neuronal proliferation and survival in the hippocampus, which is known to occur in depression and is reversed by antidepressant medication. These may be mediated by opioids’ effects in controlling the generation of new neurons from neuronal stem cells, as well as on the activity of brain-derived neurotrophic factor (BDNF.)

Lutz and Kieffer also summarize rodent research showing a strong role for mu-opioid systems in regulating social behavior, starting in utero and continuing with maternal-pup bonding and social play in adolescents and adults. They also note the correlation of a mu- receptor gene variant with the quality of human parental attachment.

This preclinical research, then, suggests complex effects of mu-opioid agonists on mood, with some suggestion of acute relief of depression-like states followed by tolerance to this effect and worsening depression on withdrawal. Delta- agonists appears to improve mood acutely, while kappa- agonism decreases mood.

Neuroimaging studies of opioid systems in humans are now beginning to appear, along with clinical trials of opioid-based medication for treatment-resistant depression and suicidality. I will discuss these in a future post.

Further Reading:

Lutz P-E, Kieffer BL. Opioid receptors: distinct roles in mood disorders. Trends Neurosci 2013; 36:195-206.

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