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Enkephalins: Functions & Associated Diseases

Written by Carlos Tello, PhD (Molecular Biology) | Last updated:
Puya Yazdi
Medically reviewed by
Puya Yazdi, MD | Written by Carlos Tello, PhD (Molecular Biology) | Last updated:

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Enkephalins are mainly involved in decreasing pain, reducing inflammation, preventing cancer cell growth, and increasing immune cell activity, and play a role in several diseases. Read more to learn about the conditions associated with high and low enkephalin levels and ways to decrease and increase them.

What Are Enkephalins?

Enkephalins are compounds (pentapeptides) found in all vertebrate animals, including humans. There are two types of enkephalins: methionine and leucine-enkephalin [1, 2].

Enkephalins are commonly found throughout the brain and in the spinal cord, but also in nerves outside the brain, the adrenal glands, small and large intestines, kidneys, testes, pancreas, heart muscle, skin tissue, lungs, joints, and bones [3, 4, 2, 5, 6].

Enkephalin Function

Enkephalins mainly work by binding and activating mu and delta-opioid receptors. They play a role in memory, learning, emotional behavior, and pain. Balanced enkephalins level are needed to maintain normal brain function [7].

Enkephalins Decrease Pain

When released, enkephalins help reduce the sensation of pain (nociception) and increase relief from pain (analgesia). They achieve these responses by binding to opioid receptors in the spinal cord and certain regions of the brain and activating their respective pathways [8].

Due to this, enkephalins act as internal opioids. Specifically, methionine- and leucine-enkephalin activate the delta and mu opioid receptors to produce their painkiller effects [8, 9].

Another way enkephalins reduce pain is through their interactions with substance P, a neurotransmitter that transmits pain sensations to the brain. In chicken embryos, enkephalins inhibited substance P release from sensory neurons, which, in turn, reduced pain sensation [10].

Health Benefits of High Enkephalin Levels

1) May Increase Metabolism

Metabolism (energy production) can be increased through the release of thyroid-stimulating hormone (TSH). TSH causes the release of the thyroid hormones T3 and T4, which stimulate energy production [11].

In humans, high levels of methionine-enkephalin stimulate the release of TSH and may increase metabolism [9].

2) May Reduce Inflammation

Enkephalins inhibit the release of cytokines that produce inflammation.

In one study, adding both methionine- and leucine-enkephalin to joint tissue cells from rheumatoid arthritis patients inhibited the release of inflammatory cytokines IL-1B and TNF-a [12].

Furthermore, in mice, high enkephalin levels activated T cells, which then increased pain relief from inflammation [13].

3) May Help Create “Runner’s High”

Many people are familiar with the term “runner’s high.” It describes the temporary state of euphoria that athletes reach after long periods of running or continuous exercise. Runner’s high is partially induced by the activation of opioid receptors by high concentrations of enkephalins and other internal opioids such as endorphins and dynorphins [9].

In a study of 10 athletes, after two hours of endurance running, they experienced higher levels of euphoria. This was associated with a decrease in opioid receptor activity in certain brain regions (prefrontal/orbitofrontal cortices, anterior cingulate cortex, bilateral insula, parainsular cortex, and temporoparietal regions) [14].

4) May Prevent Cancer Growth

In a pilot trial on 15 people with advanced pancreatic cancer, methionine-enkephalin reduced tumor growth in one patient and halted metastasis in two other patients [15].

High levels of methionine-enkephalin decreased the growth of two types of human ovarian cancer cells [16].

Additionally, an increase in methionine-enkephalin concentrations stunted the development of skin cancer (melanoma) cells in mice [17].

Likewise, high doses of methionine-enkephalin stopped further growth of human colon cancer tumors transplanted in mice. Additionally, 57% did not display tumor growth 7 weeks after being given methionine-enkephalin [18].

5) May Help with Depression

High levels of methionine-enkephalin produced antidepressant-like effects in mice and rats via activation of delta opioid receptors [19].

6) May Benefit the Heart

At high concentrations, both leucine- and methionine-enkephalin increased the strength of contraction in heart muscle cells derived from chicken embryos [20].

Negative Effects of High Enkephalin Levels

1) May Decrease Immune Cell Activity

Since several types of immune cells have receptors for enkephalins, their activity can be decreased by high concentrations of these compounds. Injections of large doses of methionine- and leucine-enkephalin decreased the production of antibodies (hemagglutinating, which clump red blood cells together) in rats and mice [21].

Of the two, methionine-enkephalin was a more potent immunosuppressant than leucine-enkephalin at high doses. However, they both were immunostimulants at low doses [21].

High concentrations of methionine-enkephalin suppressed the activity of T cells in rats [22].

On a similar note, high concentrations of methionine-enkephalin decreased the activity of macrophages (white blood cells) in clinical trials [23].

Injections of large doses of methionine-enkephalin also decreased the amounts of white blood cells in rats [24].

2) May Inhibit Insulin Release

High concentrations of methionine-enkephalin suppressed the release of insulin from rat pancreatic tissue [25, 26].

3) May Promote Overeating

The hypothalamic paraventricular nucleus is a region of the mammalian brain that controls feeding and appetite. Increased enkephalin concentrations in this brain region may cause overeating in rats and mice [27, 28, 29].

Diseases Linked to High Enkephalin Levels

The conditions we discuss here have been associated with high enkephalin levels, but this single symptom is not enough for a diagnosis. Because the majority of studies covered in this section are human association studies (which means that a cause-and-effect relationship hasn’t been established) or animal and cell-based research and the conditions are generally complex, high enkephalin levels are highly unlikely to be the only cause.

Work with your doctor to discover what underlying condition might be causing your unusually high enkephalin levels and to develop an appropriate plan to improve your health.

1) Diabetes

In a study of 37 people, the average levels of methionine-enkephalin were higher in 22 patients with type 1 diabetes than in 15 healthy women [30].

High levels of methionine-enkephalin were also observed in women with type 1 diabetes or pregnancy diabetes in another study on 57 women [31].

2) Psoriasis

The skin of 20 psoriasis patients had higher proenkephalin levels compared to the skin of 20 people without the disease in a study. Similarly, skin samples taken from people with this condition had higher levels of methionine- and leucine-enkephalin in another study [32, 33].

3) Alzheimer’s Disease

Mice exhibiting symptoms of Alzheimer’s disease had high levels of methionine-enkephalin in nerve cells of the brain regions that control memory. This suggests that elevated methionine-enkephalin levels may have contributed to the cognitive impairment and behavioral changes observed [7].

4) Cancer Immunosuppression

In a study of human and rodent colon cancer cells, the tumor-killing activity of white blood cells was inhibited when colon cancer cells released high concentrations of methionine-enkephalin [34].

Health Benefits of Low Enkephalin Levels

1) May Increase Immune Cell Activity

While enkephalins are widely known for being natural painkillers, they can also help strengthen people’s immune systems at low concentrations.

Both methionine- and leucine-enkephalin act as immunostimulants (a substance that increases the activity of immune cells) at low concentrations. As such, they can increase the pathogen-neutralizing activity of different immune cells (natural killer and dendritic cells) [35, 36, 23].

Human bone marrow-derived immune cells (dendritic cells) aged more quickly when exposed to low levels of methionine-enkephalin (over 7 days) [37].

Additionally, exposure to methionine-enkephalin caused these cells to release more cytokines (IL-12 and TNF-a), which intensified the immune response to disease-causing antigens [37].

In studies in people with cancer, low concentrations of methionine-enkephalin increased the activity of macrophages [23].

Low levels of methionine-enkephalin also increased the growth and tumor-killing activity of human toxic T cells (white blood cells that kill cancer cells) in cell-based studies [38, 37].

Likewise, low doses of methionine-enkephalin, administered over 7 days, increased the amounts of natural killer cells (NK cells), helper T cells, and toxic T cells in 50 cancer patients [39].

Additionally, other cell-based studies showed that low concentrations of methionine-enkephalin caused NK cells to release IL-2. This recruited T cells to move toward the site of exposure [40, 41, 22].

2) May Induce Insulin Release

Low concentrations of methionine-enkephalin elicited insulin release in isolated rat pancreatic tissue [25, 26].

Likewise, low concentrations of leucine-enkephalin brought about the release of both insulin and glucagon from rat pancreatic tissue [42].

3) May Protect Dopamine-Producing Nerve Cells

In midbrain nerve cells, small concentrations of leucine-enkephalin helped protect dopamine-producing rats and mice from brain cell inflammation [43].

4) May Block Tumor Growth

In bone marrow-derived mouse cells, low concentrations of methionine-enkephalin inhibited tumor growth and even caused cell death (apoptosis) of adjacent tumor cells [44].

Negative Effects of Low Enkephalin Levels

1) May Increase Depression

Mice lacking the gene for proenkephalin, the precursor protein for enkephalins, displayed a greater number of depression-like behaviors than normal mice [45].

2) May Increase Stress

In a study of male rats, those with decreased production of enkephalins in their brains displayed more anxious behaviors in response to 3 weeks of chronic stress [46].

3) May Cause Excessive Cell Growth

In addition to binding to opioid receptors, methionine-enkephalin binds to and inhibits the opioid growth factor receptor (OGFR), thus inhibiting tissue growth [47].

A certain concentration of methionine-enkephalin is needed to keep the opioid growth factor receptor active at all times. In human ovarian cancer cells, a deficiency of methionine-enkephalin caused these cells to divide more frequently. Plus, inhibition of the OGFR gene stimulated their division [16, 48].

Diseases Linked to Low Enkephalin Levels

The conditions we discuss here have been associated with low enkephalin levels, but this single symptom is not enough for a diagnosis. Because the majority of studies covered in this section are human association studies (which means that a cause-and-effect relationship hasn’t been established) or animal and cell-based research and the conditions are generally complex, high enkephalin levels are highly unlikely to be the only cause.

Work with your doctor to discover what underlying condition might be causing your unusually low enkephalin levels and to develop an appropriate plan to improve your health.

1) IBD

Low enkephalin levels are suspected to play a role in inflammatory bowel diseases. In a study of 126 people, those with Crohn’s disease (38) and ulcerative colitis (43) had lower levels of released methionine-enkephalin in their colons than 45 healthy people [49].

2) Parkinson’s Disease

Low enkephalin levels may be involved in the progression of Parkinson’s disease. Decreased levels of methionine-enkephalin were found in the brains of 12 people at early and advanced stages of Parkinson’s disease. In turn, decreased leucine-enkephalin levels were found in the brains of 6 people with advanced Parkinson’s [50].

3) Arthritis

In one study, arthritic female rats had less methionine-enkephalin in their ankle joints than those without arthritis. This suggests that low methionine-enkephalin may contribute to arthritis [5].

4) Huntington’s Disease

Decreased production of enkephalins was observed in the brains of mice genetically predisposed to Huntington’s disease, suggesting it may be an early sign of nerve cell death from this disease [51].

Ways to Increase Enkephalin Levels

The most important thing is to work with your doctor to identify the cause of your unusually low enkephalin levels and develop a treatment plan. The following complementary strategies may also help in some cases. Discuss them with your doctor and never use them instead of what they recommend or prescribe.

1) Exercise

In a clinical trial on 12 trained male athletes, they had higher concentrations of methionine-enkephalin after increasingly practicing intensive exercise on a treadmill. The highest concentrations were achieved after running a marathon [52].

However, short-term exercise increased the levels of enkephalin and opioid receptor activity in the brains of rats more than long-term exercise [53].

2) Acupuncture

Acupuncture has been found to increase methionine-enkephalin and subsequently activate delta opioid receptors in the nerves. High-frequency acupuncture may alleviate the symptoms of opiate withdrawal by activating delta-receptors [54].

A similar increase in methionine- and leucine-enkephalin during acupuncture has been observed in rat brains [55].

Likewise, electroacupuncture (a type of acupuncture where small electric currents are passed between pairs of needles) can accelerate the release of enkephalins and other internal opioids. Maximal pain relief was achieved in patients using a combination of frequencies of 2Hz and 100Hz [56].

3) Ultraviolet Radiation

Ultraviolet light, either artificial or from sunlight, increased methionine-enkephalin levels in the skin of humans [57].

4) Sexual Activity

Sexual activity increased the levels of leucine- and methionine-enkephalin in the brains of male rats [58].

5) Long-Term Stress

Higher enkephalin levels were observed in the brains of a group of male rats after being immobilized for 7 and 21 days. Remember that stress may cause many adverse effects on health, which makes this strategy not recommendable [59].

6) Low Dose Naltrexone

Low dose naltrexone inhibits opioid receptors, causing the body to increase the production of endorphins and enkephalins to compensate for the blocked receptors. Additionally, the increased levels of opioids may persist after the naltrexone has been eliminated from the body, as seen in a cell-based study [60].

Because naltrexone is a prescription-only drug not approved for this purpose, we recommend using other strategies to increase enkephalin levels.

7) Enkephalinase Inhibition

Enkephalinases are enzymes that break down enkephalins. In both animals and humans, inhibiting these enzymes can increase enkephalin levels [61, 62].

D-Phenylalanine blocks enkephalinase activity. It inhibited enkephalin breakdown in 30 chronic pain patients and increased the amount of methionine-enkephalin released from mice brains [63, 64].

Several drugs are being developed to inhibit enkephalinase and maintain the antidepressant and pain-relieving effects of enkephalins. Because none of these experimental drugs has been approved and safety data are lacking, we strongly advise against their use for this or any other purposes

RB-101 is a synthetic enkephalinase inhibitor that causes a buildup of both methionine and leucine-enkephalin in rats [61].

RB-120 and RB-3007 are also synthetic enkephalinase inhibitors tested in rats. Unlike RB-101, these compounds can be taken orally. They are undergoing clinical trials as non-opioid pain relievers for humans [61, 65].

Spinorphin and opiorphin are internal enkephalinase inhibitors. Spinorphin maintains the effects of leucine-enkephalin in mice. In rats, human opiorphin suppressed pain as effectively as morphine [66, 67].

Another potential use of enkephalinase inhibitors is to improve learning and memory formation. Semax and selank are synthetic enkephalinase inhibitors developed in Russia that can also increase leucine-enkephalin levels. Although commonly prescribed in Russia to prevent circulatory disorders (Semax) or to treat anxiety and enhance cognition (selank), none of them is approved by the FDA [68].

Ways to Decrease Enkephalin Levels

The most important thing is to work with your doctor to identify the cause of your unusually high enkephalin levels and develop a treatment plan. The following complementary strategies may also help in some cases. Discuss them with your doctor and never use them instead of what they recommend or prescribe.

1) Low-Copper Diets

Eating foods low in copper can decrease enkephalin levels. In one study on 24 men, eating a low-copper diet for 11 weeks decreased the levels of methionine- and leucine-enkephalin [69].

2) Short-Term Stress

In contrast to long-term exposure, exposure to stressful situations over a short time can reduce enkephalin levels. For example, the levels of methionine- and leucine-enkephalin decreased in the brains of mice after being immobilized or forced to swim for several minutes. Because stress can have severe negative effects on health, we recommend trying to lower enkephalins through other methods [70].

3) Long-Term Alcohol Consumption

Mice receiving small doses of alcohol over 7-56 days showed a decline in brain methionine-enkephalin levels. Due to the multiple harmful effects of alcohol consumption, we strongly advise against using it to lower enkephalin levels [71, 72].

Enkephalins and Genetics

People with three distinct mutations of the SCN9A gene (rs121908908, 1767X, and rs121908909) have higher levels of methionine-enkephalin in their sensory neurons. Yet, they also suffer from a rare genetic condition that makes them unable to feel physical pain (congenital insensitivity to pain) [73, 74].

In contrast, mice with a mutation in CPE, the gene that encodes the enzyme carboxypeptidase E, have lower levels of leucine-enkephalin in their brains due to the enzyme being inactive. These mice suffer from obesity and high blood levels of inactive insulin (hyperproinsulinemia) [75, 76].

About the Author

Carlos Tello

Carlos Tello

PhD (Molecular Biology)
Carlos received his PhD and MS from the Universidad de Sevilla.
Carlos spent 9 years in the laboratory investigating mineral transport in plants. He then started working as a freelancer, mainly in science writing, editing, and consulting. Carlos is passionate about learning the mechanisms behind biological processes and communicating science to both academic and non-academic audiences. He strongly believes that scientific literacy is crucial to maintain a healthy lifestyle and avoid falling for scams.

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