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Enkephalins: Functions & Associated Diseases

Written by Helen Quach, BS (Biochemistry) | Last updated:

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Enkephalins are mainly involved in decreasing pain, reducing inflammation, preventing cancer cell growth, 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].

Enkephalins are compounds naturally produced within organisms [2].

Enkephalins are commonly found throughout the brain, in the spinal cord, and inside the adrenal glands [3].

In addition, multiple studies in animals and humans have shown that they are present in nerves outside of the brain, the small and large intestines, the kidneys, testes, the pancreas, heart muscle, skin tissue, lungs, joint tissue, and bone tissue [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 [8].

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 its 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) High Enkephalin Levels May Prevent Cancer Cell Growth

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

In a study (pilot trial) of 15 patients with advanced pancreatic cancer, methionine-enkephalin reduced tumor growth in one patient. Meanwhile, metastasis of pancreatic cancer halted in two other patients [11].

Additionally, an increase in methionine-enkephalin concentrations stunted the development of skin cancer (melanoma) cells in mice [12].

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 [13].

2) High Enkephalin Levels 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 [14].

Furthermore, in mice, high enkephalin levels activated T cells, which then increased pain relief from inflammation [15].

3) High Enkephalin Levels 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 [16].

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

4) High Enkephalin Levels 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 human athletes, after two hours of endurance running, the athletes 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) [17].

5) High Enkephalin Levels 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 [18].

6) High Enkephalin Levels May Help with Depression

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

Negative Effects of High Enkephalin Levels

1) High Enkephalin Levels Decrease Immune Cell Activity

Since several types of immune cells have receptors for enkephalins, their activity can be decreased by high concentrations of enkephalins.  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 [20].

Of the two, methionine-enkephalin was a more potent immunosuppressant in rats than leucine-enkephalin in high doses. However, in low doses, they are immunostimulants [20].

High concentrations of methionine-enkephalin can suppress the activity of T cells in rats [21].

On a similar note, high concentrations of methionine-enkephalin decreased the activity of macrophages (white blood cells) in humans [22].

Injections of large doses of methionine-enkephalin also decreased the amounts of white blood cells in rats [23].

2) High Enkephalin Levels May Inhibit Insulin Release

High concentrations of methionine-enkephalin suppressed the release of insulin from rat pancreatic tissue [24, 25].

3) High Enkephalin Levels 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 [26, 27, 28].

Diseases Linked to High Enkephalin Levels

1) High Enkephalin Levels May Worsen Alzheimer’s Disease Symptoms

Mice exhibiting symptoms of Alzheimer’s disease had high levels of methionine-enkephalin in nerve cells of the memory regions of the brain. These elevated methionine-enkephalin levels may contribute to the cognitive impairment and behavioral changes caused by Alzheimer’s in the mice [7].

2) Cancer Cells Secrete Enkephalins that Suppress the Immune System

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 [29].

3) High Enkephalin Levels May Play a Part in Diabetes

In a study of 37 people, 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 and in diabetic pregnant women [31].

4) High Enkephalin Levels May Be Linked to Psoriasis

Sections of skin taken from patients with psoriasis contain high levels of methionine- and leucine-enkephalin [32].

In addition, the skin of 20 psoriasis patients had higher proenkephalin levels compared to the skin of 20 people without the disease [33].

Health Benefits of Low Enkephalin Levels

1) Low Enkephalin Levels 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) [34, 35, 22].

Human bone marrow-derived dendritic cells (a type of immune cell) aged more quickly when exposed to low levels of methionine-enkephalin (over 7 days) [36].

Additionally, exposure to methionine-enkephalin caused these cells to release more cytokines (IL-12 and TNF-a), which intensify the immune response to disease-causing antigens [36].

In another study, low concentrations of methionine-enkephalin increased the activity of macrophages in humans [22].

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 human and mouse cells [37, 36].

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 [38].

Meanwhile, other studies on human, rat, and mouse immune cells showed that low concentrations of methionine-enkephalin caused NK cells to release IL-2.  This release recruited T cells to move toward the site of exposure [39, 40, 21].

2) Low Enkephalin Levels Impede 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 [41].

3) Low Enkephalin Levels Induce Insulin Release

Low concentrations of methionine-enkephalin elicited insulin release in isolated rat pancreatic tissue [24, 25].

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

4) Low Levels of Enkephalins Protect Dopamine-Producing Nerve Cells

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

Negative Effects of Low Enkephalin Levels

1) Low Enkephalin Levels Cause Excessive Cell Growth

In addition to binding to opioid receptors, methionine-enkephalin binds to and inhibits the opioid growth factor receptor (OGFR). Hence, methionine-enkephalin is also known as an opioid growth factor. The growth of the tissues with this receptor can be inhibited by methionine-enkephalin [44].

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 [R].

Plus, inhibition of the OGFR gene in human ovarian cancer cell lines stimulated cell division [R].

2) Enkephalin Deficiencies May Magnify Depression

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

3) Low Enkephalin Levels May Increase Sensitivity to 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].

Diseases Linked to Low Enkephalin Levels

1) Low Enkephalin Levels May Contribute to Arthritis

In one study, arthritic female rats contained less methionine-enkephalin in their ankle joints than female rats without arthritis. Due to this, low levels of methionine-enkephalin may contribute to arthritis [5].

2) Low Enkephalin Levels May Accelerate 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 human patients with early and advanced stages of Parkinson’s disease. Meanwhile, decreased leucine-enkephalin levels were found in the brains of 6 patients with advanced stages of Parkinson’s disease [47].

3) Low Enkephalin Levels May Have a Role in Huntington’s Disease

Decreased production of enkephalins was seen in the brains of mice that are genetically predisposed to Huntington’s disease. Thus, low enkephalin levels may be an early sign of nerve cell death from this disease [48].

4) Low Enkephalin Levels May Be Involved in IBD

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

Ways to Increase Enkephalin Levels

1) Exercise Increases Enkephalin Levels

In one study of 12 trained male athletes, the men had higher concentrations of methionine-enkephalin after increasingly intensive exercise on a treadmill. They had their highest concentrations of methionine-enkephalin after running a marathon [50].

However, in rats, short-term exercise increased levels of enkephalin and opioid receptor activity in the brains of rats more than long-term exercise [51].

2) Acupuncture Increases Enkephalins

Though considered an alternative medicine, acupuncture has been accepted as a treatment for chronic pain.

Acupuncture increases methionine-enkephalin and subsequently activates delta opioid receptors in their nerves. High-frequency acupuncture may alleviate the symptoms of opiate withdrawal by activating delta-receptors [52].

A similar increase in methionine and leucine-enkephalin during acupuncture has been observed in rat brains [53].

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 in people. Maximal pain relief was achieved in patients using a combination of frequencies of 2Hz and 100Hz [54].

3) Ultraviolet Radiation Increases Enkephalin Concentrations

Ultraviolet light, either artificial or from sunlight, increased methionine-enkephalin levels in the skin of humans [55].

4) Sexual Activity May Increase Enkephalin Levels

Another way to potentially increase enkephalin levels is through sex. Sexual activity increased levels of leucine- and methionine-enkephalin in the brains of male rats [56].

5) Enkephalin Levels Are Increased Through Enzyme Inhibition

Enkephalinases are enzymes that degrade and break down enkephalins. In animals and humans, inhibiting these enzymes can increase enkephalin levels [57, 58].

D-Phenylalanine prevents enkenphalinase activity. It inhibited enkephalin degradation in 30 chronic pain patients. It also increased the amount of Met-enkephalin released from mice brains [5960].

Several drugs are being developed to inhibit enkephalinases and maintain the antidepressant and pain-relieving effects of enkephalins.

RB-101 is a synthetic enkephalinase inhibitor that causes a buildup of both methionine and leucine-enkephalin in rats. However, since it can not be taken orally, it still has no medical use in humans [57].

RB-120 and RB-3007 are also synthetic enkephalinase inhibitors that are effective in rats. Unlike RB-101, these compounds can be taken orally. They are undergoing clinical trials as non-opioid pain relievers for humans [57, 61].

Spinorphin and opiorphin are internal enkephalinase inhibitors. Spinorphin maintains the effects of leucine-enkephalin in mice [62].

Meanwhile, human opiorphin can suppress pain in rats as effectively as morphine [63].

Another 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 in humans [64].

6) Long-Term Stress Produces a Spike in Enkephalin Levels

Exposure to stressful situations, such as being unable to move, over a long time can increase enkephalins.

Higher enkephalin levels were observed in the brains of a group of male rats after being immobilized for 7 and 21 days [65].

7) Low Dose Naltrexone

Low Dose Naltrexone inhibits opioid receptors, causing the body to increase production of endorphins and enkephalins to compensate for the blocked receptors. Additionally, the increased levels of opioids persist after the naltrexone has been eliminated from the body [66].

Ways to Decrease Enkephalin Levels

1) Short-Term Stress Can Reduce Enkephalin Levels

In contrast to long-term exposure, exposure to stressful situations over a short time can reduce enkephalin levels.

For example, levels of methionine- and leucine-enkephalin levels decreased in the brains of one group of mice after being made unable to move for several minutes. They also decreased in the brains of another group of mice after being forced to swim for several minutes [67].

2) Low-Copper Diets Decrease Enkephalin Levels

Eating foods low in copper can decrease enkephalin levels in humans. In one study, levels of methionine- and leucine-enkephalin decreased in 24 men who were on a low-copper diet for 11 weeks [68].

3) Long-Term Alcohol Consumption Lowers Enkephalin Levels

Drinking alcohol over a long period can also lower enkephalin levels.

In one study, mice had a decline in brain methionine-enkephalin levels after ingesting small doses of ethanol (alcohol) for 56 days [69].

Similarly, mice receiving small doses of alcohol over 7 days had a decline in met-enkephalin [70].

Enkephalins and Genetics

People with three distinct mutations in 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) [71, 72].

In contrast, mice with a mutation in CPE, the gene for the enzyme carboxypeptidase E, have lower levels of leucine-enkephalin in their brains due to the enzyme being inactive. However, they suffer from obesity and hyperproinsulinemia (high amounts of inactive insulin in the blood) [73, 74].

Enkephalin is a drug that affects your neurotransmitters. Want to understand your variants in these genes and how they affect your mood and tendency to respond to such drugs? Check out the mood DNA Wellness Report here.

About the Author

Helen Quach

BS (Biochemistry)

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