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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.
Enkephalins are compounds naturally produced within organisms [R].
Enkephalins are commonly found throughout the brain, in the spinal cord, and inside the adrenal glands [R].
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 [R, R, R, R].
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 [R].
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 [R].
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 [R].
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 the pancreatic cancer halted in two other patients [R].
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 [R].
2) High Enkephalin Levels May Reduce Inflammation
Enkephalins inhibit the release of cytokines that produce inflammation.
Furthermore, in mice, high enkephalin levels activated T cells, which then increased pain relief from inflammation [R].
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 [R].
In humans, high levels of methionine-enkephalin stimulate the release of TSH and may increase metabolism [R].
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.
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) [R].
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 [R].
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 [R].
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 [R].
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 [R].
High concentrations of methionine-enkephalin can suppress the activity of T cells in rats [R].
Injections of large doses of methionine-enkephalin also decreased the amounts of white blood cells in rats [R].
2) High Enkephalin Levels May Inhibit Insulin Release
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 [R, R, R].
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 [R].
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 [R].
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 [R].
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 [R].
In addition, the skin of 20 psoriasis patients had higher proenkephalin levels compared to the skin of 20 people without the disease [R].
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) [R, R, R].
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) [R].
In another study, low concentrations of methionine-enkephalin increased the activity of macrophages in humans [R].
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 [R, R, R].
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 [R].
3) Low Enkephalin Levels Induce Insulin Release
Likewise, low concentrations of leucine-enkephalin brought about the release of both insulin and glucagon from rat pancreatic tissue [R].
4) Low Levels of Enkephalins Protect Dopamine-Producing Nerve Cells
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 opioid growth factor. The growth of the tissues with this receptor can be inhibited by methionine-enkephalin [R].
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 [R].
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 [R].
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 [R].
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 [R].
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 [R].
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 [R].
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 [R].
However, in rats, short-term exercise increased levels of enkephalin and opioid receptor activity in the brains of rats more than long-term exercise [R].
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 [R].
A similar increase in methionine- and leucine-enkephalin during acupuncture has been observed in rat brains [R].
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 [R].
3) Ultraviolet Radiation Increases Enkephalin Concentrations
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 [R].
5) Enkephalin Levels Are Increased Through Enzyme Inhibition
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 [R].
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 [R, R].
Spinorphin and opiorphin are internal enkephalinase inhibitors. Spinorphin maintains the effects of leucine-enkephalin in mice [R].
Another use of enkephalinase inhibitors is to improve learning and memory formation.
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 [R].
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 [R].
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 [R].
2) Low-Copper Diets Decrease Enkephalin Levels
3) Long-Term Alcohol Consumption Lowers Enkephalin Levels
Drinking alcohol over a long period can also lower enkephalin levels.
Similarly, mice receiving small doses of alcohol over 7 days had a decline in met-enkephalin [R].
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) [R, R].
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) [R, R].
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