Endomorphins are thought to be the natural opioid neurotransmitter central to pain relief .  Two known endomorphins, endomorphin-1 and endomorphin-2, are tetrapeptides , which contain the Tyr-Pro-Trap-Phe and Tyr-Pro-Phe-Phe amino acid sequences, respectively.  These sequences fold into tertiary structures with high specificity and affinity for the μ-opioid receptor, binding it specifically and strongly. Bound μ-opioid receptors usually produce inhibitory effects on neuronal activity.  Endomorphin-like immune activation centraland is present within the peripheral nervous system , where endomorphin-1 is concentrated in the brain and upper brainstem , and endomorphin-2 is concentrated in the spinal cord and lower brainstem.  Because endomorphins activate the μ-opioid receptor, which is the target receptor of morphine and its derivatives, endomorphins have significant potential as an analgesic with fewer side effects and risk of addiction .
opioids and receptors
Endomorphins belong to the opiate class of neuropeptides (protein neurotransmitters). Opiates are ligands that bind to opiate-binding receptors  and are present both endogenously and synthetically.  Endogenous opiates include endorphins , enkephalins , dynorphins , and endomorphins. 
Transcription and translation of opiate-encoding genes result in the formation of pre-propeptide opiate precursors, which are modified to become propeptide opiate precursors in the endoplasmic reticulum , migrate to the Golgi apparatus , and are further modified into the opiate product.  The exact pre-propeptide precursors of endomorphins have not been identified.  Because the precursors have never been identified and the mechanisms by which endomorphins are produced have never been elucidated, the status of endomorphin as an endogenous opioid ligand should be considered tentative.
Opioid receptors belong to the G protein-coupled receptor family and include the μ, , β, and nociceptorphanin-FQ receptors.  While activation of opiate receptors initiates a diverse array of responses, opiates commonly serve as depressants , and have been widely used and developed as analgesics . Additionally, opiate maltreatment has been linked to schizophrenia and autism .  Endomorphins exhibit high selectivity and affinity for the μ-opioid receptor, which functions in pain relief and intoxication.
Endomorphins-1 and 2 are both tetrapeptides, consisting of four amino acids. Endomorphin-1 has an amino acid sequence of Tyr-Pro-Trap-Phe, whereas Endomorphin-2 has the sequence of Tyr-Pro-Phe-Phe. Specific amino acids in these sequences dictate folding and the resulting behavior, namely the ability of these molecules to bind to μ-opioid receptors.
Endomorphins maintain a variety of functions. Mechanistically, they bind to inhibitory μ-opioid G-protein receptors, which act to close calcium ion channels and open potassium ion channels in the membranes of bound neurons.  Elimination of calcium influx and facilitation of potassium ion efflux inhibits neuronal depolarization, inhibits the generation of action potentials, and reduces the activity of excitatory neurons.  In other instances, endomorphin binding causes stimulation, where activation of phospholipase C and adenylyl cyclase initiates an increase in calcium ion concentration, cellular depolarization, and the release of norepinephrine and serotonin. 
The specific roles of endomorphins remain largely undetermined and depend on the pathway in question.  Opioid systems influence physiological processes of pain, reward, and stress. They also play a role in immune responses and functions of the gastrointestinal, respiratory, cardiovascular and neuroendocrine systems. 
The concentration and resulting effect of most neurotransmitters, including endomorphins, is determined by the rate of synthesis and degradation. Degradation involves the defective configuration or breakdown of functional molecules into parts, reducing the total activity of the molecule type. The enzyme, DPP IV, breaks down endomorphins into defective parts, thus controlling endomorphin activity.
The location of endomorphin activity within the human, rat, rat and monkey nervous system has been isolated using radioimmunoassay and immunocytochemistry.  Both endomorphin tetrapeptides can be found in certain areas of the brain. In the midbrain, endomorphin-1 can be found in the hypothalamus, thalamus, and striatum. Within the telencephalon, endomorphin-1 has been identified in the nucleus accumbens and lateral septum. In the anterior brain, more endomorphin-1 reactive neurons have been detected than endomorphin-2. Alternatively, endomorphin-2 is mainly found in the spinal cord, particularly in the presynaptic terminals of afferent neurons in the dorsal horn region. It has been found to co-localize with calcitonin as well as with the pain-relieving neurotransmitter, substance P. Neither endomorphin-1 or 2 has been identified in the amygdala or the hippocampus.
In addition to endomorphins, morphine and morphine-like opiates target the μ-opioid receptor. Thus, endomorphins hold significant potential as analgesics and morphine substitutes.  In vitro evaluation of endomorphine as an analgesic reveals behavior similar to that of morphine and other opiates, where drug tolerance leads to dependence and addiction. Other side effects that are common to opiates such as vasodilation, respiratory depression, urinary retention, and gastrointestinal reactions develop. However, endomorphine-induced side effects prove to be slightly less severe than those of the morphine-derived analgesics that are commonly used today. Additionally, endomorphins potentially produce more potent analgesic effects than their morphine-derived counterparts. 
Despite their pharmaceutical merit, low membrane permeability and vulnerability to enzymatic degradation of endomorphins limit their incorporation into drugs. Consequently, endomorphin analogs are being generated to allow transport across the blood-brain barrier, increase stability and reduce side effects.  Two endomorphin modifications that approach these problems include glycosylation and lipidation. Glycosylation adds carbohydrate groups to endomorphin molecules, allowing them to cross membranes via glucose transporters. Lipidation adds lipoamino acids or fatty acids to endomorphin molecules, increasing the hydrophobicity and therefore the membrane permeability of the molecules.
frequently Asked question For Endomorphin
What is an endomorphin?
There are two types of endomorphins: endomorphin-1 and endomorphin-2. Both are chemical substances found inside cells called neurons, which are the basic building blocks of the brain, nervous system, and spinal cord. Endomorphins affect many physical and mental functions, for example pain perception, stress response, and cardiovascular, respiratory, and digestive functions. These substances are endogenous, meaning that they are produced by the body itself, and they are also opioid peptides, which means that they work specifically to bind to other substances called opioid receptors that primarily work in the brain. , spinal cord, and are found in the digestive tract. Endomorphins are the subject of much research, and some scientists believe that they could be used to develop a variety of medicines, including new pain relievers,
There are many different endogenous opioid peptides, including endomorphins, endorphins, dynorphins, enkephalins, and beta-endorphins. In the body, different opioid peptides bind to different types of opioid receptors. There are three main types of opioid receptors called delta, kappa, and mu receptors. Endomorphins specifically bind to mu receptors. Opioid peptides were first discovered by scientists in the 1970s, although endomorphins were not isolated and identified until later in the brain of mammals.
Endomorphin-1 is found in many different regions of the brain, while endomorphin-2 is mainly found in the spinal cord, spleen, and lower brain. Both substances affect the central nervous system, which means the brain and spinal cord, and the peripheral nervous system, which means the nerves and nerve cells in the rest of the body. Scientific studies show that endomorphins are strongly linked to the body’s ability to feel pain. This is research focused on the development of a new type of analgesic, or pain reliever, based on endomorphine. Other research has focused on the effects of endomorphins on the immune system, as well as on cardiovascular and gastrointestinal functions.
Research has indicated that endomorphins may be useful in the development of new drugs. For example, endomorphin-2 has shown some promise as a potential treatment for Alzheimer’s disease, while some studies have indicated that endomorphin-1 may reduce the pain and inflammation of arthritis. However, there are many difficulties in developing drugs that use endomorphins, and all medical research using these substances is experimental and preliminary. Difficulties include that endomorphine can cause addiction and serious breathing problems. In addition, endomorphin-1 rapidly degrades into the bloodstream, decreasing its effectiveness as a medical treatment.