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Endomorphins
Endomorphins are endogeneous opioid neurotransmitters central to pain relief and intoxication pathways. The two known endomorphins, endomorphin-1 and endomorphin-2, are tetrapeptides, consisting of Tyr-Pro-Trp-Phe and Tyr-Pro-Phe-Phe sequences respectively. Both endomorphins maintain high specificity and affinity for the μ-opioid receptor. Endomorphin exists within the central and peripheral nervous systems, where endomorphin-1 is concentrated in the brain and upper brainstem, and endomorphin-2 is concentrated in the lower spinal cord and lower brainstem. As the major ligand of the μ-opioid receptor, which is the target receptor of morphine and its derivatives, endomorphins possess significant potential as analgesics with reduced side effects and risk of addiction.

Opioids and receptors
Endomorphins belong to the opiate class of neuropeptide neurotransmitters. Opiates are ligands that bind opium-binding receptors, and exist endogeneously, synthetically, and semisyntheticly. Endogenous opiates include endorphins, enkephalins, dynorphins, and endomorphins. Transcription and translation of opiate-encoding genes results in the formation of pre-propeptide opiate precursors, which are modified in the endoplasmic reticulum to become propeptide opiate precursors, transferred to the golgi apparatus, and further modified into the opiate product. The exact pre-propeptide precursors of endomorphins have not bee identified. Opioid receptors belong to the G protein-coupled receptor family and include μ, κ, δ, and nociceptinorphanin-FQ receptors. While activation of opiate receptors initiates a diverse array of responses, opiates usually serve as depressants, and are widely used and developed as analgesics. Additionally, opiate malfunction has been linked to schizophrenia and autism. Endomorphins demonstrate high selectivity and affinity for the μ-opioid receptor, which functions in pain relief and intoxication.

Structure
Both endomorphins-1 and 2 are tetrapeptides, meaning they both consist of four amino acids. Endomorphin-1 has the primary structure of Tyr-Pro-Trp-Phe, while Endomorphin-2 has the primary structure of Tyr-Pro-Phe-Phe. The endomorphins must not be confused with the peptides structures of enkephalins, endorphins, and dynorphins, which are comprised of the amino acid sequence, H-Tyr-Gly-Gly-Phe.

Function
Endomorphins are complex opioid neurotransmitters which have a variety of functions. Complex opioid systems control physiological processes which includes pain, reward, stress, immune responses, gastrointestinal, respiratory, cardiovascular and neuroendocrine systems. These processes are regulated by the binding of endogenous opioid endormophins to specific membrane bound opioid receptors. More specifically, there are two different types of endomorphins: endomorphin-1 and endomorphin-2. Both of these endomorphins are endogenous opioid peptides with a high affinity and high selectivity for the μ-opioid receptor.

Enzyme degradation
Most of the opioid peptides undergo enzymatic degradation. Degradation prohibits competitive inhibition of μ-opioid receptors. This reduces competition for the receptor binding sites, facilitating biological activity. Endomorphins are vulnerable to enzymatic cleavage which results in endomorphin degradation. The protein, DPP IV catalyzes endomorphin degradation.

Neurophysical role
There are multiple areas where μ-opioid receptors and endomorphins dictate biological processes. Such processes include pain, stress, and complex functions including autonomic, cognitive, neuroendocrine, and limbic homeostasis. Endomorphins control the nociceptive pathways. There is a transmission of nociceptive information that is a direct input from primary afferents neurons. Endomorphin-2 is more heavily involved in the early stages of nociceptive information processing, which serves a regulatory function that hyperpolarizes the membranes of the neurons on the dorsal horn and decreases the postsynaptic response. The development of tolerance limits the use of opioid as pharmacological agents. With the repeated endomorphin activity, tolerance develops. Not only will just the treatment of endomorphins increase tolerance, but even the pre-treatment will increase the development of tolerance. Eventually, tolerance leads to addiction. Locomotor activity with the administration of endomorphin-1 and endomorphin-2 were evaluated and corresponded with an increase in the horizontal and vertical activity known as hyperlocomotion. This is still a topic of debate.

Location
The location of endomorphin activity has been isolated using radioimmunoassay and immunocytochemistry within human, mice, rat, and monkey nervous systems. Both endomorphin tetrapeptides are co-localized in the central nervous system and can both 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 hindbrain, more endomorphin-1 reactive neurons have been detected compared to endomorphin-2. Alternately, endomorphin-2,, is predominantly found in the spinal cord. Specifically, endomorphin-2 is found in the dorsal horn region of the spinal cord, especially in the presynaptic terminals of afferent neurons leading to the spinal cord. It has been found co-localized with calcitonin as well as substance P. Neither endomorphin-1 or 2 were found in the amgydala or the hippocampus.

Clinical application
In addition to endomorphins, morphine and morphine-like opiates target the μ-opioid receptor. Thus, endomorphins pose significant potential as analgesics and morphine substitutes. In vitro assessment of endomorphins as analgesics reveals similar behavior to morphine and other opiates, where drug tolerance leads to dependence and addiction. Other side effects common to opiates such as vasodilation, respiratory depression, urinary retention, and gastrointestinal reaction develop. However, the endomorphin-induced side effects prove less severe than those of the morphine-derived analgesics commonly used today. Additionally, endomorphins produce more powerful analgesic effects than their morphine-derived counterparts. Mechanistically, endomorphins inhibit the release of substance P, the pain neurotransmitter, inhibit excitatory neurons, and increase the release of norepinephrine and serotonin. Despite its pharmaceutical aptitude, the low membrane permeability and vulnerability to enzymatic degradation of endomorphins limits their incorporation into drugs. Resultantly, endomorphin analogues 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 the endomorphin molecules, allowing them to pass membranes through glucose transporters. Lipidation adds lipoamino acids or fatty acids to the endomorphin molecules, increasing hydrophobicity and, thus, membrane permeability of the molecules.