Endorphin




INTRODUCTION

The perception of pain and pleasure is comprehended by the brain throughtransmission of impulses. Nerve impulses are relayed by chemical messengersknown as neurotransmitters. Neurons manufacture and subsequently releasean array of neurotransmitters upon the arrival of a stimulus. Transmittermolecules diffuse from the terminal end of one neuron and become associatedwith specific receptor sites on the receiving neuron, thereby relaying chemicalinformation. Endorphins are included in a new family of brain chemicalsthat relay information: the neuropeptides.

Neuropeptides are chains of amino acids ranging in length. Neuropeptidesare actually chemical messengers slightly different from neurotransmittersand should be termed neuromodulators (6). The term neuromodulatory is oftenused in reference to a peptide's action. A unique feature of the neuropeptidesin the brain is the global nature of some of their effects. Thus, they servea multitude of roles associated with particular functions, such as painor pleasure (5).

The pain-killing and pleasurable effects of morphine, the narcotic drugderived from the opium poppy, is widely known. Endorphins and enkephalins(a smaller amino acid¿e of the endorphin molecule) are chemicals thatbear a surprising similarity to morphine. It is interesting to note thatthe term "endorphin" is a contraction of "endogenous morphine"(that is, morphine formed within the body)(12). It was wondered why morphineand other opiate drugs should produce such powerful effects on the nervoussystem. Thus, the discovery of endorphins followed the realization thatcertain regions of the brain bound opiate drugs with high affinity.

The binding occurs at receptor sites known as opiate (opioid) receptors.The opiate receptors were detected by measuring the binding of radioactivelylabeled opiate compounds to membrane fragments of neurons. Three researchgroups, led by Solomon H. Synder and Candace B. Pert at Johns Hopkins UniversitySchool of Medicine, Eric J. Simon at the New York University School of Medicineand by Lars Terenius at the University of Uppsala, developed the receptor-labellingtechnique. They found that the opiate receptors were concentrated in thoseregions of the mammalian brain and spinal cord that are involved in theperception and integration of pain and emotional experience (7).

In 1975, John Hughes and Hans W. Kosterlitz of the University of Aberdeenisolated two naturally occurring peptides in the brain that bound tightlyto the opiate receptors and named them enkephalins. The endorphin moleculewas subsequently isolated from the pituitary gland (5). Isolation of endorphinand enkephalin substantiated that the opioid receptors normally binds thepeptide endorphin and only secondarily and coincidentally do they bind thenarcotic opiates. Other studies have suggested that several procedures thattreat chronic pain (acupuncture, direct electrical stimulation of the brainand even hypnosis) may act by inducing the release of enkephalins or endorphinsin the brain and spinal cord. This hypothesis is based on the finding thatthe effectiveness of treating pain implemented by these procedures is blockedby administration of naloxone, a drug that specifically blocks the bindingof morphine to the opiate receptor. Subsequent pages will discuss the structure,function, and regulation/control of endorphins.




STRUCTURE

Endorphin Structure

1. Discovery
2. 3 types of endorphins
3. Similarity to morphine
4. Production of endorphins

DISCOVERY

Endorphins are the body's own natural pain killers, or "feel-good"drugs. Ever since their discovery, it seems that endorphins may behave likeopiate drugs such as morphine and function as an internal mechanism forcontrolling pain sensations. Modern research hopes to develop a more naturalsubstitute for morphine that is not addictive. The natural functions ofendorphins have a wide range, covering everything from temperature to senseof well-being (13).


THREE TYPES OF ENDORPHINS

  • Enkephalins: Met- and Leu-
  • Endorphins
  • Dynorphins
Endorphins are neuropeptides that can range from 2 to 39 amino acids inlength. Neuropeptides are peptide molecules produced and released in thenervous system that act like transmitters (2). There are three differentneuropeptide sequences including enkephalins, endorphins, and dynorphins.Each arises from its own gene (13). Two different structures exist for enkephalins.Although both consist of 5 amino acids, they differ in their terminal aminoacid. One has methionine and the other has leucine. Endorphins are largerwith 30 or more amino acids. Dynorphins are similar in structure to leu-enkephalin,but is much more potent and mediates more sedative actions at the corticallevel.


SIMILARITY TO MORPHINE

The main purpose of endorphins is to depress activity in the cerebral cortexand thalamus. Endorphins have an amazing similarity to morphine (5). Thiswas discovered upon the realization that particular parts of the brain havea high affinity for opiate drugs li`ine. These receptors were concentratedin areas of the brain and spinal cord that are involved with the perceptionand integration of pain (5). It has been found that there is an antagonistto morphine called naloxone. This drug blocks the binding of morphine tothe opiate receptor. The structure of naloxone is such that it not onlyblocks stimulation- induced analgesia, but also blocks placebo analgesia(12). The similarity of morphine to endorphins is demonstrated by the factthat naloxone decreases the pain reducing effects (analgesia) of naturalendorphins as well as morphine (5). Naloxone and morphine are quite similarin structure as
they both contain a number of benzene rings within the compound.


PRODUCTION OF ENDORPHINS

  • POMC ---> ß-lipotropin ---> ß-endorphin & met-enkephalin
  • Pro-enkephalin ---> met-enkephalin & leu-enkephalin
  • Pro-dynorphan ---> dynorphan & leu-enkephalin
The naturally occurring endorphins are produced by pro-hormones. Beta-endorphinis made in the pituitary (11). Methionine and Leucine enkephalins are madein the chromaffin cells of the adrenal medulla (10). Pro-opiomelanocortin(POMC) is a precursor for beta lipotropin (6). The POMC gene is expressedin the pituitary and its products are released into the blood as a resultof stress. Beta-lipotropin contains beta-endorphin and met-enkephalin (14).The beta-lipotropin will undergo hydrolysis by a trypsin-like enzyme toyield beta endorphin (B-End) (263). Pro-enkephalin will yield the two typesof enkephalin molecules. Specifically, it will release 4 copies of the Met-enkephalinand one copy of the Leu-enkephalin. Pro-dynorphin results in the releaseof three copies of leu-enkephalin and a series of dynorphins. Dynorphinis an opioid tridecapeptide with an NH2 terminus resembling leu enkephalin.It is found in the pituitary, hypothalamus, and spinal cord (10).
The endorphins serve a very useful purpose in the body. They act in serioussituations when you must act quickly to situations such as child birth.Their broad range of actions makes them an invaluable part of the humanbody.




FUNCTION

Function:

1.Role in Evolution
2.Modulation of Pain: Pain Pathway
3.Endorphins and Hormones
4.Endorphins and Stress
5.Endorphins and Live Birth
6.Endorphins and Behavior
7.Endorphins and Emotions
8 Endorphins and Runner's High
9.Endorphins and Schizophrenia


ROLE IN EVOLUTION

It has been argued that endorphins have provided the foundation for changein brain structure. The change has occurred throughout the brain's longevolutionary journey and has provided changes of behavior that modulatespain reception and emotion so that organisms can respond in an adaptiveway to eliminate or cope with the causes of pain. These feelings have madepossible our gradual mastery of the environment (7).

The feeling of analgesia has proved to be extremely advantageous towardsurvival. Endorphins ensure that survival comes first, and recuperationcomes later (7). Pain would ordinarily produce behaviors that would hurtyour chances of survival. For instance, if an animal is attacked and stopsto lick its wounds instead of fleeing away from its attacker, the animal'slife is put in danger. But, the emotion of fear triggers an endorphin systemthat inhibits the processing of pain. Therefore, it is an evolutionary advantagefor species who have developed a degree of pain control in times of stress.A phylogenetic study has shown that endorphins exist in the brain in allvertebrates from hagfish to humans (14). Humans can view themselves as partof a biological heritage. This heritage produced an endorphin system forthe control of pain also known as analgesia. (7).


MODULATION OF PAIN: THE PAIN PATHWAY

The main function of endorphins is the control of pain. The arrival of apain stimulus comes from pain receptors in the skin. The pain receptorsin the skin generate nerve impulses that travel a pathway up the spinalcord to the thalamus and then to the sensory and motor cortices (4). Thepain receptor's impulses signal the body of pain by releasing excitatoryneurons containing a transmitter called substance P. Substance P is a neuropeptidefound in neurons on each side of the dorsal horns of the spinal cord andfunctions as a transmitter of pain. Substance P provokes other neurons inthe spinal cord to fire. These transmitter neurons, containing substanceP, diffuse across the fluid-filled cleft between neurons and bind to specificreceptor sites on the postsynaptic membrane of the dorsal horns on eitherside of the spinal cord. The neurons sensitive to substance P then proceedto send the pain message to the brain .

The dorsal horns also house endorphin-containing neurons. The endorphin-containingneurons release enkephalin. Enkephalin is the smaller five amino acid chainof the endorphin family. Enkephalins released from the endorphin-containingneurons inhibit the release of substance P by synapsing between the terminalend of one neuron and the receiving surface of another pain transmittingneuron. This causes the receiving neuron in the spinal cord to receive lessexcitatory stimulation and hence sends fewer pain-related impulses to thebrain (5).


ENDORPHINS AND HORMONES

Effects of narcotic analgesics on pituitary hormone release are observedwith the endorphins. Endorphins can be injected either intraventricularlyor parenterally . Like morphine, they stimulate the release of growth hormone,prolactin, ACTH, and anti diuretic hormone and inhibit the release of luteinizinghormone, follicle stimulating hormone, and thyrotropin. All of these effectsare reversible by naloxone. The mechanism of opioid effects on pituitaryhormone secretion is not understood. However, the evidence points to anaction at the level of the hypothalamus, rather than effects directly onthe pituitary gland (14). The hypothalamus is important in mediating someof the output of the limbic system as well as it being essential to thenormal functioning of the pituitary gland, which lies directly beneath itand whose importance lies in the fact that many hormones are stored andreleased here. The hypothalamus also has a role in the control of feeding,drinking and the expression of emotional behavior (1).


STRESS AND ENDORPHINS:

There is a behavioral linkage between stress and endorphin release. Betaendorphin and adrenocorticotropin, the classic stress hormones were foundto originate from the same precursor molecule that has been located in arange of places in the body such as the hypothalamus and other areas ofthe brain, as well as several peripheral tissues including the placentaand gastrointestinal tract. The pro-opiomelanocortin gene is expressed inthe pituitary, and its peptide products are released into the blood streamin response to stress (7).


ENDORPHINS AND LIVE BIRTH

Endorphins counter stress of live birth with their analgesic powers. Duringthe gestation period, the placenta provides necessary nourishment for thedevelopment of the fetus. The placenta also contains the crucial precursormolecule pro-opiomelanocortin from which beta endorphin, met-enkephalinand adrenocorticotropin are all derived (11). In the human placenta, beta-endorphinand met-enkephalin are present in the placental tissue and placental bloodat higher levels than usual during pregnancy and labor.


ENDORPHINS AND BEHAVIOR

The limbic system contains prominent structures that include the amygdala,septum pellucidum, hippocampus and cingulate cortex (7). All of these structuresact with the hypothalamus as the integrator of emotional responses. Thelimbic system contains some of the highest concentrations of opiate receptorsand endorphins in the brain. The evidence for linkage between brain endorphinsand the concept of social behavior began to emerge in 1978 from experimentsthat administered morphine to young puppies and guinea pigs. They becameless inclined to cry when they were separated from their mothers. The symptomsof separation distress were reduced. The antagonist naloxone, on the otherhand increased the incidence of separation cries. This implicated the roleof endorphins in this critical behavior of social bonding.


ENDORPHINS AND EMOTIONS

Neuroscientists have agreed that emotions are mediated by the limbic systemof the brain. The amygdala and the hypothalamus are both classically consideredthe main components of the limbic system. Experiments were performed showingthe connection between emotions and the limbic system. Neurologists foundthat when they used electrodes to stimulate the cortex over the amygdalathey could evoke a whole array of emotional displays--- powerful reactionsof grief, pain, pleasure associated with profound memories and also thetotal somatic accompaniment of emotional states. A map locating the opiatereceptors in the brain, by a method involving radioactive molecules, foundthat the limbic system was highly enriched with opiate receptors, forty-foldhigher than in other areas in the brain. These hot spots correspond to veryspecific nuclei or cellular groups that physiological psychologists haveidentified as mediating such processes as sexual behavior, appetite, andwater balance in the body (8).



ENDORPHINS AND RUNNER'S HIGH

Euphoria and exhilaration are reported by many runners while in the courseof their run (7). It has been tempting to relate these feelings ("therunners high") to an increase in brain endorphins. There is circumstantialevidence that a connection might exist. It has been found that physicallyuntrained volunteers going through a two-month exercise program producedsignificantly higher levels of adrenocorticotropin and beta-endorphin intheir blood system. In another study, for trained runners, beta-endorphinlevels in blood plasma increased after an eight-mile race to levels threeand a half times higher than levels taken immediately beforehand. It ispossible however, that the endorphin increases could have been secondaryto the adrenocorticotropin increases and that we might be seeing a generalresponse to the stress of physical exertion (7).


SCHIZOPHRENIA AND ENDORPHINS

Schizophrenia is a mental disorder consisting of agitation, disorientation,delusions and frequent hallucinations. Possible connections between schizophreniaand endorphins have been drawn by several experimental observations. Ithas been suggested that levels of endorphins are related to schizophrenia.This suggestion is based on the appearance of a catatonic-like state ininjected animals. Other studies showed a high endorphin level in the cerebrospinalfluid of schizophrenics (7).




REGULATION & CONTROL

Regulation/Control of Endorphins
1. Overview of Function
2. Control of endorphin function by receptors
A. Receptors
i. Definition and role in function
ii. Receptor types and distribution
iii. Properties of Receptors
3. Receptors in relation to pharmaceuticals
A. Goal of pharmaceutical industry
B. Mu receptor subtypes
4.Regulation of endorphins by enzymes
A. Enzymatic degradation
i. Specific enzymes involved

OVERVIEW OF FUNCTION


Neurons containing endorphins show high concentration levels in regionsof the brain and spinal cord involved in the perception and integrationof pain and emotional experience. The neurons release endorphins upon astimulus. The existence of opioid receptors sites on nearby neurons enableendorphins to fulfill their function in relatively low concentrations (6).The endorphin molecule is released from the axon terminal and travels rapidlyacross the fluid filled space to the membrane of the receiving neuron. Therethe endorphin interacts with specific receptor sites on the synaptic regionsof the neuron. The endorphin molecule binds to a receptor site on an adjacentneuron causing inhibition. For example, the release of enkephalins is followedby binding to the receptor site of a neuron containing substance P (a transmitterof pain). Binding causes the neuron to reduce the release of substance P.This inhibitory effect disrupts the pain pathway and less pain is felt asa result.


CONTROL OF ENDORPHIN FUNCTION BY RECEPTORS


---Definition of receptor and role in function
Receptors enable endorphins to perform their specific function.Opioid receptors are large protein molecules embedded in the semi-fluidmatrix of the cell membrane of the receiving neuron. The surface of thereceptor protein contains a region that is the precise size and shape tomatch the structure of the endorphin molecule. The endorphin molecule preciselyfits into the specific receptor site. The binding of the neuropeptide withits specific receptor (opioid receptor) alters the three-dimensional shapeof the receptor protein, thereby causing a neuron to be excited or inhibited(10). As in the case of endorphins, inhibition of the neuron will reducethe release of substance P. In other words, the opioid receptor translatesthe precise messages encoded by the molecular structure of the endorphinmolecule into a specific physiological response. Thus, receptors act asa control mechanism thereby regulating the function of endorphins.

--Receptor types and distribution
  • µ receptor
  • n receptor
  • / receptor
The three main types of opioid receptors are µ (mu), n(delta),and /(kappa). The receptors are defined by the types of opiate and opioidpeptide molecules that bind to them. Different classes of opioid receptorsmediate different actions depending upon their location and type of endorphinbound to it. In other words, receptors located in different regions of thebrain help regulate function by controlling the binding of specific molecules.

The µ receptor preferentially binds enkephalins. It also binds morphineand its antagonist naloxone. Naxolone and its derivatives are the only knownmolecules that block the receptor; thus they are defined as antagonist.When the naloxone drug occupies the receptor, neither the opiates nor theenkephalins can bind to the receptor. The µ receptor is localized primarilyin the pain pathways in the brain.

The n receptor also displays a high affinity for enkephalins. This receptoris localized in limbic parts of the brain and may be related to influenceson emotions.
The / receptor preferentially binds dynorphins. This receptor is believedto mediate more sedative actions at the cortical level(13).

--Properties of receptors
  • stereospecificity
  • temperature and pH
  • conformational changes
The following properties demonstrate the specific nature ofreceptors. Binding of an endorphin molecule will occur only under certainphysiological conditions. Controlling the factors involved for binding,regulates the activity of the endorphin.

Receptors are very stereospecific, enabling only certain isomers of moleculesto bind. The opioid peptide must reside in its D and not L configurationin order for binding to occur. The D configuration has a higher affinityof binding to the opiate receptor(1).

Specific binding has also been shown to be temperature and pH dependent.Maximum binding occurs at 37° Celsius. There is an optimum pH of 7.4for specific binding. Binding does not occur below pH 5 or above pH 10.There is an obvious correlation of the binding constraints in relation tothe atmosphere of the body(3).

The opiate receptor can exist in two conformational states by the presenceof sodium ions. When sodium binds to the receptor it acts as allostericeffector which produces a conformational change in the receptor. Alterationof the shape decreases the ability to bind antagonists (naloxone)but increasesthe ability to bind antagonist (enkephalin and morphine)(14).


PHARMACEUTICAL IMPLICATIONS OF RECEPTORS


--Goal of the pharmaceutical industry
Morphine has been used for centuries to relieve pain; opiatesare still considered the most effective drug. Opiates mimic the actionsof endorphins by binding to opioid receptors. The major problem with theuse of morphine is the adverse side effects: respiratory depression, constipation,and dependence. Studies have shown that the receptors responsible for manyopiate side effects differ from the receptors responsible for controllingpain.

The receptor implicated in this finding is the µ receptor with subtypesµ1 and µ2. Identification of two subtype receptors of the µreceptor family has major implications in understanding opiate action. Thepharmaceutical industry's aim is to produce a highly specific opiate drugthat will bind only to the µ receptor subtype that is responsible foranalgesia.
µ receptor subtypes

Morphine binds to µ2 and µ1 receptor while enkephalin preferentiallybind to µ1 and n receptors. The µ1 receptor produces pain-killingeffects with no adverse side effects. Furthermore, the µ1 receptordoes not appear to mediate most of the signs of morphine withdrawal. Theµ2 receptor has been implicated in causing respiratory depression andconstipation (9). The discover of the µ subtypes provides a continuedunderstanding of the action of opiates in the body and the role of multiplereceptors. The ability to produce highly selective opiate drugs that onlybind to the µ1 receptor is within site.


REGULATION OF ENDORPHINS BY ENZYMES


--Degradation of opioid peptide
Once the endorphin molecule has served its function which wasmediated by receptors, the endorphins are rapidly inactivated, experiencinga relatively short life. Enzymatic degradation of endorphin molecules appearsto be the principle mechanism for inactivation of neuropeptides. The classof enzymes that break down endorphins are peptidases.

--Specific enzymes involved in degradation
  • endopeptidase-24.11 known also as enkephalinase A
  • aminopeptidase
  • angiotensin converting enzyme (ACE)
The three specific enzymes involved in degradation are, endopeptidase-24.11known also as enkephalinase A, aminopeptidase, and angiotensin convertingenzyme (ACE). Endopeptidase 24.11 and aminopeptidase are important in enkephalinmetabolism in the central nervous system while ACE serves its function inthe cerebrospinal fluid (16). Hydrolysis occurs by cleaving amino acidsfrom the free C-terminus. The enzymes cleave both [Leu]-and [Met] enkephalinwhich is a pentapeptide to a tri-and dipeptide making the enkephalin moleculesinactive. Enkephalin metabolism revealed that the Gly3-Phe4 bond of enkephalinsis a major site of hydrolysis (3). The enzyme uses an ionic interactionof an arginyl residue in the active site with the C-terminal carboxylateof enkephalins. The substrate enkephalin fits into the active site in thismanner and the amino acids are cleaved (10). Endopeptidase-24.11 is moreefficient in rapidly breaking down enkephalins.


MORPHINE AND ENDORPHINS

After studying the structure of endorphins, morphine seemsto be the most easily linked structure to them. Both function in the lesseningof pain (analgesia) although endorphins are naturally occurring and morphineis a drug.

It is interesting to make the comparison between these two compounds. Endorphinsserve to suppress pain, as for example in the immune response. Morphinecan also affect the immune system a great deal. It has been shown that peoplewho frequently ingest morphine (cancer patients or even opiate addicts)have altered immune responses (1). These consist of the following: depressedphagocytic capability and depression of respiratory burst activity by thesecells (1). Respiratory burst activity involves the metabolization of oxygento yield some toxic intermediates, with which to fight infection (1). Morphinecan also inhibit the uptake of immunoglobulin G (IgG) complexes which areessential in the immune response (1).

It is known that the drug Naloxone can inhibit the effects of morphine.This is true for endorphins as well. Naloxone was shown to inhibit the uptakeof IgG in experiments done by Singhal et al. thus inhibiting immune response.

In a study of the analgesic effects of morphine after surgery, it was concludedthat there can be specific local opioid receptors to help handle pain bybinding morphine in a particular area (2). This is similar to the endorphinsthat also have very specific opiate receptor binding sites.



LITERATURE CITED

1 Singhal, Pravin C. Et al "Effect of Morphine on Uptake of immunoglobulinG complexes by mesangial cells and macrophages." American PhysiologicalSociety. 17 Mar 1992: F859 F866.

2 Stein, Christoph et al. "Analgesic Effect of Intraarticular Morphineafter Arthroscopic Knee Surgery." New England Journal of Medicine.17 Oct 1991: 1123-1126.


MORPHINE AND ENDORPHINS

After studying the structure of endorphins, morphine seemsto be the most easily linked structure to them. Both function in the lesseningof pain (analgesia) although endorphins are naturally occurring and morphineis a drug.

It is interesting to make the comparison between these two compounds. Endorphinsserve to suppress pain, as for example in the immune response. Morphinecan also affect the immune system a great deal. It has been shown that peoplewho frequently ingest morphine (cancer patients or even opiate addicts)have altered immune responses (1). These consist of the following: depressedphagocytic capability and depression of respiratory burst activity by thesecells (1). Respiratory burst activity involves the metabolization of oxygento yield some toxic intermediates, with which to fight infection (1). Morphinecan also inhibit the uptake of immunoglobulin G (IgG) complexes which areessential in the immune response (1).

It is known that the drug Naloxone can inhibit the effects of morphine.This is true for endorphins as well. Naloxone was shown to inhibit the uptakeof IgG in experiments done by Singhal et al. thus inhibiting immune response.

In a study of the analgesic effects of morphine after surgery, it was concludedthat there can be specific local opioid receptors to help handle pain bybinding morphine in a particular area (2). This is similar to the endorphinsthat also have very specific opiate receptor binding sites.



LITERATURE CITED

1 Singhal, Pravin C. Et al "Effect of Morphine on Uptake of immunoglobulinG complexes by mesangial cells and macrophages." American PhysiologicalSociety. 17 Mar 1992: F859 F866.

2 Stein, Christoph et al. "Analgesic Effect of Intraarticular Morphineafter Arthroscopic Knee Surgery." New England Journal of Medicine.17 Oct 1991: 1123-1126.


PEPTIDASE AND ENDORPHINS

The time course and extent of neuropeptide actionis determined, in part, by the mechanisms involved in the reduction of theneuropeptide concentration around the receptor. Enzymatic degradation isthe principle mechanism for inactivation of neuropeptides.

Peptidases catalyze the hydrolysis of peptide bonds in endorphins (6).
In general, proteolytic enzymes are described as either exopeptidases orendopeptidases. The exopeptidases hydrolyze peptides from either their C-orN-terminal regions by removal of single amino acids (or dipeptides). Theendopeptidase acts in the interior of the peptide chain by cleaving internalbonds to convert the neuropeptide into a biologically inactive peptide.Endopeptidases often show specificity with regard to the nature of the peptidebond but are rarely specific to only one type of substrate. A probable reasonfor this is that the specificity of cleavage is determined by the three-dimensionalstructure (conformation) of the peptide substrate and the peptidase (6).Thesubstrate region containing the susceptible peptide bond must match theactive site of the enzyme for hydrolysis to occur. Thus, peptidases maydegrade diverse substrates with homologous conformations. This is very similarto how receptors will bind different substances with common conformationssuch as morphine and enkephalin(14).

Examples of exopeptidases that degrade endorphins are carboxidipeptidasesknown as endopeptidase-24.11 also termed enkephalinase A. Endopeptidase-24.11functions as an exopeptidase in its action, but it is considered an endopeptidasebecause it hydrolyses some C terminally extended enkephalins efficiently.The enzyme uses an ionic interaction of an arginyl residue in the activesite with the C-terminal carboxylate of enkephalins. The substrate enkephalinfits into the active site in this manner and the amino acids are cleaved.Endopeptidase-24.11 is most efficient in rapidly breaking down enkephalins(3,16).


LITERATURE CITED

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