And endorphins

Enkephalins and Endorphins. Morphine (142), an alkaloid found in opium, was first isolated in the early nineteenth century and widely used in patent medicines of that eta. It is pharmacologically potent and includes analgesic and mood altering effects. Endogenous opiates, the enkephalins, endorphins, and dynotphins were identified in the mid-1970s (3,51) (see Opioids, endogenous). Enkephalins and endorphins ate Hsted in Table 9. 

Haber, S. Hatsukami, T. Berger, P. Barchas, J.D. and Akil, H. Naloxone bloeks amphetamine-induced rearing Potential interaetion between eateeholamines and endorphins. Prog Neuropsychopharmacol 2 425-430, 1978. 

If opiates are such addictive and potentially lethal compounds, why does the body respond to them As with the cannabinoids (Chapter 7), it has been discovered that the body and brain possess numerous opiate-specific receptor sites. As many as nine receptor subtypes have been identified, with three of them being the most important p (mu), k (kappa) and 8 (delta). The finding that the distribution of opiate receptors did not parallel the distribution of any known neurotransmitter prompted the search for and identification of a number of endogenous compounds specific to these receptors. These enkephalins and endorphins are manufactured within the brain and other body systems (especially the gut and intestines) and form the body s natural response to pain. They appear to be produced in bulk chains of amino acids called polypeptides , with each active neurotransmitter being composed of around five amino acid molecules. These active neurotransmitters are subsequently cleaved from the larger polypeptides at times of demand for example, it has been demonstrated that the plasma levels of these active compounds rise during childbirth, traumatic incidents and vigorous physical exercise. 

Verapamil Verelan Calan, Isoptin Capsule 120, 180,240, 360 mg Film-coated tablet 40, 80, 120 mg Extended-release tablet 120, 180, 240 mg 80-480 mg/day combination with other drugs (e.g., carbamaze-pine, valproate, antipsy-chotics). L-type Ca+ channels Alters Ca+-Na+ (change Decreases 5-HT, DA, and endorphin activity... 

Calmodulin (CaM) undergoes drastic conformational change when it binds Ca2+ and amphiphilic peptides such as mas to po ran and endorphin, which results in the modulation of many important biochemical reactions. The N-terminal and C-terminal of rigid structured globular domains are bridged with a long flexible peptide of a-helical structure. Each domain binds two Ca2+ ions to its hydrophobic sites. 

Figure 1.2 Serotonin is one of the brain s neurotransmitters. This image depicts serotonin transmission between neurons and the drug Ecstasy s effects on that transmission. Serotonin is normally removed from the synapse shortly after being released. Ecstasy blocks this mechanism, increasing the amount of serotonin in the synapse. This causes the postsynaptic neuron to be overstimulated by serotonin. Serotonin is one of many neurotransmitters that nerve cells can secrete. Other common neurotransmitters include dopamine, glutamate, gamma aminobutyric acid (GABA), noradrenaline, and endorphins.

Hormones are intercellular messengers. They are typically (1) steroids (e.g., estrogens, androgens, and mineral corticoids, which control the level of water and salts excreted by the kidney), (2) polypeptides (e.g., insulin and endorphins), and (3) amino acid derivatives (e.g., epinephrine, or adrenaline, and norepinephrine, or noradrenaline). Hormones maintain homeostasis—the balance of biological activities in the body for example, insulin controls the blood glucose level, epinephrine and norepinephrine mediate the response to the external environment, and growth hormone promotes normal healthy growth and development. 

Basbaum AI, Fields HL. (1984). Endogenous pain control systems brainstem spinal pathways and endorphin circuitry. Anna Rev Neurosci. 7 309-38. 

Glucagon is a second pancreatic hormone that, like insulin, influences carbohydrate metabolism. However, most of its actions oppose those of insulin. The enkephalins and endorphins are the body s natural painkillers they are thought to be responsible for runner s high. These, among many others, are proteins or are closely related to them. 

In terms of chemical nature, some of these are steroids, e.g., estrogens and androgens some are poly peptides for example insulin and endorphins and some others are amino acid derivatives such as epinephrine and norepinephrine. 

A clue to possible treatments for pain was discovered in the 1970s when scientists found specialized receptor cells in neurons called opiate receptors. These receptors appeared to he well suited for accepting natural painkillers that occur in the body, such as the enkephalins and endorphins. Enkephalins and endorphins are naturally occurring painkillers similar in their action to opium, morphine, and codeine. 

The plant alkaloids mimic the endogenous peptides enkephalins and endorphins (Chapter 12), which meditate nociception and sleep. There are three types of widely distributed opiate receptors. Mu receptors are concentrated in neocortex, striatum, thalamus, hippocampus, amygdala and spinal cord, delta receptors in neocortex and amydala, and kappa receptors in striatum, amygdala and hypothalamus (Mansour et al., 1988). 

Calcium antagonists (e.g., verapamil, nimodipine) can also block dopamine, 5-HT, and endorphin activity, alter sodium activity via a sodium-calcium counter-exchange, and act as anticonvulsants. Any or all of these actions could be involved in their putative antimanic effects ( 35). 

The demonstration of the existence of strictly defined SARs. which is perhaps Ihe most important criterion of drug action at a specific receptor site, has made possible the most important pharmacologic discoveries. For example, the analgesic actions of morphine and related agents, which are indicative of specific receptors, led to die discovery of endogenous opiate peptides, i.e., the leucine and methionine enkephalins and endorphins. 

The opium alkaloids codeine and morphine served as models for the synthesis of naloxone, an important analog used to treat and diagnose opiate addicts, and also led to the discovery of endogenous opioids (enkephalins and endorphins) (see Chapter 47). Similarly, A9-tetrahydro-cannabinol (THC), the component of Cannabis sativa responsible for the central nervous system (CNS) effect, has also been found to reduce nausea associated with cancer chemotherapy (see Chapter 18). 

In the 1970s, researchers were able to discover exactly how morphine works in the brain. When stimulated by tiny electric currents, certain nerve tracts within the core of the brain can produce a painkiller strong enough to allow abdominal surgery in lab rodents. The painkiller consists of simple amino acids that, in their naturally folded state, mimic the structure of the morphine molecule. They were named enkephalins, for in the head, and endorphins, for the morphine within. ... 

Cho TM, Law PY, Loh HH. A proposed mode of action for narcotic agonists and antagonists. In Loh HH, Ross DH, eds. Neurochemical Mechanisms of Opiates and Endorphins. New York Raven Press, 1979 69-102. 

Opioid peptides have also been tested in animal models of depression and of antidepressant activity. Enkephalins and endorphins decreased immobility in the forced swim test and in the learned helplessness paradigm, demonstrating... 

SP, which can function as a neurotransmitter in various brain regions, suppresses the action of morphine and endorphins and is thought to play a protective role against stress-determined disturbances. 

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