And enkephalins

Three endogenous opioids have been identified enkephalins, dynorphins and beta-endorphins. These opioid peptides selectively bind to the seven transmembrane GPCRs delta (8), kappa (k), and mu (p). Although dynorphin binds predominately to the k receptor, P-endorphines and enkephalins bind to p and 8 opioid receptors. It is important to note that the analgesia induced by opioids is mediated predominately throngh the p opioid receptor. In vitro studies have shown a decrease in the immnne function and proliferation following p-endorphin administration in rodents (Ray and Cohn 1999) and that the immunosuppressive effects by P-endorphins are steroid-independent (Berkenbosch et al. 1984 Nelson et al. 2000). 

Two different peptides (TRH and enkephalin, substance P and CCK) coming from different precursors. These combinations are intriguing in that TRH is excitatory yet enkephalins are inhibitory — complex postsynaptic effects can be envisaged. Substance P is excitatory and CCK acts on two receptors, A and B, with the former being the predominant CNS form. 

Lamina II is also known as the substantia gelatinosa (SG) and can be divided into two layers, the outer layer (IIo) and the inner layer (Ili). This layer is densely packed with small neurons and lacks myelinated axons. Neurons with cell bodies in Hi receive inputs from low-threshold mechanoreceptive primary afferents, while those in IIo respond to inputs from high-threshold and thermoreceptive afferents. The intrinsic cells which comprise the SG are predominantly stalk and islet cells. Stalk cells are found located in lamina IIo, particularly on the border of lamina I, and most of their axons have ramifications in lamina I although some also project to deeper layers. These cells are thought to predominantly relay excitatory transmission. Islet cells, on the other hand, are located in Hi and have been demonstrated to contain the inhibitory neurotransmitters, y-aminobutyric acid (GABA), glycine and enkephalins in their dendrites. Hence these cells have been proposed to be inhibitory interneurons. 

McLawhon, R.W. West, R.E., Jr. Miller, R.J. and Dawson, G. Distinct high-aff1nity binding sites for benzomorphan drugs and enkephalin in a neuroblastoma-brain hybrid cell line. Proc Natl MM USA, 78 4309-4313, 1981. 

Arvidsson U, Dado R, Riedl M. Lee J, Law P, Loh HH, Elde R, Wessendorf W. Delta-opioid receptor immunoreactiv-ity distribution in brainstem and spinal cord, and relationship to biogenic amines and enkephalin. J Neurosci 1995 15 1215-1235. 

There are several biologically important peptides which contain tyrosine but not tryptophan. These include small molecules with molecular weights of about 1000 or less. Molecules such as oxytocin, vasopressin, and tyrocidine A are cyclic, while others such as angiotensin II and enkephalin are linear. Schiller 19) has reviewed the literature up through 1984 on fluorescence of these and several other peptides. One major finding that has been reported recently is that the anisotropy and fluorescence intensity decays of many peptides are complex. This is especially evident in some of the tyrosine-containing peptides, and we expect that there will be considerable effort made over the next few years toward understanding the physical basis for these complex kinetics. 

Endorphins, dynorphins, and enkephalins are a particularly interesting group of neuropeptides. They act as endogenous opiates by producing analgetic, sedative, and euphoriant effects in extreme situations. Drugs such as morphine and heroin activate the receptors for these peptides (see p. 354). 

The 1960 s and 1970 s saw several other hypotheses proposed and dis-proven. The monoamine oxidase (MAO) deficiency hypothesis was based on the observation of diminished activity of platelet MAO-B in schizophrenia, although this was likely to be an artifact of drug treatment and the small deficits could not, in any case, account for changes in monoamine transmitters. Other hypotheses relating to, among other transmitter molecules, noradrenaline and enkephalin/endorphin have also been proposed. Each of these have had propo-... 

The chemical transmitters may be small molecules— notably acetylcholine, norepinephrine, epinephrine, serotonin, dopamine, or histamine. Acetylcholine and norpeinephrine are the dominant neurotransmitters in the parasympathetic and sympathetic nervous systems, respectively. Dopamine and serotonin are employed primarily in the central nervous system. Neurotransmitters may also be more complex peptides (small proteins) such as substance P, vasopressin, endorphins, and enkephalins. The latter agents are of particular importance to our considerations of opium since they represent the endogenous opiates—agents that exist within the body whose actions are mimicked by exogenous, or outside, agents such as morphine, heroin, codeine, and so on. These neurotransmitters serve to convey information between neurons across the synaptic cleft (the junction where two neurons meet) or at the neuroeffector junction (the site between neuron and an innervated organ such as muscle or secretory gland). 

Opioid refers to any compound that acts like morphine, the most abundant alkaloid compound in opium. The term opioid includes substances that are derived from plants (such as morphine and codeine), those that occur naturally in the body (such as endorphins and enkephalins), and synthesized compounds (such as heroin and fentanyl). [Endorphins and enkephalins are discussed in Chapters 2 and 3. Fen-tanyi is discussed in Chapter 3.]... 

Codeine also activates pain-control circuits that descend from the section of the brain called the midbrain to the spinal cord, causing the release of naturally produced opioids called endorphins and enkephalins. The endorphins and enkaphalins bind to and activate receptors on cells in the spinal cord that prevent the transmission of pain signals. As discussed in Chapter 3, endorphins and enkephalins are your body s natural chemicals that allow you to feel no pain. ... 

So, there s actually a biological basis to the euphoric sensation associated with high-level physical activity, such as the runner s high described by long-distance runners and exercise gurus The euphoria is caused by the body s release of endorphins and enkephalins produced by prolonged exercise or stress on the body. 

Endorphins, dynorphins, and enkephalins are natural peptide neurotransmitters that activate the opioid... 

To achieve a reasonable degree of absorption, peptide and protein pharmaceuticals may need permeation enhancers to promote passage across mucosal cells. Another concern is that studies of insulin and enkephalin in animals suggest that protease activity may be high, especially in the rectal cavity [5,6]. On the other hand, the density of lymphatic vessels and drainage therein at these sites may be advantageous compared with other routes of administration. 

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