Morphine and enkephalins

Naloxone will block the effects of opiate drugs and is used to treat overdoses. It was found that during trauma the use of naloxone would increase pain and prevent naturally induced analgesia. It was only a matter of time until the endogenous opiates, the endorphins (for endogenous morphine) and enkephalins, were discovered. Now there exists a whole nomenclature of opiate receptor types and their various effects. 

More recently, we have been addressing a problem described previously concerning the relationship between morphine and enkephalin. The inherent mobility of the enkephalin framework, its rapid degradation in vivo/1341 and the existence of multiple receptor sub-types 135 136] have hampered the assessment of its bioactive conformations. Conformationally... 

Takagi H (1980) The nucleus reticularis paragigantocellularis as a site of analgaesic action of morphine and enkephalin. Trends Pharmacol Sci 1 182—184... 

Opiates iateract with three principal classes of opioid GPCRs )J.-selective for the endorphiQS,5-selective for enkephalins, and K-selective for dynorphias (51). AU. three receptors have been cloned. Each inhibits adenylate cyclase, can activate potassium channels, and inhibit A/-type calcium channels. The classical opiates, morphine and its antagonists naloxone (144) and naltrexone (145), have moderate selectivity for the. -receptor. Pharmacological evidence suggests that there are two subtypes of the. -receptor and three subtypes each of the 5- and K-receptor. An s-opiate receptor may also exist. 

Endorphins are found primarily in the limbic system, hypothalamus, and brainstem. Enkephalins and dynorphin (in smaller quantities) are found primarily in the periaqueductal gray matter (PAG) of the midbrain, the limbic system, and the hypothalamus. These endogenous substances mimic the effects of morphine and other opiate drugs at many points in the analgesic system, including in the dorsal horns of the spinal cord. 

Wybran, J. et al., Suggestive evidence for receptors for morphine and methionine enkephalin on normal human blood T-lymphocytes, J. Immunol., 123, 1068, 1979. 

Opiate drugs encompass morphine and its many synthetic derivatives including heroin. Opiates act by mimicking endogenously occurring morphine-like neurotransmitter peptides termed the enkephalins or endorphins. 

Hine B. (1985). Morphine and delta 9-tetrahydrocannabinol two-way cross tolerance for antinociceptive and heart-rate responses in the rat. Psychopharmacology (Berlin). 87(1) 34-38. HokfeItT, Elde R, Johansson 0, Terenuis L, Stein L. (1977). The distribution of enkephalin-immunoreactive cell bodies in the rat central nervous system. Neurosci Lett. 5 25. 

Introini I, McGaugh JL, Baratti C. 1985. Pharmacological evidence of a central effect of naltexone, morphine, and beta-endorphin and a peripheral effect of met- and leu-enkephalin on retention of an inhibitory response in mice. Behav Neural Biol 44(3) 434-446. 

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 three-dimensional disposition of the nitrogen function to the aromatic ring allows morphine and other analgesics to bind to a pain-reducing receptor in the brain. The terminal tyrosine residue in the natural agonists Met-enkephalin and Leu-enkephalin is mimicked by portions of the morphine structure. 

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 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.]... 

Sequence Determination of the Brain Peptide Leucine Enkephalin A group of peptides that influence nerve transmission in certain parts of the brain has been isolated from normal brain tissue. These peptides are known as opioids, because they bind to specific receptors that also bind opiate drugs, such as morphine and naloxone. Opioids thus mimic some of the properties of opiates. Some researchers consider these peptides to be the brain s own pain killers. Using the information below, determine the amino acid sequence of the opioid leucine enkephalin. Explain how your structure is consistent with each piece of information. 

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. 

Further radiolabeled ligand-binding assays have been reported for a wide variety of analytes, namely morphine and leu-enkephaline [30], (S )-propanolol [33], atra-zine [47], 17-jS-estradiol [59], 2,4-dichlorophenoxyacetic acid (2,4-D) [32], yohimbine and corynanthine [60], and corticosterone/cortisol [29]. Other assays are summarized in Table 3. 

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