Enkephalin: Difference between revisions

== General function ==

'''Enkephalins''' were the first reported evidence of endogenous opioids in the brain, by John Hughes and Hans Kosterlitz in 1975 <ref>John Hughes, Terry Smith, Barry Morgan, Linda Fothergill, Purification and properties of enkephalin — The possible endogenous ligand for the morphine receptor, Life Sciences,

Volume 16, Issue 12,1975,Pages 1753-1758,ISSN 0024-3205,https://doi.org/10.1016/0024-3205(75)90268-4.</ref> <ref>Hans W. Kosterlitz, John Hughes,

Some thoughts on the significance of enkephalin, the endogenous ligand, Life Sciences, Volume 17, Issue 1, 1975, Pages 91-96, ISSN 0024-3205, https://doi.org/10.1016/0024-3205(75)90243-X.</ref>. They are pentapeptides that can be divided into two groups based on their carboxy-terminal amino acids: '''methionine-enkephalin''' and '''leucine-enkephalin'''.

Enkephalin is mainly distributed throughout the central, peripheral and autonomic nervous system in mammals <ref name="cullen"/>. However, opioid receptors are broadly distributed in the body, such as the cardiac and gastrointestinal systems.

== Structure ==

Met-enkephalin amino acid sequence is Tyr-Gly-Gly-Phe-Met, while leu-enkephalin amino acid sequence is Tyr-Gly-Gly-Phe-Leu. As we can see, <scene name='89/897677/Tyr1_and_phe4/1'>tyrosine and phenylalanine rings</scene> of leu-enkephalin are on opposite sides of the backbone and point in different directions. A similar conformation was found for met-enkephalin in Bic/PG <ref name="marcotte"/>.  

===Analgesia===

Enkephalins belong to one of the four major families of endogenous opioid ligands <ref name="corder">Corder, G., Castro, D. C., Bruchas, M. R., & Scherrer, G. (2018). Endogenous and Exogenous Opioids in Pain. Annual review of neuroscience, 41, 453–473. https://doi.org/10.1146/annurev-neuro-080317-061522</ref>. Opioid receptors couple to inhibitory G proteins and when they are activated Gα and Gβγ subunits dissociate and induce a signaling cascade that leads to a reduced neurotransmitter release <ref name="corder"/>. All four opioid receptors inhibit N-, P/Q- and L-type voltage-gated calcium channels <ref name="corder"/> <ref>Rusin, K. I., Giovannucci, D. R., Stuenkel, E. L., & Moises, H. C. (1997). Kappa-opioid receptor activation modulates Ca2+ currents and secretion in isolated neuroendocrine nerve terminals. The Journal of neuroscience : the official journal of the Society for Neuroscience, 17(17), 6565–6574. https://doi.org/10.1523/JNEUROSCI.17-17-06565.1997</ref> by the Gβγ subunit, which inhibits the entry of calcium to the pre-synaptic neuron, preventing the fusion of calcium-dependent synaptic vesicules with the membrane terminal and therefore blocking the neurotransmitter release. Transmission of pain signals is thus blocked. Enkephalins can be released from infiltrating immune cells at the site of injuries and from neurons in the central nervous system <ref name="corder"/>.

===Stress response regulation===

Several studies showed the importance of enkephalins in anxiety and stress. A polymorphism in the gene encoding neutral endopeptidase involved in enkephalin metabolism, was identified in patients with anxiety disorders <ref name="henry">Henry, M. S., Gendron, L., Tremblay, M. E., & Drolet, G. (2017). Enkephalins: Endogenous Analgesics with an Emerging Role in Stress Resilience. Neural plasticity, 2017, 1546125. https://doi.org/10.1155/2017/1546125</ref> <ref>Comings, D. E., Dietz, G., Gade-Andavolu, R., Blake, H., Muhleman, D., Huss, M., Saucier, G., & MacMurray, J. P. (2000). Association of the neutral endopeptidase (MME) gene with anxiety. Psychiatric genetics, 10(2), 91–94. https://doi.org/10.1097/00041444-200010020-00007</ref>. Moreover, an enkephalin KO mice model had increased anxiety with the elevated plus maze (EPM), open field (OF) and light-dark box (LDB) tests, as well as an exaggerated startle response (SR), which is an unconscious defensive response to unexpected or threatened stimuli, and a reduced duration in the social interaction test (SI) <ref name="henry"/> <ref>Ragnauth, A., Schuller, A., Morgan, M., Chan, J., Ogawa, S., Pintar, J., Bodnar, R. J., & Pfaff, D. W. (2001). Female preproenkephalin-knockout mice display altered emotional responses. Proceedings of the National Academy of Sciences of the United States of America, 98(4), 1958–1963. https://doi.org/10.1073/pnas.041598498</ref> <ref>Bilkei-Gorzo, A., Racz, I., Michel, K., Zimmer, A., Klingmüller, D., & Zimmer, A. (2004). Behavioral phenotype of pre-proenkephalin-deficient mice on diverse congenic backgrounds. Psychopharmacology, 176(3-4), 343–352. https://doi.org/10.1007/s00213-004-1904-9</ref> <ref>König, M., Zimmer, A. M., Steiner, H., Holmes, P. V., Crawley, J. N., Brownstein, M. J., & Zimmer, A. (1996). Pain responses, anxiety and aggression in mice deficient in pre-proenkephalin. Nature, 383(6600), 535–538. https://doi.org/10.1038/383535a0</ref>. This suggests that a reduced enkephalin neurotransmission relates with the expression of anxiety. However, in other studies it appears that enkephalins enhanced the reactivity to chronic stress, as enkephalin KO mice were resistant to anxiety and depression-like behaviors after a chronic mild unpredictable stress <ref name="henry"/> <ref>Melo, I., Drews, E., Zimmer, A., & Bilkei-Gorzo, A. (2014). Enkephalin knockout male mice are resistant to chronic mild stress. Genes, brain, and behavior, 13(6), 550–558. https://doi.org/10.1111/gbb.12139</ref>. It seems that enkephalins have different effects on anxiety and stress and this might depend on the central nervous system region. In response to stress, Corticotropin-Releasing Factor (CRF) is released and stimulates the production of endogenous opioids such as endorphins and enkephalins. Enkephalin has been found to modulate the release of CRF from the paraventricular nucleus of the hypothalamus <ref name="cullen"/>. More knowledge on enkephalin pathways and their role is needed in order to fully understand stress regulation and a variety of stress- and anxiety- related  disorders.

===Formation of social memory===

Enkephalin has a depressant or inhibitory function of neuronal communication, and it is produced by VIP neurons <ref>Blasco-Ibáñez JM, Martínez-Guijarro FJ, Freund TF. Enkephalin-containing interneurons are specialized to innervate other interneurons in the hippocampal CA1 region of the rat and guinea-pig. Eur J Neurosci. 1998;10:1784–95.</ref>, located in a small area of the hippocampus called CA2, which is known to be involved in the formation of social memory <ref>Oliva A, Fernández-Ruiz A, Leroy F, Siegelbaum SA. Hippocampal CA2 sharp-wave ripples reactivate and promote social memory. Nature. 2020;587:264–9.</ref>. In mice, it is observed that VIP neurons show greater activity during the encounter with an unknown individual than against another relative and also when faced with a new object <ref>Leroy, F., de Solis, C.A., Boyle, L.M. et al. Enkephalin release from VIP interneurons in the hippocampal CA2/3a region mediates heterosynaptic plasticity and social memory. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01124-y</ref>. With the release of enkephalin by VIP interneurons in CA2, a special type of plasticity is induced, called ITDP (Input-timing-dependent plasticity), which is essential for the formation of social memory <ref>Leroy F, Brann DH, Meira T, Siegelbaum SA. Input-timing-dependent Plasticity in the Hippocampal CA2 region and its potential role in social memory. Neuron. 2017;95:1089–102.e5.</ref>.

== Pathophysiology ==

== Clinical relevance ==

== References ==

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