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,

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"/>.

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===

== Clinical relevance ==

Activation of δ opioid receptors acts against oxidative stress in the central nervous system and promotes neuron survival. Enkephalin is able to cross the blood-brain barrier; it has been hypothesized to be a promising strategy to promote '''neuron regeneration''', especially in brain damage caused by stroke <ref>Liu, Y., Fu, N., Su, J., Wang, X., & Li, X. (2019). Rapid Enkephalin Delivery Using Exosomes to Promote Neurons Recovery in Ischemic Stroke by Inhibiting Neuronal p53/Caspase-3. BioMed research international, 2019, 4273290. https://doi.org/10.1155/2019/4273290</ref>. Multifunctional fluorinated enkephalin analog, LYS739 can be considered as a potential lead for ischemic stroke research and may provide advantages given the multimeric peptide-opiate structure<ref>Rashedul Islam, M., Yang, L., Sun Lee, Y., J Hruby, V., T Karamyan, V., & J Abbruscato, T. (2016). Enkephalin-fentanyl multifunctional opioids as potential neuroprotectants for '''ischemic stroke treatment'''. Current pharmaceutical design, 22(42), 6459-6468.</ref>.

The main and most known effect of enkephalins is '''analgesia''', which makes the therapeutic use of enkephalins to treat pain one their main clinical relevant aspect. However, enkephalins have a relatively low stability ''in-vivo'', due to their degradation by endogenous peptidases <ref name="cullen"/>. Two approaches have been proposed to this issue: the first one is the '''chemical modification''' of enkephalins while preserving their analgesic efficacy. One example of this is the design of D-Ala-methionine-enkephalin in 1976 by Pert et al. <ref>Pert, C. B., Pert, A., Chang, J. K., & Fong, B. T. (1976). (D-Ala2)-Met-enkephalinamide: a potent, long-lasting synthetic pentapeptide analgesic. Science (New York, N.Y.), 194(4262), 330–332. https://doi.org/10.1126/science.968485</ref>. Kropotova et al. in 2020 have designed different modified enkephalins that are less accessible to endopeptidases <ref>Kropotova, E. S., Ivleva, I. S., Karpenko, M. N., & Mosevitsky, M. I. (2020). Design of enkephalin modifications protected from brain extracellular peptidases providing long-term analgesia. Bioorganic & medicinal chemistry, 28(1), 115184. https://doi.org/10.1016/j.bmc.2019.115184</ref>. Squalene-based nanoparticles have opened exciting perspectives for drug delivery due to their biodegradability and their non-toxicity as Leu-Enkephalin Nanomedicines for pain alleviation. LENK-SQ bioconjugates show exclusively peripheral activity (no BBB penetration) so no CNS addiction and take advantage of the inflammatory process to optimize drug concentrations at the site of injury <ref>Lepetre-Mouelhi S., Feng J., Couvreur P. (2021) New Enkephalin Nanomedicines for Pain Alleviation, Overcoming the Side Effects of Morphine. In: J.M. Abadie M., Pinteala M., Rotaru A. (eds) New Trends in Macromolecular and Supramolecular Chemistry for Biological Applications. Springer, Cham. https://doi.org/10.1007/978-3-030-57456-7_10</ref>.  

The second approach to increase enkephalin stability ''in-vivo'' is the '''blocking of the peptidases''' themselves, such as enkephalinase and aminopeptidase. One example is DENKIs <ref name="cullen"/>.Dual Enkephalinase Inhibitors (DENKIs) are a novel therapeutic approach for opioid use disorders. This class of compounds physiologically activates the endogenous opioid system by inhibiting the enzymes responsible for the breakdown of enkephalins, protecting endogenous enkephalins, increasing their half-lives and physiological actions <ref>Alvarez-Perez, B, Poras, H, Maldonado, R. THE INHIBITION OF ENKEPHALIN CATABOLISM BY DUAL ENKEPHALINASE INHIBITOR: A NOVEL POSSIBLE THERAPEUTIC APPROACH FOR OPIOID USE DISORDERS. Br J Pharmacol. 2021. Accepted Author Manuscript. https://doi.org/10.1111/bph.15656</ref>.  

== References ==

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