Paige Bonner, Adam Fendos, Zaynab Hassan, Annalise Ho, Max Ho, Jeremy Kaine, Alec Lau, Chr istopher Monty, Simon Ng, Richard Sear,

Aleksandra Zielonka

Teacher : Mar y A. Haasch

Mentor : Chr is Cunningham, PhD.

Opioid Oppression

MODEL INFORMATION

- Sheets......................................................................Dodgerblue- Helices 1, 2, 3, 4, 7, 8...................................................Darkblue- Helix 5 (contain the active binding si te)..................Turquoise- Helix 6 (contain the active binding si te)................Char tr euse- Hydrogen Bonds...........................................................Skyblue- Str uts................................................................................White- Cys140 - Cys217 (Disulphide br idge).......................Limegreen- Thr279 (stabi l i ty for inactive protein)...........................Yellow- I le256 (stabi l i ty for inactive protein).............................Yellow- Arg165 (salt br idge)....................................................Darkgold- Asp164 (salt br idge)....................................................Darkgold- Lys233 (forms covalent bonds to l igands l ike opioids)......Red- His297 (interacts exclusively w ith morphine).............Orange

BETA-ENDORPHINS

Proopiomelanocor tin (POMC) is a r elatively large precursor protein which is created in the frontal pi tui tar y gland and is broken dow n into other proteins, one of which is the beta-endorphin. Depending how many of the smaller proteins are needed, production of POMC is turned on and off . Beta-endorphins cause a painki l l ing effect by binding to opioid r eceptor s (especial ly the ?-opioid r eceptor ). In the per ipheral ner vous system, the cascade resulting from the binding prevents the r elease of tachykinins (which cause pain). However, in the central ner vous system, the pain-ki l l ing effect is achieved by r eleasing excess amounts of dopamine (which causes pleasure). Injection of too many external opioids (such as morphine or heroin) prevents the production of natural endorphins. Chronic injection of these opioids harms the POMC protein. Additionally, this decreases the amount of ?-opioid r eceptor s. This loss decreases the eff icacy of the ?-opioid r eceptor s as a whole.

OPIOIDS VS. OPIATES

The terms opioid and opiate are often used inter changeably, but there is a di f ference. Opioid r efer s to any chemical which has agonist effects (e.g. pain r el ief ) w i th opioid r eceptor s. This is as opposed to antagonists, which simply bind to r eceptor and have no effect. Opiate r efer s only to natural opioids. Opiates are der ived from the opium poppy plant. Synthetic opioids have a simi lar str ucture to opiates, but are fabr icated in a laborator y. Opioids cause a euphor ic effect, but shut dow n internal organs, eventually r esulting in death.

CONCLUSION

Opioid abuse is one today's most pressing issues, costing bi l l ions of dol lar s and thousands of l ives each year. Along w ith painki l l ing proper ties, opioids have ser ious side effects that can lead to death, yet r emain one of the most prescr ibed drugs in the U.S. Alr eady in use, Narcan®, or naloxone, acts as an antagonist to block the action of opioids fol low ing an overdose. In the future, scientists such Chr is Cunningham PhD. are working to create a drug or drugs that could activate the ?-receptor to provide pain r el ief, whi le deactivating the ?-receptor to el iminate the bui lding of tolerance.

?The SMART Team Program is suppor ted by the National Center for Advancing Translational Sciences, National Insti tutes of Health, through Grant Number 8UL1TR000055. I ts contents are solely the r esponsibi l i ty of the authors and do not necessar i ly r epresent the off icial views of the NIH.?

Difference between the cascade reactions fol low ing the binding of natural beta-endorphin and synthetic morphine to a ?-opioid r eceptor

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Bibliography:

EFFECT OF OPIOID DRUGS IN THE U.S.Opioids are the most prescr ibed drugs in the United States. Whi le they are highly effective painki l ler s, they are also extr emely addictive. The CDC calls the addiction to prescr iption pain medication in Amer ica an epidemic. Each year, over 11,000 people die from opioid-r elated poisonings. In addition, the impacts of addiction cost the U.S. society $193 bi l l ion per year.

Source: National Center for Health Stat ist ics/CDC, National Vital Stat ist ics Repor t, Final death data for each calendar year (June 2014). * includes opium

ABSTRACT

Opioid abuse is now a leading cause of accidental death in Nor th Amer ica10; yet, opioids r emain the most prescr ibed drugs in the United States. Opioid drugs are power ful painki l ler s, but their adverse side effects ? addiction, tolerance, and extr eme constipation ? severely l imit their medical use. Chr is Cunningham, PhD., is working to create a drug or drugs which w i l l bind to ?OR w ithout causing tolerance. ?-opioid r eceptor (?OR), is one of the G protein-coupled r eceptor s (GPCR) tr aversing the cel l membranes of pr imar i ly neuronal cel ls in the brain and spinal cord. ?OR is found on the outside of presynaptic cel ls in the brain. Normally, endorphins (such as beta-endorphins, which are classed as opiates) bind to the r eceptor, which r esults in a r elease of ions and a cascade to effector proteins (such as ion channels), ultimately leading to var ious r eward cir cui t or iented behavior s and analgesic effects. Other opiates (natural der ivatives, e.g. morphine), opioids (synthetic der ivatives), and simi lar compounds instead bind to ?OR, which prevents normal endorphin-binding activi ty. ?OR is a single chain protein w ith 8 helices. I ts active si te is on the inside of the protein; binding involves 14 r esidues. Interactions between the other hel ices, disulf ide bond (Cys140-Cys217), and salt br idge (Arg165-Asp164) stabi l ize the protein str ucture. Polar bonding between Thr279-I le256 maintains the protein in the inactive state. Lys233 covalently binds to both morphine (agonist) and beta-FNA-funaltr examine hydrochlor ide (antagonist). Cur rently, Chr is Cunningham PhD., has investigated naltr indole which par tial ly exci tes the ?-active si te whi le also binding to a ?-OR receptor sl ightly r educing tolerance. Other chemicals need to be investigated that w i l l provide an effective analgesic whi le el iminating al l side effects. The Wauwatosa West SMART (Students Modeling a Research Topic) Team used 3D pr inting technology to study

16. PDB ID: 4DKL A. Manglik , A.C. Kruse, T.S. Kobi lka, F.S. Thian, J.M. Mathiesen, R.K. Sunahara, L. Pardo, W.I. Weis, B.K. Kobi lka, S. Granier (2012). Cr ystal Str ucture of the Mu-opioid Receptor bound to a Morphinan Antagonist. Nature. 485: 321-326

Agonist vs. Antagonist Binding

PDB ID: 4DKL

Binding si te for agonists and antagonists

View dow n center of protein from top.

side view of protein

In MiceData shows pain is par tial ly control led.

Data from C. Cunningham, PhD.