ENDORPHIN : A NATURAL ANALGESIC AND PLEASANT

HORMONE

BY: NEHA JAIN M.Phil.Bioscience

2

Endorphins "endogenous morphine"

Beta-endorphin the best in pain relief

Endorphins production is hereditary, and due to this, its production level varies from one person to another.

High concentrations of endorphins in the brain produce a sense of euphoria, enhance pleasure, and

suppress pain, both emotionally and physically.

Low concentrations of endorphins in the brain people feel anxious and they are also more aware of pain.

OVERVIEW OF PRESENTATION

1) History2) What is Endorphin3) Types of Endorphin4) Control of Secretion5) Transport and distribution 6) Receptors of endorphin7) Binding: endorphin and receptor8) Function as analgesic 9) Mode of action10)Can we get endorphin ?11)Abnormalities of endorphin receptors12)Receptors used by exogenous opioid (morphine)13)what is drug addiction ?14)Can Methadone Fix to endorphin Receptors?15)Future of endorphin’s and other’s receptors

HISTORY

In 1970’s that many research allowed us to understand how the exogenous opioid drugs work by studying the “endogenous opioid system”.

In 1973, H. Solomon Snyder and Johns hopkins discovered the “endogenous opioid system”. Researchers also determined the existence of opiate binding sites in the brain through the use of radioligand

binding assays.

In 1974, Rabi Simantov and Solomon H. Snyder isolated endogenous opioid from the brain of a calf , and term is given "endorphin" (i.e. Endogenous morphine).

In 1975, an endogenous opiate-like factor called enkephalin was found and shortly after this two more classes of endogenous opiate peptides were isolated, the dynophorins and the “endorphins”.

WHAT IS ENDORPHIN?A peptide hormone named Endorphin produced in

the brain and anterior pituitary.Endorphin inhibits pain perception. It is popularly

called Body’s natural analgesic or opiate.Endorphin is produced at the time of physical or

emotional stress, such as labor of child birth.Endorphin binds to the same receptors that binds

exogenous opiates.

“Endorphin Affect Your Mood And Emotions And May Be Responsible

For Your Body Feeling Pleasure Even Euphoria For Your Body Feeling Pleasure”

alpha (α) endorphin -

beta (β) endorphin Most powerful

gamma (γ) endorphin -

sigma (σ) endorphin -

TYPES OF ENDORPHINHuman body produces at least 20 different

endorphins ( benefits and uses are investigating)Special types are as follows:

(made all by 16 to 31 amino acids )

β -ENDORPHIN

• β -Endorphin is peptide hormones (consist of chains of amino acids) ----NH2 / NH3 + COOH

• β -Endorphin is a 31 amino acid polypeptide• SEQUENCE: Ac - Tyr - Gly - Gly - Phe - Met - Thr - Ser

- Glu - Lys - Ser - Gln - Thr - Pro - Leu - Val - Thr - Leu - Phe - Lys - Asn - Ala - Ile - Ile - Lys - Asn - Ala – His - Lys - Lys - Gly - Gln – OH

• β-endorphin is released by pituitary

(into blood ) and hypothalamus ( into the

spinal cord and brain )• β-endorphin is a cleavage product of pro-

opiomelanocortin (POMC)

HypothalamusCorticotropin releasing factor

(CRF)

Anterior PituitaryPro-Opiomelanocortin

(POMC)

Endorphin Hormone(EP)

Central NervousSystem

Environmental Cue

“Stressor”( pain)

•Step 1: Cue perceived by CNS

•Step 2: Signal sent to hypothalamus (in brain)

•Step 3: Hypothalamus secretes CRF (peptide), travels to pituitary

•Step 4: CRF causes proteinpro-Opiomelanocortin

hormone (POMC) to be cleaved, releases Beta lipotropin

•Step 5: lipotropin gets convertinto Endorphin.

•Step 6: Endorphin binds to the nerve fiber.

Brain

(enzymatic cleavage)

Beta-lipotropin

ENDORPHIN HORMONE : AS CLEAVAGE PRODUCT

pro-opiomelanocortin polypeptide (POMC)

ACTHb-lipotropin

g-MSH g-lipotropina-MSH

CLIP b-endorphin

b-MSH

MET-enk

RECEPTORS OF ENDORPHIN• All of the endorphins bind

to the opioid receptors in the brain.

• These analgesia- producing receptors are located in your brain, spinal cord, and other nerve endings.

Mu ( ) Receptor Analgesic (most important )

Delta( ) Receptor

Analgesic (predominantly )

Kappa () Receptor

Analgesic (hyper-analgesic )

TRANSPORT AND DISTRIBUTION β-endorphin is released by :

1. Pituitary (into blood ) and

2. Hypothalamus ( into the spinal cord and brain )

Beta endorphin containing nerve fibres spread widely from neurones in the hypothalamus, to make inhibitory contacts with target neurones to reduce pain.

Free hormones are rapidly eliminated from circulation through

kidney or liver.

Hypothalamus

An Easy Way to Think of Receptors and Endorphins binding

• Is to think of the substance as a key and the receptor as a lock.

• When the substance binds to the receptor it opens the lock.

• This in turn sends another signal or causes the release of a substance.

• When a lot of signals are sent a function happens like the release of a hormone.

BINDING OF ENDORPHIN & RECEPTOR

Portion of molecule

Where ligand binds

Is called binding site. If the molecule

Is a receptor (like in a cell membrane) the binding site is called receptor site.

The purpose of binding to target tissue is to

elicit a response by

the target cell.

FUNCTION AS ANALGESIC Pain impulse feel Pain impulse stop

Before endorphin release After endorphin release

FUNCTION AS ANALGESIC PAIN IMPULSE STOP BY ENDORPHIN : MECHANISM

hyp

oth

ala

mu

s

FUNCTION AS ANALGESIC PAIN IMPULSE STOP : BY ENDORPHIN

MODE OF ACTIONThe mu receptor is the strongest binding site of the body’s natural pain killer, the class of opioid peptides called the endorphin. The mu receptor is a G-protein linked receptor. When endorphin binds to the delta receptor is induces a conformational change that causes the activation of a specific G-protein.

This G-protein inhibits the membrane bound enzyme adenylate cyclase and prevents the synthesis of cAMP. The transmission of the pain signal requires cAMP to act as a secondary messenger, and so inhibition of this enzyme blocks the signal .(Pain-relieving effect by blocking the release of substance P)

Adenylcyclase

Endorphin

ATP cAMP AMP

18

Calcium channels closed

Potassium channels open K+

AC

Gi

[cAMP]

Calcium entry blocked

[Ca2+ ]

Decreased release of neurotransmitters

Endorphin Receptor2. Direct action on K channels (alpha & beta subunit)

Net effects:

K+ conductance hyperpolarize neurons Ca+ conductance

neurotransmitter release

1. Couple to Gi &

Go protein

(neuronal excitability)

Pain reduced

MODE OF ACTION

CAN WE GET ENDORPHIN ?Yes we can get : BY

Chili Runner’s high

Exercise Music

Laughing

Meditation

Acupuncture

ABNORMALITIES OF ENDORPHIN RECEPTORS

However with some people :

When the lock (receptor) is damaged.No matter how much Endorphins may be near the receptor because it does not function right the lock can not be opened.By Genetics/Birth DefectA person can be born with defective receptors. This can make an individual more susceptible to addictionBy Exogenous drugAnd using opiates - not for pain - but when the brain is flooded over and over again – the receptors stop working normally.

ENDORPHIN RECEPTORS USED BY EXOGENOUS OPIOID (Morphine)

Morphine

CarbonHydrogen

NitrogenSulfurOxygen

Naturalendorphin

(a) Structures of endorphin and morphine.

Naturalendorphin

Endorphinreceptors

Morphine

Brain cell(b) Binding to endorphin receptors

ENDORPHIN MORPHINEEndogenous opioid. Exogenous opioid

Powerful analgesic 18 to 500 times than morphine(Β-endorphin is 80 times)

Less analgesic than endorphin

similar Molecular structure & Different chemical properties.

It also

Non-addictive Addictive

Does not cause addiction Side-effects : euphoria/ dysphoria, constipation, respiratory depression, nausea/ vomiting etc.

Receptors are : mu, kappa, delta

Receptors are : mu, kappa, sigma

Metabolized quickly Metabolized slowly

HOW DOES POTENCY DIFFER?

WHAT IS DRUG ADDICTION ?In the normal course Opiate Receptors and Endorphins are kept in balance with one another.

When the brain is flooded with exogenous opiates, (heroin a morphine derivative) it mimic of endorphins so system gets confused.

It thinks it is making too many endorphins and shuts that down, But it still has all this excess (heroin) and thinks that it also needs to make more receptors.

Heroin addiction

What Happens Next….• As more Opiate Receptors are

made you need more heroin to get the same effect so you use more.

• And more receptors are made to accommodate the extra what the brain thinks is endorphins.

• For decreasing this effect- You need more substance to get the same effect.

Can Methadone Fix to endorphin Receptors?

• Methadone does normalize the damage caused by drug use(heroin).

• Synthetic. Long half-life Used to reduce withdrawal symptoms of heroin addicts

• And there is some evidence that for persons who have not used drugs very long that methadone will stop the damage they are doing and over time can normalize the system.

• But this is a small minority – 30%.

72-84 hr (Slow excretion)

Half-life > 24 hr

Half-life > 12 hr

Methadone

Heroin

2 hr ( fast excretion)

FUTURE OF ENDORPHIN’S AND OTHER’S RECEPTORS

• The future of Opioid Analgesics seems to be linked to the study of the Kappa Receptor. The kappa receptor induces analgesia without the dangerous and unwanted side effects that the mu and delta receptors are associated with.

• However there are not any selectively strong agonists to this receptor as of now.

• Another area of research important to the future of opioid analgesics is the study of the endogenous opioid peptides.

FUTURE OF ENDORPHIN’S AND OTHER’S RECEPTORS

• Because these peptides are endogenous, on metabolic degradation (unlike opiates) they break down to amino acids. Hence, the metabolites are nontoxic and to not cause kidney and liver damage

• Also, because they are made from amino acid residues, a large number of analogs can be synthesized from a few basic building blocks and simple modifications may be attempted to develop analogs with a desired biological effect .

SUMMARY

• Endorphin is best analgesic endogenous opioid.

• For future research endorphin receptors are very important.

Thanks !!!