Drugs and the BrainPart 3Opiates

An Introduction• "If we could sniff or swallow something that would, for

five or six hours each day, abolish our solitude as individuals, atone us with our fellows in a glowing exaltation of affection and make life in all its aspects seem not only worth living, but divinely beautiful and significant, and if this heavenly, world-transfiguring drug were of such a kind that we could wake up next morning with a clear head and an undamaged constitution-then, it seems to me, all our problems (and not merely the one small problem of discovering a novel pleasure) would be wholly solved and earth would become paradise."

– ALDOUS HUXLEY, 1894 - 1963

What are Opiates?

• Opium is an extract derived from seedpods of the opium poppy, Papaver somniferum.

• Perhaps the most ancient class of medicinal drugs and drugs of abuse– The poppy plant was cultivated in the ancient

civilizations of Persia, Egypt and Mesopotamia.  

• Active ingredient, morphine, 1st isolated in 1805• Best known are heroin & morphine• Heroin is a derivative made by adding 2 acetyl

groups to morphine; first synthesized in 1875• Highly addictive

Opiate History• Archaeological evidence suggests that

Neanderthal man may have used the opium poppy over thirty thousand years ago.

• The first known written reference appears in a Sumerian text dated around 4,000 BC.

• Homer’s Odyssey (8th C. Greece) describes opiate use as a drug called nepenthe:– But then Helen “...had a happy thought. Into the

bowl in which their wine was mixed, she slipped a drug that had the power of robbing grief and anger of their sting and banishing all painful memories.”  

Opiate History (continued)• Egyptian pharaohs entombed with opium

artifacts• Opium could be readily bought on the street-

markets of Rome. • By 8th C. A.D., opium use had spread to Arabia

and India. – Arabs used opium b/c the Prophet had prohibited the

use of alcohol, not hashish or opiates.

• Opium was also widely used in Chinese antiquity• Opium flourished in Europe throughout the

Middle Ages and made its way to the New World• Thomas Jefferson cultivated opium poppies at

his garden in Monticello.

The Opium Wars• Opium used in China as a recreational drug. • The Imperial Chinese court banned its use but

large quantities were still being smuggled in. • In 1839, the Qing Emperor, Tao Kwang,

ordered his minister to take action. • Queen Victoria ignored his petition for help.• In reaction, the Emperor instructed the

confiscation of 20,000 barrels of opium and detained some foreign traders.

• The British retaliated by attacking the port-city of Canton.

• Thus began the First Opium War.

The Opium Wars (continued)

• The Chinese were defeated. • They were forced to sign the Treaty of Nanjing

in 1842. • The British required that the opium trade be

allowed to continue, that the Chinese pay a large settlement and open five new ports to foreign trade, and that China cede Hong Kong to Britain.

• Peace didn't last.

The Second Opium War• The Second Opium War began and

ended in 1856 over western demands that opium markets be expanded.

• The Chinese were again defeated. • In 1858, by the Treaty of Tientsin,

opium importation to China was formally legalized.

• Opium poured into China in unprecedented quantities. By the end of 19th C., over a quarter of the adult male Chinese population were addicted.

Medicinal Opium

• Classical Greek physicians ground the whole plant or used opium extract.

• Galen lists its medical indications:– "...resists poison and venomous bites, cures

chronic headache, vertigo, deafness, epilepsy, apoplexy, dimness of sight, loss of voice, asthma, coughs of all kinds, spitting of blood, tightness of breath, colic, the lilac poison, jaundice, hardness of the spleen stone, urinary complaints, fever, dropsies, leprosies, the trouble to which women are subject, melancholy and all pestilences."  

Medicinal Opium (continued)

• 16th C. development of laudanum• In freebase form, alkaloids found in opium are

less soluble in water than in alcohol.• Philippus Aureolus Theophrastus Bombastus

von Hohenheim (1490-1541), (Paracelsus) concocted laudanum by extracting opium into brandy, producing, tincture of morphine.

• By the 19th C., vials of laudanum and raw opium were available at any English pharmacy

• Opium viewed as a medicine, not a drug of abuse.

The Active Ingredient

• Morphine 1st isolated from opium in 1805 by a German pharmacist

• The development of the hypodermic syringe in the mid-19th C. allowed the injection of pure morphine.– It was believed that injecting

morphine wasn't addictive.

Changing Attitudes• By the mid 19th C. attitudes were changing as

addictive properties became clearer• Morphine addiction was rampant in the US after

its extensive use by injured soldiers on both sides of the Civil War.

• Racism also fueled change• Dr Hamilton Wright, US opium commissioner,

blamed "the Chinese vice" for corrupting the nation's youth:– "One of the most unfortunate phases of the habit of

smoking opium in this country (was) the large number of women who have become involved . . . with Chinese . . .”

Drug Development Continues

• The search began for a powerful non-addictive alternative to opium and morphine.

• In 1874, English pharmacist C.R. Alder Wright boiled morphine and acetic acid to produce diacetylmorphine, C17H17NO (C2H3O2)2.

• Diacetylmorphine was synthesized and marketed by the German pharmaceutical giant, Bayer.

• In 1898, Bayer launched the best-selling drug-brand of all time, Heroin.

Morphine & Heroin

Mechanism of Action• Experiments showed that the pain

relieving effects of opiates correlate with changes in all neurotransmitters– Which neurotransmitters are actually involved

in pain relief?• What is the initial trigger of opiate action?• Because opiates are extremely potent,

scientists believed they bound specific receptor sites.

• Existence of opiate agonists and antagonists was further evidence that opiates bound specific receptor sites in the brain.

Agonists and Antagonists• Receptors are complex – include recognition

site & associated 2ND messenger that translates recognition into cellular activity

• Agonist – – A molecule that binds a receptor and causes a series

of events that alter cellular function. – This causes a measurable physiological change (e.g

pain relief or euphoria for opiates)

• Antagonist – – A molecule that binds without causing subsequent

cellular alterations. – Prevents other molecules binding receptor.– Reverses the effect of another compound without

producing the same physiological effects

Opiate Antagonists

• Opiate antagonists produce no euphoria but can reverse effects of opiates

• Example: – Naloxone can reverse effects of a heroin

overdose, revive patients in coma

• Existence of opiate antagonists suggested that opiates act at receptors

Discovery of the Opiate Receptor

• Mid 1950’s scientists tried mixing radioactive morphine with brain membranes– Failed to demonstrate presence of specific

opiate receptors– Opiate receptors are sparse – 1/1,000,000 of

brain’s weight– Charged molecules also could engage in non-

specific binding at other sites

• 1973 – Pert, Snyder et al, isolated opiate receptors in the brain– Used radio-labeled opiate antagonist, naloxone

How Opiates Work• Small differences in sodium ion

concentrations cause dramatic differences in opiate behavior

• Opiate agonists become less potent in the presence of sodium

• Antagonists are either unaffected or bound more tightly to receptor in presence of sodium

• Cyclic AMP is second messenger for opiates• Cyclic AMP levels are regulated by an enzyme

that uses sodium ions

Distribution of Opiate Receptors

• Opiate receptors are distributed in distinct patterns in the brain

• Highest densities of opiate receptors are concentrated in areas involved in pain pathways

• Dense in substantia gelatinosa of the spinal cord, where sensory nerves make 1st contact

• Also concentrated in the medial area of the thalamus - conveys sensory input associated with deep pain

• Dense clusters in the periaqueductal gray zone of the midbrain – integrates pain information

• Dense in the limbic system – a major regulator of emotional behavior – explains euphoria

Distribution of Opiate Receptors

The distribution of opiate receptors in the brain of a guinea pig.  Red areas = highest density; yellow = moderate density,blue, purple & white = low density.  

Types of Opiate Receptors• Four types of opiate receptors identified: mu1,

mu2, kappa and delta receptors.  • Opioids exert their effects by activating one or

more of these receptors.  • The actions of opioids on receptors can vary

depending on the location within the body– A particular opioid may act as an antagonist at the

kappa receptors in the brain, but as an agonist at the same type of receptors in the large  intestines.

• Tolerance to activation of one receptor type does not necessarily lead to tolerance to the others. 

• Sometimes analgesic medication is prescribed to activate only certain receptors

Role of Receptor Types• Mu2 receptors are are involved in

respiratory depression and intestinal constipation.

• Analgesia involves activation of Mu1 receptors in the brain and kappa receptors in the spinal cord. 

• The contribution of delta receptors to analgesia is unclear, and may be more closely related to euphoria. 

• Activation of Mu1, Mu2, and delta receptors close potassium channels, while kappa receptors are linked to calcium channels. 

Addiction to Opiates• Morphine and other opiates bind to

opiate receptors concentrated in the ventral tegmental area (VTA) which is part of the reward pathway

• Dopamine neurons in the VTA project through the lateral hypothalamus to the forebrain

• Thus opiates stimulate dopamine release in the reward pathway.

• This is the basis of addiction.

Pathway of Addiction• Rat self-administering

heroin thru a needle in the nucleus accumbens

• Dopamine release is increased in the reward pathway

• Since more dopamine is available, it binds more receptors activating reward pathway

• Rat keeps pressing the bar to get more heroin because it feels good.

• Heroin is a reward & positively reinforces behavior.

Dopamine & Opiate Addiction• Three types of neurons participate in opiate

action: one that releases dopamine, a neighboring terminal containing a different neurotransmitter (probably GABA), and the post-synaptic cell containing dopamine receptors (in pink).

• Opiates bind to opiate receptors (yellow) on the neighboring terminal and this sends a signal to the dopamine terminal to release more dopamine. – one theory is that opiate receptor activation

decreases GABA release, which normally inhibits dopamine release--so dopamine release is increased.

A Synapse in the Nucleus Accumbens.

Tolerance to Opiates• In the case of morphine or heroin, tolerance

develops at the level of the cellular targets. – When morphine binds to opiate receptors, it

triggers the inhibition of an enzyme (adenylate cyclase) that orchestrates several chemicals in the cell to maintain the firing of impulses.

– After repeated activation of the opiate receptor by morphine, the enzyme adapts so that the morphine can no longer cause changes in cell firing.

• Thus, the effect of a given dose of morphine or heroin is diminished.

Tolerance & the Brain• The development of tolerance to the

analgesic effects of morphine involves areas of the brain separate from those in the reward pathway.

• 2 important areas are involved: the thalamus and the spinal cord

• Both are important in sending pain messages and are responsible for the analgesic effects of morphine.

Dependence on Opiates

• The development of dependence to morphine also involves specific areas of the brain, separate from the reward pathway.

• The thalamus and brainstem are key areas• Many of the withdrawal symptoms from

heroin or morphine are generated when the opiate receptors in the thalamus and brainstem are deprived of morphine.

The Brain’s Morphine• Why do opiate receptors exist?• Endorphins – “endogenous morphine –like

substances” – term coined before actual discovery

• First such compounds were discovered by Hughes & Kosterlitz – 2 similar small peptides – called them enkephalins

• Names result in confusion – used interchangeably; enkephalins are these 2 specific peptides; endorphins all such molecules

• Natural pain killers, but synthetics have have been less effective than morphine & addictive