Chapter Opener

• Opiates belong to a class known as narcotic analgesics– Reduce pain with causing unconsciousness

• As opposed to anesthetics

– Produce sense of relaxation and sleep• High doses can cause coma and death

– Euphoria– Gastrointestinal distress– Physical dependence

• Opium is extracted from the poppy plant

• Dry the milky juice from seed capsules and form a powder

• Majority is grown in southeast Asia, India, China, Iran, Turkey, and southeastern Europe

• Been used medicinally for several thousand years

• Modern use began in Europe• Brought back by religious

crusaders• Opium was acceptable in

Islamic countries– Alcohol was prohibited

• Laudanum – opium, cinnamon, and cloves

dissolved in wine• Laudanum was an accepted

form of opiate use in Victorian England and America

• Women considered it more respectable than common alcohol consumption

• In the early nineteen hundreds laudanum was a common ingredient in remedies for a variety of problems– Teething pain– Restlessness in infants– Muscle aches– alcoholism

• In the early nineteen hundreds laudanum was a common ingredient in remedies for a variety of problems– Teething pain– Restlessness in infants– Muscle aches– alcoholism

Molecular structure

• Minor differences in molecular structure determines the behavioral effects of opiates

• The principle active ingredient in opium was called morphine– After the Roman God of dreams (Morpheus)

• Morphine was isolated in the early 1800s• Opium has other active ingredients

– Codeine– Thebaine– Narcotine

• Notice that the chemical structure for morphine and codeine are nearly identical– Codeine has a methoxy group

CH3O– Rather than a hydroxyl group

OH

• Not much of a molecular difference, but makes a big difference physiologically

• Codeine has less analgesic effects and fewer side effects, but remains a powerful cough suppressant

• Heroin was a slight modification of morphine• Today we know that the pharmacological effects

of morphine and heroin are basically identical– Heroin is converted to morphine in the brain

• Heroin is 2-4 times more potent when injected and much faster acting because it is more lipid soluble than morphine– Crosses into the brain more readily

• Some modifications of morphine produce partial agonists– High affinity for opiate receptors, but lower efficacy– When injected alone they produce a partial opiate effect– If taken with an opiate that has higher efficacy they would

compete for binding sites and reduce the action of that drug

• Other modifications of morphine produces pure antagonists– Naloxone– High affinity, but zero efficacy– Can reverse the effect of opiate agonists– IV Naloxone can revive an unconscious opiate user in seconds

• Effective treatment for overdose

• Other modifications of morphine produce mixed agonist-antagonists– Work as an agonist on some opiate receptors– Work as an antagonist on other opiate receptors

• Pentazocine (Talwin)• Nalbuphine (Nubain)• Buprenorphine (Buprenex)

– Loss potent analgesics than morphine– But don’t cause respiratory depression or constipation– Reduced risk for physical dependence

• Some drugs are considered semisynthetic– Chemical modification of natural opioids

• Hydromorphine (Dilaudid)• Oxycodone (percocet = oxycodone and acetominophin)

• Some are entirely synthetic– Meperidine (Demerol)– Propoxyphene (Darvon)

10.4 Relationship of selected natural and synthetic opiate drugs

• Morphine is usually administered IM or PO for medical use

• Recreational users – Smoke– Snort– SC (skin popping)– IV (mainlining)

• Opiates cross the placental barrier– Newborns can experience withdrawal– Can be treated with low doses of opiates

CNS effects

• CNS– Low to moderate doses

• Analgesia• Respiration is depressed• Pupils constricted• Drowsiness• Decreased sensitivity to the environment• Impaired concentration• May relieve “psychological pain”

– Anxiety– Feelings of inadequacy– Hostility

• Suppresses cough reflex in a dose dependent manner• Effects hypothalamus

– Decreased appetite– Drop in body temperature– Reduced sex drive

CNS effects

• Higher Doses– Abnormal state of elation or euphoria (whole

body orgasm)– Nausea and vomiting is more pronounced at

higher doses• Effects the Area Postrema in the brain stem

– Elicits vomiting

• Sickness predicts euphoric effects (good sick)– May be the result of classical conditioning

• Seems to be true for rats as well– CTA vs CPP

CNS effects

• At highest doses– Leads to unconsciousness– Body temperature falls– Blood pressure falls– Pupils very constricted

• One indication of opiate overdose in the emergency room

– Respiration dangerously impaired• Can lead to death

Gastrointestinal (GI) tract effects

• Provides relief from diarrhea and dysentary (microbes in unsanitary water can lead to damage of the intestinal lining)

• Opium can promotes constipation and can stop life threatening loss of fluids.– Is a life saving drug in some developing countries

• Modern treatments – Loperimide (doesn’t cross blood-brain-barrier)

• Slows GI tract without affecting the CNS

• When opiates are used for pain management constipation becomes a side effect

• Three types of opiate receptors– Mu (μ)

• Spread throughout the brain and spinal cord• Brain areas with a lot of μ-receptors

– Medial thalamus (analgesia)– Periaquaductal grey (analgesia)– Median raphe (analgesia)– Nucleus accumbens (reinforcement)– Brain stem (cough, nausea, vomiting)– Thalamus, striatum (sensorimotor integration)

10.7 Autoradiograms of opiate receptor subtype binding in rat brain (Part 1)

• Delta (δ)– Predominantly found in forebrain areas

• Neocortex• Striatum• Olfactory area• Substantia nigra• Nucleus accumbens

– May play a role in modulating olfaction, motor integration, reinforcement, and cognitive function

10.7 Autoradiograms of opiate receptor subtype binding in rat brain (Part 2)

• Kappa (κ)– This receptor was first isolated with a drug called

ketocyclazocine.• Opiate analog that produces hallucinations and dysphoria

– Salvia Divinorum may work at κ-receptors

– κ-receptors are found in the striatum and amygdala, but also in hypothalamus and pituitary

• Seem to regulate pain perception and gut motility– Can cause dysphoria.

• Also may modulate water balance, feeding, temperature control, and neuroendocrine function.

10.7 Autoradiograms of opiate receptor subtype binding in rat brain (Part 3)

Endogenous opiates?

• In the 1970s peptides were discovered that bound to opiate receptors

• Three main endogenous opiates– Endorphins (μ + δ)– Enkephalin (δ)– Dynorphins (κ)

• It looks like all three opiate receptors are linked to Gi proteins (metabotropic)– Inhibit adenylyl cyclase (prevents synthesis of cAMP)

• The overall effect of opiates is to reduce membrane excitability, slow cell firing, and reduce neurotransmitter release

• There are three principle ways that endorphins reduce synaptic transmission

• 1) post synaptic inhibition– Opiate receptor G-protein activation can open

K+ channels– Increases K+ conductance– Leads to IPSPs

• Because K+ leaves the cell

10.11 Inhibitory actions of endogenous opioids

• 2) axoaxonic inhibition– Also known as presynaptic inhibition– Opiate receptor G-protein activation can close voltage

gated Ca++ channels.• Reducing the amount of Ca++ influx that occurs when an

action potential arrives at the terminal button• Reduces the amount of neurotransmitter released

– In this way opiates can modulate the release of other neurotransmitters

• Opioid induced presynaptic inhibition of NE and DA has been shown

10.11 Inhibitory actions of endogenous opioids

• 3) presynaptic autoreceptors– Activate G-proteins– Can close Ca++ channels or open K+

channels on the presynaptic membrane• Thus reducing neurotransmitter release

– Can reduce the release of co-localized (coexistent) neurotransmitters

10.11 Inhibitory actions of endogenous opioids

Opiates and Pain

• Two components of pain– 1) early pain

• Signals onset of pain• Provides precise location of pain

– 2) late pain• Has a strong emotional component

– Unpleasant sensation

• Adaptation to late pain occurs slowly– Attracting our attention to the pain and motivating

behaviors to limit further damage and aid recovery

• Aδ (A-delta) fibers carry first pain signals– Have larger diameter myelinated axons– Thus, they conduct action potentials very

quickly• Sharp localized brief pain

• C fibers carry second pain signals– Thin diameter unmyelinated axons

• Dull aching prolonged pain

10.12 Ascending pain pathways

• Also note that in the previous slide the final destination for Aδ and C fibers differ– Aδ fibers project to thalamus and then to primary and

secondary somatosensory cortex• Primary – sensation• Secondary – perception (recognition and memory of past

pain).

– C fibers first project to thalamus, but also have collaterals that project to limbic structures

• Hypothalamus• Amygdala• Anterior cingulate cortex

• Ploner et al. (2002).– Caused pain to subjects– Measured the brains reactions in real time using

magnetoencephalography• Similar to EEG• Superimposed activity on an MRI image

– First pain • Highly associated with contralateral primary somatosensory

cortex activity

– Second pain• Highly associated with anterior cingulate cortex activity

10.13 Location and time course of pain-evoked neural activity in human subjects

• Opiate drugs mimic the inhibitory action of endogenous opioids at many stages of pain transmission– Within spinal cord

• At inhibitory interneurons– Opioid interneurons inhibit activation of projection neurons

» Opiates can directly stimulate these neurons» Reducing pain signals

– At descending analgesia pathways (gate theory of analgesia)• Originating in the periaquaductal grey (PAG)• Can inhibit pain signals in a variety of ways

– See next slide

– At higher brain sites• Anterior cingulate cortex

– Regulates emotional aspects of pain

10.14 Pain transmission in the spinal cord

10.15 Descending pain modulation pathways

Zubieta et al. (2001)

• Caused sustained pain in participants and looked at brain activity with the PET scan.– Used displacement of a radio-labeled ligand to image

opiate activity.• Sensory pain

– found a significant negative correlation between μ-opioid activity and reported sensory pain

• In nucleus accumbens, amygdala, and thalmus

• Affective component of pain– Found a negative correlation between μ-opioid activity

and reported affect scores• In anterior cingulate cortex, thalamus, and nucleus

accumbens

10.16 PET scans showing endogenous opioid activation during sustained pain

Reinforcing properties of opiates

• ICSS (intracranial self stimulation)– Morphine and other opioids lower threshold in reward

pathway• Self administration

– Animals seem to regulate intake of opiates to achieve optimal levels

• Over time they increase self-administration and then level off

• Some endorphins are self-administered– Blocked by μ or δ antagonists

• Implies they are most involved in reward

• κ-receptor agonists are not self-administered– May induce aversive states

• Microinjection studies– Implicate the mesolimbic pathway– Animals will self-administer into the VTA

• Increases firing rate of VTA• Thus, increases release of dopamine in NA

• Intraventricular injection of endorphins produce similar results

• These results argue for a direct action of opiates on the mesolimbic reward pathway

• However, κ-agonists reduce dopaminergic activity in the mesolimbic pathway– Also can cause conditioned place aversion

• Thus, it is possible that the mesolimbic pathway may mediate both the rewarding and aversive properties of opiates

• It looks like endorphins work by inhibiting GABA neurons that normally inhibit DA neurons in the VTA– Increasing the firing rate of VTA neurons

10.17 Model of the effects of opiates on mesolimbic dopaminergic cells

• Dynorphin (endogenous κ-opioid) acts on κ-receptors on the terminals of DA neurons (in NA) thus, decreasing release– Axoaxonic (presynaptic) inhibition

10.17 Model of the effects of opiates on mesolimbic dopaminergic cells

• There is a lot of evidence that the mesolimbic pathway is involved in the rewarding properties of opiates

• Remember though, that lesioning the mesolimbic pathway does not abolish opiate self-administration– Thus, opiates must be rewarding in other

ways as well.• Independent of the mesolimbic pathway.

Tolerance

• Tolerance does not occur to all effects at the same rate– Tolerance to analgesic effects occur rapidly,

but peripheral effects (constipation, pinpoint pupils) persist

• Cross tolerance can occur– Codeine elicits a smaller effect in a heroin

addict– Seems to be receptor specific. Agonist of the

μ-receptor, but have little effect on κ-receptors

• Sensitization– Some would argue that drug craving becomes

sensitized– Rewarding effects diminish

• Physical dependence– Opiates depress CNS activity– Withdrawal causes a rebound hyperactivity– Injection of an opiate antagonist causing a very

severe withdrawal syndrome• Because of the rapid displacement of the drug.

• Opiate withdrawal is not considered life threatening

• The longer the duration of the action of the opiate the longer withdrawal will last, but the intensity of the symptoms will be less– Methadone – long lasting

(several weeks) low intensity

– Morphine – shorter lasting (7-10 days) high intensity

• Physical dependence commonly occurs following chronic opiate use.

• Does not necessarily lead to abuse or addiction

• Patients treated with opiates for pain will show tolerance and dependence– Gradually reducing drug can reduce

withdrawal effects– Rare that these individuals become addicted

• Himmelsbach (1943)– Acute morphine disrupts homeostasis– Repeated morphine exposure initiates an

adaptive mechanism that restores homeostasis

• Tolerance

– During abstinence there is no drug effect, but the adaptive mechanism remains active and overcompensates

• withdrawal

10.19 Model of tolerance and withdrawal (Part 1)

• Sharma et al., (1975)– Physiological correlate of the Himmelsbach model.

• Cells with opiate receptors in culture• Acute morphine = decreased cAMP activity• After 2 days of continuous morphine cAMP

returned to normal levels– Tolerance

• When morphine was removed, or an antagonist was added to the solution cAMP rose above control levels.– A rebound affect; akin to withdrawal

10.19 Model of tolerance and withdrawal (Part 2)

• Siegel would argue that these compensatory changes can be conditioned to environmental cues– Leading to context specific tolerance

• Explain overdose?

• Can NMDA antagonism prevent the development of learned tolerance?– Remember the NMDA receptor is thought to

play a role in LTP and learning and memory

4.18 The tail-flick test of analgesia

• MK-801 NMDA antagonist– Binds to PCP site

• Tested for tolerance to analgesic effects using tail flick test.

• Note that the tolerance to morphine was substantially reduced when given with MK-801– purple vs. green

• Also note that MK-801 is not analgesic itself– Blue vs. red– Also purple vs. green first few

days

• If MK-801 is given after tolerance has developed it has no effect– This is important to note because it indicates

that it prevents neural changes that occur during the development of tolerance, rather than reversing some effect.

• MK-801 also reduces signs of withdrawal

• Many NMDA receptor antagonists have now been tested and shown to reduce tolerance and withdrawal.

• Including nitric oxide synthase inhibitors– Nitric oxide is a second

messenger– Also may be involved in

retrograde communication

Box 10.2 Role of NMDA Receptors in Tolerance and Dependence (Part 3)

Methadone maintenance

• Methadone is a long lasting opiate agonist that relieves the patient from withdrawal and allows them to focus on getting their lives together

• Oral administration of this opiate agonist prevents withdrawal and euphoria produced by other opiates

– Euphoria can occur with very high doses of opiate

• Some evidence that is fairly effective

• Have to take it under supervision because injection will cause euphoric effects

• Recently other opiate agonists have been produced that last even longer (less doctor visits), and are only mildly euphoric so that a prescription can be given

– buprenorphine