What opiods are naturally occuring?
- aka Opium
- from opium poppy
- multiple active ingredients: morphine & codeine - strongest effects
- Morphine
- Codeine
- Thebaine
- Narcotine (mainly just unpleasant): causes vomiting
What opiods are semi-synthetic?
- synthesised from naturally occuring:
- Diamorphine/diacetylmorphine (heroin): from morphine
- Desomorphine (krokodil): from codeine
- Buprenorphine
- Hydrocodone
- Oxycodone (aka oxycontin)
What opiods are fully synthetic?
- not derived from naturally occuring:
- Fentanyl: 100x stronger than morphine
- Carfentanil: up to 10,000x stronger than morphine
- Methadone
What basic principle can be determined from these categories?
potency: synthetic > semi-synthetic > naturally occuring
Why is the history of opiods important in understanding where we are today, in terms of opiod addiction?
History repeats itself:
- early-mid 19th c, opiods sold in drug stores: concerns about safety, long-term health issues, dependence
- late 19th c, “problem of morphine has been solved by heroin”: heroin marketed as non-addictive substitute for morphine
- cycle repeated itself w/ buprenorphine & hydromorphone
- cycle repeated itself again w/ Oxycontin & Percocet
- cycle matters: prescription (mis)use predicts subsequent street drug use
What are three routes of opioid administration?
- oral – e.g. methadone substitution
- drug replacement therapy
- inhalation – “chasing the dragon”
- put solution onto foil & heat it up, move solution around in foil while cooking
- use straw to chase smoke
- intravenous injection – “mainlining”
- cooking heroin into solution, put into syringe & inject into vein
What determines potentcy of opioids?
- potency determined by lipid solubility: ability to cross BBB
- e.g. Morphine vs. heroin
- difference: heroin has 2 Acetyl groups, more lipid soluble, higher bioavailability
- Acetyl groups improve BBB permeability
- active metabolites are norm
- related: drug testing for heroin?
- difficult to say if person used it legally/illegally
- look for unique metabolites
- heroin: monacetylmorphine
What is the endogenous opioid system?
- endogenous NTs are large peptides (mini piece of protein)
- peptides cleaved from v. large propeptidespropetides = larger, bigger peptides
- Proopiomelanocortin: produces beta-endorphin
- Proenkephalin: produces met-enkephalin & leu-enkephelin
- Prodynorphin: produces dynorphin A & B, neoendorphins
- Pronociceptin (weird one): produces nociceptin/ orphanin FQ
What are the four types of opioid receptors and differing effects at these receptors?
- beta-endorphin, met- & leu-enkephalin bind to & activate mu & delta receptors
- dynorphin A & B, neoendorphins bind to & activate kappa receptor
- nociceptin binds to & activates ORL-1 receptor
- mu & delta critical for pain relief, euphoria & addiction
- kappa related to occasional hallucinogenic effects of opioids
- e.g. Salvinorin A in Salvia divinorum agonises kappa receptor
- may activate other receptors
- ORL-1: pain-causing
- all endogenous opioid receptors are G-protein coupled receptors (GPCRs)
- activation of receptors reduces neuronal activity
- one effect: activation of receptors open GIRKs
What are GIRKs? Why are they relevant to the effects of opiods?
GIRKs: G-protein-coupled inward rectifying K+ channel
- activate GPCRs, G-proteins bind to & open GIRKs for K+ to flow
- opened GIRKs:
- not much of effect at baseline, as K+ near its equilibrium
- locks membrane into place, more K+ channels open & more K+ flows out to counteract Na+ entering:
- increasing permeability
- block excitation, fix cell around resting membrane potential
- prevent Na+ from depolarising cell
What is euphoria in relation to opioids?
- rush, high, nod (extreme sense of calm & disconnection w/ world), straight (period of normalcy after opioids warn off & before cravings)
- tolerance builds for euphoric effects
- consequence: escalation of intake related to tolerance
What is naloxone? Why is it important? Based on its pharmacodynamics, what effects would you expect if someone were to take naloxone on its own?
- potent opioid receptor antagonist
- for opioid overdose: taken too high of dose, administer naloxone & will block effects
- have opposite effects of opioid agonists
- if taken alone, feels unpleasant & like withdrawal
What are the effects of opiods?
- both CNS & PNS
- explains opioids’ variety of uses thruout history
acute pharmacological effects:
- analgesia
- constipation
- decreased blood pressure
- euphoria
- hypothermia
- relaxation
- respiratory depression
What is the mechanism of analgesia?
- descending pain modulation pathway: pain modulation starts at brain & travels downwards into spinal cord
- brain produces endogenous opioids for pain relief
- endogenous opioids mimic these effects
- opioids block pain signals at multiple sites, including in brain
What is nociception and analgesia?
- nociception: perception of pain
- analgesia: perception of pain relief
What are spinal cord interneurons?
short axons that project onto pain pathway & release endogenous opioids
What are notable regions for endogenous opioid neurons?
- periacqueductal gray (PAG): induce analgesia
- sends axons to raphe nucleus & release opioids
- raphe nucleus sends axons down to spinal cord
- spinal cord: releases 5-HT & lands on interneurons
- spinal cord interneurons
What are the symptoms of opioid withdrawal?
- opioid withdrawal is extremely aversive
- symptoms:
- pain sensitivity
- diarrhea
- increased blood pressure
- dysphoria & depression
- hyperthermia
- restlessness
- hyperventilation
What are opioids’ effects on dopamine functioning?
- opioid use increases DA release from VTA onto NAcc, by inhibiting GABA neurons
- VTA:
- opioid receptors on GABA neurons
- drugs bind to receptors, cause GABA neurons to stop releasing GABA
- inhibiting GABA inhibition
- DA neurons fire more
- NAcc:
- variety of opioid receptors on GABA neurons: project from NAcc back to VTA
- inhibitory neurons that inhibit DA’s subsequent release, block feedback effect
- more DA released into NAcc
- more activation within motivational reward-based system
- seek out drugs more & cues associated w/ drugs gain incentive salience
What is conditioned place preference? What does it tell us?
- reinforcing effects of opioids easily paired w/ environmental stimuli
- studied in animal models via CPP
- training: animal placed in different chambers: neutral, vehicle (injection w/ nothing), drug (injection w/ opioid)
- free testing condition: animal placed in neutral chamber & doors to other chambers opened:
- animal goes back to drug chamber
- spends far more time in drug than vehicle chamber
Why is opioid overdose dangerous?
- tolerance develops for all effects:
- leads to escalation of intake
- subjective & physiological effects tolerating at same speed, ppl try to feel subjective effects but put themselves in more physiological danger
- long-term use can even lead to reduced activity at Na-K pump:
- membrane sits at lower level than resting membrane potential (e.g. -68mV)
- leads to hyper-excitable neurons, neurons more easily excited & left a little depolarised
What does opioid overdose look like?
overdose: potentially lethal
- severe respiratory depression
- weakness
- inability to speak
- bluish lips & skin
- unconsciousness
What are the various reasons why opioids are such a societal problem?
- potential for lethal consequences, esp. w/ fentanyl
- repetition of history as regards prescription opioids:
- ~75% of heroin users started on prescription opioids: prescription goes away, but still feel need for opioids
- makers/family behind oxycodone sued: claims newest form of heroin much safer than previous one
- sweet spot for addiction: opioid use has severe withdrawal & substantial incentive sensitisation
- fentanyl easy to traffic
- contamination and/or errors trivial, but not their effects
Why not simply ban or eliminate all currently legal opioid use in society?
- opioids are the “gold standard for pain”
- fentanyl patches in terminal cancer, IV in surgery
- not so useful for neuropathic/idiopathic pain
- effective in treating diarrhea
- not so needed as cough suppressant
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(2) neuropsychopharmacology basics20
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(3) brain basics26
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(4) neural communication I26
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(5) neural communication II & drug properties (midterm 1)14
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(5) neural communication II & drug properties (midterm 2)28
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(6) addiction26
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(7) psychostimulants37
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Previous Lectures4
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(8) nicotine & caffeine36
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(9) alcohol34
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(10) opioids24
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(11) cannabis22
