Lesson 15/16: Opiates and Opioids

Opiate

• derived directly from opium poppies (morphine, codine)

opioid

• synthetic or semi synthetic drugs that resemble opiates chemically but may not come from opium (heroin, oxycodone, fentanyl, neloxone)

How to make heroin

• opium → scrape white residue from scored poppy flower buds

• morphine → soak in warm sodium carbonate, skim top layer

• heroin → mix purified morphine with acid and heat until crystallized

Opioid routes of administration

• medical → pill, suppository, injection, or nasal spray

• recreational → injection, smoking, inhaling, sublingual

  • hit faster and more intense

Absorption

• opioids are weak bases

• lots of first pass metabolism → less effective taken orally

  • morphine and heroin

• more lipid soluble are better absorbed orally

Distribution

• opioids concentrate in

  • heart, liver, lungs, kidney, and spleen

  • less in the muscles and brain. in brain there are higher concentrations in

    • basal ganglia (movement, reward, motivation

    • amygdala (mood)

    • periaqueductal grey (pain)

Elimination

• often metabolized by CYP450 enzyme

  • not morphine, heroin, and ozymorphone

  • enhanced by st johns wort

• some people have multiple copies of CYP450 gene → ultra fast opioid metabolism

• others have non functioning alleles → slower metabolism

• opioid metabolites may be inactive, or even more active than their parent molecule

Opioid receptors

• all metabotropic and inhibitory

  • when a molecule binds to them, they release a G protein that creates a protein synthesis chain that will do something inside the neuron, excitatory or inhibitory, depending on G protein

  • generally hyperpolarize the cell

• When activated, they release G protein subunits that

  • stimulate potassium channels to open and potassium exits cell

  • stimulate Ca2 channels to close

    • cAMP production inhibited

mu opioid receptor

• respiration + sedation + reward

• linked with addiction and overdose

• effects → euphoria, addiction, respiratory depression

• beta endorphins have affinity

delta opioid receptor

• pain signaling (relief) + positive mood

• effects → analgesia, mild euphoria

• enkephalins and beta endorphins have affinity

kappa opioid receptor

• pain sensing + sedation + dysphoric mood

• not very well understood

• counteract some of the pain related effects, sedation and dysphoric mood

• dynorphins have affinity

ORL1 opioid receptor

• newly discovered and not well understood

• nociceptin has affinity

Primary effects

• analgesia (pain killer)

• antitussive (cough suppressant)

Major side effects

• euphoria/warmth/wellbeing

• sedation

• respiratory depression

• habit formation, dependence, addiction

• endocrine system suppression

• constipation

• nausea and vomiting

• itching

• convulsions

• death

Effects on reward

• mu → found on GABAergic interneurons in VTA

  • increased activation removes GABA inhibition of DA projections from VTA to NAcc → increased reward signalling

• delta → found in cortex and limbic system

  • may contribute to drug craving and reward in these regions

• kappa → may work as a negative feedback mechanism in mesolimbic DA circuit to counteract drug induced DA increases

Effects on human behavior

• cognitive

  • inattention, memory deficits, psychomotor impairment, diminished sleep quality, sleepy trance like state

• mood

  • initially positive, euphoric

  • after tolerance → short periods of euphoria quickly replaced by more negative moods

Effects on animal behavior

• is a discriminative stimulus

• stimulant at low doses

• depressant at high doses

• catalepsy at very high doses

• conditioned place preference learning depends on mu receptor agonism to signal reward, and delta receptor agonism to enable contextual learning

  • kappa receptor inactivity to precent conditioned place aversion

• self administer

tolerance

• 3-4 months → intake increases 10x

  • levels that would kill a non tolerant user several times over

• rapid tolerance to most effects

  • partial tolerance to pupil constriction, no tolerance to constipation

• complete tolerance to the analgesic and positive reinforcing effects

• cross tolerance among opioids

sensitization

• hyperalgesia - increased sensitivity to pain

• caused by neurotoxic effects in dorsal horn of spine → prevents analgesic effects

withdrawal

• less severe

• first chills/hot flashes, restlessness, agitation, short and rapid breaths

• then, deep sleep followed by flu like symptoms, twitching and sweating

Treatment - Detoxification

• eliminate physical dependence by helping guide the patient through withdrawal

• 2 approaches

  • abrupt → increases risk

  • gradual → switching to a maintenance drug, and slowly tapering off that

Maintenance therapy

• methadone

  • mu agonist (long lasting)

  • blocks withdrawal, reduces relapse

  • less of a rush from administration

• buprenorphrine

  • partial mu agonist, delta/kappa antagonist

  • less dependence risk

  • longer lasting

  • more withdrawal symptoms, less positive reinforcement

Agonist therapies

• naltrexone

  • blocks all opioid effects

  • slow release

  • high noncompliance issue

• naloxone

  • reverses overdose

    • halts the action of opioid receptor agonists

    • displaces other opioid molecules from mu receptor sites without having an agonistic effect of its own

  • life saving, widely available