give examples of opiates (4)
morphine, codeine, thebaine, oripavaine
give examples of endogenous opioids (4)
B-endorphin, met-enkephalin, dynorphin, endomorphins
what exact substance is heroin and how does it differ to morphine?
diamorphine- it passes through the BBB more rapidly than morphine and then gets broken down
name an agonist to each of the three types of opioid receptors
mu- DAMGO
delta- DPDPE
kappa- U50/ 488-H
what does the mu-opioid receptor do? (3)
is responsible for reward feelings, recruits B-arrestin2, activates cell response pathways.
what is the mechanism of opioid receptor tolerance relating to B-arrestin2?
- mu receptor gets sequestered into the membrane by B-arrestin2.
- The membrane endocytoses the receptor.
- This process is thought to be important in tolerance.
- When b-arrestin is recruited to the receptor it brings with it associated kinases that can signal other cellular effects, different to the g-protein ones.
what are the 4 mechanisms of morphine tolerance?
- receptor tolerance
- cell tolerance and withdrawal
- system tolerance and withdrawal
- synaptic plasticity in tolerance and withdrawal
what therapies are there for opioid use disorder? (5)
- psychosocial therapies (CBT)
- methadone (mu receptor agonist)
- Buprenorphine (mu-receptor partial agonist and K-receptor antagonist). Combined with naloxone in suboxone with reduce potential for diversion.
- naltrexone (opioid antagonist)
- Detoxification- symptomatic relief- anti-inflammatory drugs; antiemetics; anti-diarrhoeal medications. Lofexidine (a2 adrenergic receptor agonist) or other opioids
how does morphine act on the central dopaminergic pathway?
- when morphine is applied the GABA-ergic action potentials essentially stop
- baseline lowers slightly
- decrease in GABA inhibition results in increase dopamine release from the dopaminergic neurons
what type of opioid receptors are required for morphine reinforcement?
mu receptors (MOP-/- mouse model experiment)
which side effects of opioids is B-arrestin2 potentially involved in?
respiratory depression and constipation
what does an absence of B-arrestin2 result in? (mouse model)
reduced morphine tolerance (tail withdrawal test)
what is the influence of B-arrestin2 on morphine actions?
- increased basal analgesia mediated by MOPrs
- decreased morphine tolerance/dependence
- decreased respiratory depression
- decreased constipation
- decreased locomotion
- increased reward
psychomotor effects (only in rodents not in humans) require which receptors?
mu-opioid receptors
what is required for full locomotion associated with MOPrs?
B-arrestin2
what functions does dopamine regulate? (5)
- locomotion
- cognition
- reward
- emotions
- endocrine function
dopamine dependent disorders includes; (5)
- schizophrenia
- bipolar disorder
- depression
- Parkinson’s disease
- drug abuse/dependence
what synthesises dopamine?
tyrosine hydroxylase (TH)
what are the five main dopamine signalling pathways?
nigrostriatal, mesolimbic, mesocortical, tuberoinfundibular and tuberhypophysial
where do the nigrostriatal neurons originate from?
substantia nigra and VTA, projecting to the caudate putamen and NA respectively
what are the types of dopamine receptors?
D1-5
D1-like are D1 and D5, D2-like are D2, D3 and D4
what do the two kinds of dopamine receptors do to adenylyl cyclase?
D1 activates it, D2 inhibits it
which kind of dopamine receptors are required for morphine CPP?
D2
what do TH-/- mice show?
no morphine locomotion (restored by L-dopa injection)
still exhibit morphine reward
