opioids and receptors

Question 1

what are the endogenous peptides acting at opioid receptors

Answer 1

1. enkephalins
   found mostly on CNS and immune cells. mu and delta agonists
2. endorphins
   found in brain. mu agonists
3. dynorphins
   CNS. highly selective for kappa
4. endomorphins
   mu agonists, most potent. highest affinity binding

they are derived from cleavage of precursors (prohormones)

Question 2

what are the opioid receptor subtypes

Answer 2

mu (in periphery spinal cord and brain)
delta (in periphery, increased expression in inflammation)
kappa (in spinal cord)
nociceptin

Question 3

describe signalling cascades of opioid receptors

Answer 3

Gai coupled receptors
upon agonist binding GDP exchanged for GTP at alpha subunit
G protein dissociates
Ai subunit inhibits adenylyl cyclase leading to decreased ATP conversion to cAMP
if expressed post synaptically:
Beta gamma subunit activates GIRK channels leading to potassium efflux and hyperpolarization of neuronal membrane.
if expressed pre-synaptically:
inhibits voltage gated sodium channels reducing Ca2+ influx inhibiting NT release.
both conditions explain analgesic effects and lead to the inhibition of NT

Question 4

describe effects of opioids

Answer 4

theraputic:
anti-tussive (effective cough reflex supression from CNS at sub analgesic doses)

anti-diarrhoea

analgesia (inhibit nocioception. effective in acute severe pain and chronic pain)

side effx:
respiratory depression (decrease in respiratory rate through MOP receptor in brainstem. All analgesic doses lead to dis)

nausea & vomitting (transient)

dizziness & confusion

constipation (inhibition of GI tone and motility. slows drug absorption)

tolerance

pruritis (opioid independent independent. due to histamine release from mast cells)

pupiloconstriction

non-medicinal:
euphoria and sense of well being asf (mu opr. mediated, offset by KOP dysphoria

Question 5

explain dependence tolerance and withdrawal

Answer 5

tolerance: need to increase dose to maintain effects. develops rapidly, increases risk of side effects when dose increased. can be detected after 12-24 hours of morphine administration.
ex: effective pain relief requires higher dose of opioids. tolerance to some side effects but not constipation. dose escalation needed usually after 15 months

dependence:
physical > development of withdrawal
psychological > craving to take drug irrespective of adverse consequences

withdrawal: occurs when a person dependent on opioids suddenly stops or reduces their opioid use, leading to physical and psychological symptoms.

also: opioid induced hyperalgesia due to sensitization of pro-nociceptive mechanisms.

Question 6

provide alternative hypotheses for opioid tolerance

Answer 6

no evidence for pharmacokinetic changes such as reduction in amnt available due to increased metabolism or increased removal for ex: by Pglycoprotein efflux transporter numbers increasing

GPCR regulation
1. receptor phosphorylates and uncouples from G protein
2. arrestin is recruited and binds to the phosphorylated receptor
3. arrestin facilitates receptor internilization
4. if stimulus removed receptor can be recycled to the plasma membrane . prolonged stimulation can lead to receptor degredation.

lower efficacy drugs lead to increased Mu opioid receptor tolerance.
ex: internilisation is higher with endogenous peptide ligands. high efficacy morphine leads to less internilisation

other hypothesis:
adneylyl cyclase superactivation (leading to increase in cAMP)
co-activation of NMDA (NMDA antagonists like ketamine reduce opioid tolerance and dependence in animals)

Question 7

identify therapeutic alternatives for opioid withdrawal

Answer 7

symptoms treated with:
diarrhoea (loperamide: peripheral opioid agonist)
stomach cramps: mebeverine
headache/muscle pain: paracetamol or NSAID
nausea: metcolopromide
insomnia: short acting benzo
clonidine/lofexidine (a2 agonists) alleviate symptoms by reducing sympathetic NS activity which is increased during withdrawal.

Question 8

describe opioid withdrawal

Answer 8

symptoms:
fever, insomnia, nausea, sweating, goos pimples, involuntary leg movements, yawning, diarrhoea, dilated pupils

peak around day 2-3 dissapear by day 10. reversed by re administration of opioid agonist and symptoms can be produced by administration of opioid receptor antagonist naloxone

Question 9

how can opioid addiction be treated

Answer 9

medical social and psychological intervention
substitution therapy reduces craving

methadone: opioid receptor agonist with longer half life. does not produce IV heroin like high via oral administration. still danger of OD

buprenorphine: partial agonist. ceiling effect reduces danger of OD can still cause withdrawal effects by displacing other opioids if they are present in the system.

Question 10

give examples of drugs that act on da opioid receptors

Answer 10

agonists:
buprenorphine
codiene
morphine
heroin/diamorphine
methadone
fentanyl
loperamide

antagonist:
naloxone used to reverse OD has short half life
naltrexone longer half life prevent abuse.