Opioids Flashcards
What is the main function of opioids?
analgesia
Where can you find naturally occurring opioids?
in alkaloids found in the opium poppy
What are opiates?
opiates are the naturally occurring opioid
What caused a surge in US opioid use?
end of the civil war; soldier’s disease
production of hypodermic syringe
What is heroin?
a semi-synthetic opioid
What is the potency of heroin?
5x more potent than morphine as it is more lipid soluble due to addition of 2 acetyl groups
What is the pharmacological effect of heroin?
identical to morphine as it is largely metabolised into morphine
How does administration affect the pharmacological effect?
oral; analgesia but no euphoria/rush
IV/smoking/snorting; analgesia and euphoria
What are the major clinical effects of opioids?
analgesia euphoria conditioned place preference reduced gastrointestinal motility cough suppression
What are the major side effects of opioids?
reduced gastrointestinal motility
respiratory depression
nausea/vomiting
What are the effects of repeated opioid administration?
sensitisation
tolerance
withdrawal
What opioid effects can become sensitised?
stimulant effects; with VTA administration
rewarding effects
What opioid effects can become tolerated?
analgesia
euphoria
respiratory depression
What withdrawal effects are seen with opioid use?
symptoms are opposite to the acute effects
How can respiratory depression be reversed?
administration of naloxone
What is saturable binding?
the maximum effects observed in opioids suggests that there is a finite number of mechanisms on which opioids can act
How can we predict analgesic effects in humans from animal studies?
opioids causing contractions of the intestine in the guinea pig predicts human analgesia
What are the endogenous ligands/peptides that act on μ receptors?
endorphins
endomorphins
What propertied/precursor peptide is used to create μ peptides?
POMC
unknown
What are the endogenous ligands/peptides that act on δ receptors?
enkephalin
endorphin
What propertied/precursor peptide is used to create δ peptides?
proenkephalin
POMC
What are the endogenous ligands/peptides that act on κ receptors?
dynorphins
What propertied/precursor peptide is used to create κ peptides?
prodynorphin
What is the structure of opioid receptors?
a chain of amino acids that span the cell membrane 7 times
How can the structure of opioid receptors affect there pharmacological effects?
alternative splicing can produce different receptor sequences, these SNP’s cause individual variation such as; liability to alcoholism
Where are opioid receptors most frequently found?
in areas involved in emotion and pain; striatum, thalamus cortex
What method can be used to detect opioid receptors?
washing brain slices with a radioactive ligand and then PET scanning
What type of receptor are opioid receptors?
metabotropic g-protein coupled
What actions can the g-protein coupled receptors have?
postsynaptic; decreases firing by K+ release
axoaxonic; decreases NT release by closing Ca2+ channels
presynaptic autoreceptors; decreases NT release
How are neuropeptides released?
generally co-released with another transmitter
large vesicle with precursor peptides (pro peptides) is broken down by peptidases to liberate peptides
Where are the μ analgesic receptors found?
dorsal horn
PAG
limbic region
What mechanisms can relay pain information?
early; synapsing on interneurons in the spinal chord
late; direct projections up the spinal chord to the hindbrain, midbrain and thalamus
What is the spinal mechanism for pain sensation?
sensory neurons synapse with an interneuron/projection neuron to provide a basic reflexive response to avoid painful stimuli
How can spinal analgesia be induced by opioid drugs/endogenous opioids?
projection neurons have opioid receptors, opioids can inhibit the projection neurons
What is the supra-spinal pain modulation pathway?
PVG → PAG → raphe → dorsal horn → spinal chord
What evidence is there for a downward modulatory pathway?
stimulation of the PAG prevents neuronal firing in the dorsal horn
lesions on the raphe blocks analgesic effects
How is pain information relayed by the supra-spinal pathway?
5-HT usually acts to inhibit projection neurons in the dorsal horn
GABA is activated when pain is experienced and acts to inhibit 5-HT, disinhibiting projection neurons
How do opioids affect the supra-spinal pathway?
opioids inhibit GABA, releasing 5-HT from inhibition so it can returning to inhibiting projection neurons in the dorsal horn
Which brain regions are involved in sensory pain perception?
NAcc
amygdala
thalamus
Which brain regions are involved in affective pain perception?
NAcc
thalamus
ACC
Can the opioid system be influenced by cognitive factors?
a placebo experiment (Zubieta et al., 2005) found that when patients expected pain relief, the opioid system became more active, this effect was inhibitable by naloxone
Do morphine and heroin have different pharmacological actions?
evidence shows that they act on different receptors
Schuller et al. (1999); CXBK and MOR-1 knockout mice were insensitive to morphine but not heroin
Are kappa agonists abused?
no, they produce aversive, psychotomimetic effects in humans and are not self-administered by animals
How do the μ receptors influence DA release?
μ agonists release dopamine from inhibition by GABA and increases levels in the NAcc
What evidence is there for the role of DA in opioid mechanisms?
morphine is no longer self-administered following DA lesions or DA antagonism
morphine place-preference abolished in D2 knockouts (Maldonado…Borrelli 1997)
Are all opioid effects mediated by DA?
no, subjective pleasure expressions not influenced by DA are influence by opioid administration
Where do the major reward and locomotion effects take place?
μ receptors in the VTA
Where do the major analgesic effects take place?
μ receptors in the dorsal horn, PAG and limbic system
Where do the major gastrointestinal motility effects take place?
μ and k receptors in the stomach and intestines
Where do the major respiratory depressive effects take place?
μ receptors in the medulla and nucleus of solitary tract
