Opioids Flashcards
What are opioids
Endogenous or synthetic substance with morphine-like effects, antagonized by naloxone
‘Opiate’ synthetic morphine-like drug with non-peptide structure
Opioid actions include analgesia, respiratory depression, euphoria and sedation
Led to discovery of receptor subtypes
Morphine analogues
Agonists - morphine, diamorphine (heroin), codeine
Antagonists – naloxone
Synthetic derivatives: pethidine, fentanyl, methadone
What are agonists, partial agonists and antagonists
Opioids produce their effect by acting at the opioid receptors in the nervous system
-opioid receptor most important
Agonists
bind to the receptor and stimulate physiological activity
Partial agonists
bind to the receptor but do not produce maximum stimulation
Antagonists
have no intrinsic pharmacological effect, but bind to the receptor and can block the action of an agonist
describe the opiate chemical structure
form an alkaloid
add two acetyl groups to morphine you get heroine
CH3C=O and CH2=CH groups
opioid peptide and receptor families
the first thing to say is there are four opioid receptor types.
Three classical receptors mu, delta and kappa and a forth, originally identified by homology screening after the cloning of the receptors that identified a related receptor, orginally called the opioid receptor like 1 receptor.
Proopiomelanocortin (B- endorphin—- MOP and DOP)
proenkephalin (enkephalin) acts on DOP
prodynorphin (dynoprhin) acts on KOP
pronociceptin (nociceptin) acts of NOP
in each of these, the opioid peptides act on the opioid receptors
It not only shared homology but was also a classical Gi/Go coupled 7 transmembrane spanning receptor and it turned out to have an endogenous ligand that shared sequence homology with classical endogenous opioid peptide ligands that had already been identified as acting at the mu, delta and kappa opioid receptors.
MOP, DOP, KOP and NOP! The four receptors have four families of endogenous ligands that act at them.
POMC that gives rise to b-endorphin, Proenkephalin producing at least four distinct enkephalins, Prodynorphin producing two dynorphins and two neo-endorphins and pronociceptin that produces nociceptin and two other biologically active compounds, one nocistatin which is an antagonist at the NOP receptor.
Structure of opiate receptors:
Mu opiate receptor:
intracellular and extracellular domain
Comparison of the amino acid sequences of the cloned mouse deta and kapa and rat mu receptor. The blue indicated common amino acid sequences. G protein couple receptors.
Describe the structural homology of opioid receptors
Mu opioid receptors: intracellular and extracellular domain
Comparison of the amino acid sequences of the cloned mouse deta and kapa and rat mu receptor. The blue indicated common amino acid sequences. G protein couple receptors.
Met-enkephalin Tyr-Gly-Gly-Phe-Met
Leu-enkephalin Tyr-Gly-Gly-Phe-Leu
Dynorphin A Tyr-Gly-Gly- Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln
ß-endorphin Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu…
Nociceptin(OFQ) Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln
Endomorphine No precursor found
How can radiographic sections show us where opiate receptors are located
radographic coronal sections
shows where mu opioid receptor is localied and distributed, shown in red
high levels of mu opioid receptor in regions of award- nucleus accumbens
explains why opioids are addictive- due to high density in areas associated w award
high areas in periaquedutal grey- associated w modulation of pain. explains why opioids are analgesics beause they bnd to regions associated w pian
These are coronal sections from fore to the beginning of the hindbrain and all of the images I will show you conform to the same colour coding. Blue is low, with increasing receptor levels from green through yellow to red and black. There is widespread expression in many brain regions, including the rostral to caudal cortex, motor regions such as the caudate, limbic structures such as the amygdala, stria terminalis, reward areas such as the accumbens and of course pain processing structures such as the thalamus and the colliculi.
pharmacological effects of opioids (factors to consider)
Consider:
Analgesia
Supraspinal
Spinal
Peripheral
Respiratory depression
Pupil constriction
Reduced gastric motility
Euphoria
Dysphoria
Sedation
Physical dependenceEffects of opioids on respiratory depression
Respiratory depression
reduced sensitivity of respiratory centre to CO2
Mediated by mu receptors
Most troublesome side effect, occurs at therapeutic doses
Commonest cause of death in opiate poisoning
Morphine used as reference compound
Euphoria likened to orgasm and sudden ‘rush’
usually when you have too mucb co2 signal is sent to your lungs from brain to lungs to hyperventilate and expel co2. this is desensitised by opioids
means co2 levels increase in blood and death occurs due to asphyxia
Describe opioids as analgesics
Enalodine, U50488 (KOP)/low dependence liability BUT psychotomimetic effect (withdrawn)
Peripheral acting KOP for peripheral pain and itching
DOP agonists poor analgesics but have antidepressant properties. However, proconvulsant effects
codeine reduces coughing
opioids induce nausea and vomiting initially as opioid receptors are found in emesis centre of brain and in chemoreceptor trigger zone
other actions of opioids on systems?
Cough reflex
Codeine used in cough medicine to suppress cough
Mechanism unclear, can occur at subanalgesic doses
Nausea and vomiting (Q. how?)
Occurs in 40% of patients
Opioid action in CTZ () and vomiting centre ()
Pupil constriction
Pinpoint pupils used as diagnostic feature in opiate poisoning
Other causes of respiratory depression & coma cause pupil dilatation
GI tract
tone and motility, constipation
Other actions
Morphine releases histamine from mast cells - itching
effector mechanisms of opioids
Opioid receptors: mu delta kappa/ inhibition
G-protein coupled receptors (Gi/Go)
increased K+ channel opening, hyperpolarization
decreased opening of voltage-gated Ca2+ channels
Reduce neuronal excitability (K+) and reduce neurotransmitter release (Ca2+)
Inhibition of adenylyl cyclase, decrease cAMP, PKA
mu delta and kappa receptors are all gpcrs- gi or go
so if heroine binds, receptor couplingw a Gi/go protein occurs
activates different 2nd messengers
beta gamma subunit of the g protein opens potassium ions causing them to leave (more conc in the neurone than outside)
causes hyperpolarisation of neurone
inhibits calcium channels- inhibits release of neurotransmitters from neurones
Mechanism for how opioids block pain?
Shows how opioids block pain- how they act as an analgesic
so let’s look at how pain is transmitted from periphery to brain
AFFERENT neurones have cell body in dorsal root ganglion with 2 projections: one projection to periphery and other towards dorsal horn of spinal cord
pain receptors called nociceptors are activated by mechanical/chemical/inflammatory stimulation
nociceptors carry action potential when activated along neurone, leading to dorsal horn of spinal cord
leads to release of neurotransmittes: substance P and glutamate
acts on neighbouring neurons which project from dorsal horn of spinal cord ot the brain where pain is detected
so this is how pain transmission NORMALLY works
anything that blocks the transmission of neurotransmitters from the periphery to the brain can be used as an analgesic
opioids by acting on opioids receptors in the periphery, dorsal horn of spinal cord as well as the brain act as ideal analgesics can block the transmission of pain , acting on 3 LEVELS of transmission making them great analgesics
Describe the dorsal spinal cord
afferent neurones project from periphery, carrying pain info
release substance p and glutamate
transmit to neighbouring neurone, projecting to brain
mu opioids receptors found post synaptically on cell body of neurones
also found pre-synaptically on afferent neurones , also post-synaptically on dorsal horn
morphine acting pre-synaptically would inhibit the release of substance p and glutamate (pain inducing neurotransmitters)
therefore pain is transmitted from periphery to brain
Describe the descending control system
Opioids excite the PAG neurons and neurons in the nucleus reticularis paragigantocellularis (NRPG) stimulating neurons in the nucleus raphe magnus (NRM)
The 5-HT and enkephalin neurons of the NRM run to the dorsal horn and inhibit transmission
Opioids can act directly on the dorsal horn (and on peripheral terminals)
NAergic neurons of locus coeruleus also inhibits dorsal horn
the periaqueductal- PAG area of the brain is activated by opioids
stimulates descending inhibitory neurones
PAG to DLF
stimulates other inhibitory neurones like serotonin and enkephalin
release in dorsal horn of spinal cord
suppress information from periphery to dorsal horn of spinal cord to block transmission of pain
