Opioids and Opioid Receptors: Flashcards
What is the definition of an opioid?
naturally-occurring, synthetic or semi-synthetic compounds which act at opioid receptors
What are these naturally-occurring compounds also called?
Opiates - they are derived from the resin of the opium poppy
Give 3 examples of opioids
Morphine
Codeine
Thebaine
What are morphine esters derived from? What do they include?
Morphine esters are derived from opium.
They include morphine prodrugs such as diacetylmorphine - AKA heroin
What do semi-synthetic opioids include? What are they derived from?
o Semi-synthetic opioids (derived from opium or morphine esters) include buprenorphine and oxycodone
What do synthetic opioids include?
o Synthetic opioids include fentanyl, pethidine, methadone, and tramadol
What do endogenous opioids include?
Enkephalins and endorphins
What are the effects of opioids? Is their abuse potential low or high?
Effects:
o Surge of pleasurable sensation (“rush”)
o Reduced stress and anxiety
o Sedation
o Impaired mental function
o Cardiac and respiratory function slows – can be life-threatening
o Reduced pain – physical and psychological
Opiates (in the form of opium) have been used and abused since antiquity – evidence suggests the opium poppy was cultivated as far back as 3400BC
• Opioids (includes opiates) have a very high abuse potential
Is diacetylmorphine an active drug?
No, but it is rapidly metablised into active drugs
What is diacetylmorphine metabolised into? Which of them are active compounds?
Diacetylmorphine –> 6-monoacetylmorphine (active) + 3-monoacetylmorphine (inactive) –> morphine (active)
What gives diacetylmorphine its lipid solubility? What are the implications of this?
o The 2 acetyl groups make the compound highly lipid soluble – it can cross the BBB much more easily than morphine
Which gene encodes proenkephalin?
The PENK gene
How many forms of enkephalin are there? What are they called and why?
2 forms:
[Met]enkephalin - AA sequence is Tyr-Gly-Gly-Phe-Met
[Leu]enkephalin - AA sequence is Tyr-Gly-Gly-Phe-Leu
What does xM mean?
Extended [met]enkephalin
What is the ratio of the amount of [met]enkephalin to [leu]enkephalin produced by the body?
4:1 ratio
Which gene is prodynorphin encoded by?
PDYN
How many isoforms of dynorphin are there? Name 5 of these.
7 isoforms:
α-neo-endorphin β-neo-endorphin Big dynorphin A Dynorphin A (various sizes) Leumorphin Dynorphin B Leu-enkephalin
Which gene encodes beta-endorphin?
POMC gene, encodes proopiomelanocortin. Beta-endorphin is the only opioid produced by POMC
Which N-terminal sequence is encoded by all endogenous opioids?
either [Met]- or [Leu]-enkephalin
Name the four types of opioid receptors, their endogenous agonists, their signalling mechanism, and the downstream effects of this mechanism
δ – agonised by β-endorphin, [Leu]enkephalin and [Met]enkephalin
κ – agonised by big dynorphin and dynorphin A
μ – agonised by β-endorphin, [Leu]enkephalin and [Met]enkephalin
NOP – agonised by nociceptin/orphanin FQ
All signal via Gi/o signalling - many downstream messengers and effects:
Affects K+ and Ca2+ channels
Desensitisation via interactions with GRK, βarr, PKC, PKA
Endocytosis via interactions with AP2, PLD2, Dyn, βarr, clathrin
Interacts with ERK, JNK, and βarr for G-protein-independent signalling
List 4 uses of opioid receptor agonists and state what they are used to treat
Agonists – used for pain management:
- Acute pain management
- Pain management in palliative care
- Long-term pain management
- Supplement to general anaesthesia
- Primary anaesthesia
What are opioid receptor antagonists used to treat? Name one.
Antagonists – treat opioid overdose:
o Naloxone – non-selective competitive opioid receptor antagonist
Briefly describe the sensory transduction pathways for noxious and non-noxious stimuli.
Non-noxious and mechanical stimuli are transduced into action potentials within Aβ-fibres of the PNS; these are then relayed through the dorsal root ganglion to the CNS (thalamus and primary sensory cortex)
Noxious mechanical stimuli are transduced into APs within Aδ-fibres of the PNS; these are then relayed through the dorsal root ganglion into a motor neuron (to effect an immediate response) and to the CNS (thalamus and primary sensory cortex)
Noxious heat and chemical stimuli are transduced into APs within C-fibres of the PNS; these are then relayed through the dorsal root ganglion into a motor neuron and to the CNS (thalamus and primary sensory cortex)
What is rate coding?
Coding of intensity – weak stimuli have APs firing less frequently
o Strong stimuli have APs firing more frequently
o APs don’t get bigger; they become more frequent as the intensity of a stimulus increases
• At the spinal cord, the AP from the dorsal root ganglia/nodose ganglia/trigeminal ganglia triggers neurotransmitter release to pass the signal along to the CNS
How do opioids suppress pain?
Opioids do not block the neurotransmitter receptor
μ-opioid receptors are Gi/o-coupled; therefore these negatively couple (or suppress) the activity of Ca2+-channels (voltage dependent and voltage independent) –> reduced synaptic transmission
Explain, with the aid of a diagram, descending control of nociception in the spinal cord.
There is a descending 5-HT projection (in the dorsolateral funiculus) from the Raphe nuclei which stimulates GABAergic and enkephalinergic interneurons, causing these to release GABA and enkephalins (respectively). The 5-HT projection also inhibits the spinal projection neuron via a 5-HT1AR.
GABAergic interneurons inhibit the spinal projection neuron by releasing GABA.
Enkephalinergic neurons inhibit spinal projection cells via opioid receptors (coupled to K+ channels –> cell hyperpolarisation ∴ suppressing APs).
Enkephalins also depress Glu release from the primary afferent neuron (bringing pain signals from the PNS).
Primary afferent neuron normally excites the spinal projection neuron, causing pain detection. Therefore by blocking the mechanisms listed, we can control nociception.
(Diagram in lecture notes)
What are the major sites of analgesic opioid actions? Are they pre- or post-synaptic?
- Periaqueductal grey: opioid receptor activation causes activation of periaqueductal grey projection neurons, by inhibiting the ongoing synaptic inhibition they normally receive
- Presynaptic terminals of primary afferent nociceptors: this depresses the release of glutamate and therefore depresses synaptic excitation
- Post-synaptically in spinal cord projection neurons – this inhibits activity in the spinothalamic tract by activating K+ channels –> hyperpolarisation of the neuron
List 5 situations wherein pain sensation may be reduced.
Inhibition of which pathways may play a role in this?
o Fakirs – Sufi Muslims who have taken vows of poverty and worship, renouncing all relations and possessions; they’re self-sufficient and possess only the spiritual need for Allah. Renowned for lying on nail-beds and feeling no pain
o Battlefields or accidents – people not noticing injuries, or overcoming normal human limits such as mothers lifting cars to get their children out
o Redirection of attention – focussing on something else
o Hypnosis
o Altered emotions/motivation -
o Acute injuries – stimulating the skin near the site of the injury
Descending inhibition of the periaqueductal grey, presynaptic terminals of primary afferent nociceptors, and postsynaptically in spinal cord projection neurons
List 6 side effects of taking opioids
• Addiction o Often --> abuse • Tolerance o Occurs on a clinical, behavioural, and cellular level • Sedation • Itching • Dry mouth • Dizziness • Nausea • Vomiting • Respiratory depression • Constipation
Why is constipation a health economics issue? Present a potential solution.
Health economics issue – patients who’ve undergone major surgery are usually treated with opioids for post-surgical pain relief –> constipation.
Patients can’t be discharged until they’ve defecated – opioid treatment –> bed-blocking
This occurs because opioids reduce normal neurotransmitter release in the GI tract. Normally, GI motility relies on a fine balance between excitatory and inhibitory neurotransmitters released by myenteric neurons acting on smooth muscle
Taking opioids –> abnormal coordination of smooth muscle contraction and relaxation –> increased muscle tone in the small and large intestinal circular muscle; causing constipation
Solution:
Peripherally-restricted μ-opioid antagonists:
Alvimopan
Polar molecule ∴ low lipid solubility so can’t cross BBB well
In oral formulations it’s very poorly-absorbed –> concentrating effect in GI tract
Explain the molecular mechanisms which may contribute to opioid tolerance. Use a diagram.
Initially (0-0.1s) – prolonged agonist binding desensitises GPCR (G-proteins uncoupled)
Long term (1s-hours) – c-terminus sites are phosphorylated –> β-arrestin2 binding, signals to other clathrin-coated mechanisms –> endocytosis of receptor, so no longer activated by exogenous agonists
Reversal of these processes via receptor cycling reduces tolerance
Describe a piece of evidence in favour of beta-arrestin2 being involved in tolerance
β-arrestin2 KO mice don’t develop an anti-nociceptive morphine tolerance – suggests β-arrestin2 is required for tolerance development.
Tested via hot-plate response latency (plate at 56°C); tested maximum possible effect (MPE).
%MPE = 100% x ((drug response time-basal response time))/((maximum test duration-basal response time))
Maximum test duration is usually 30s to avoid tissue damage
Why are synthetic opioids such as fentanyl more potent than natural opioids in vivo, despite similar binding and potency in vitro? How does this contribute to the lethality of fentanyl?
Fentanyl has greater potency in vivo but similar binding and potency in vitro compared to heroin
Receptor binding Ki = 1.35nm (morphine) 1.17nm (fentanyl)
[35S]GTPγS binding (functional) logEC50 = -6.4 (morphine) -6.8 (fentanyl)
Difference in potency is due to fentanyl being ~3000x more lipophilic than morphine, so fentanyl can cross the BBB more easily and therefore produce more potent (and potentially fatal) effects at lower doses
Log P 1.07 (morphine) 4.28 (fentanyl)
More drug in the CNS –> more μ-opioid receptor activation –> greater CNS effects (e.g. greater respiratory depression via μ-opioid receptors in respiratory areas in the brain stem), potentially death
