Opioids Flashcards
What is the definition of opioids?
Naturally occurring, synthetic or semi-synthetic compounds which act at opioid receptors
What are the effects of opioids?
Surge of pleasurable sensation, reduced stress and anxiety, impaired mental function, slowed cardiac and respiratory function, reduced pain
The two acetyl compounds of diacetylmorphine (heroin) make it easier to what?
Cross the BBB
What is the generic structure of metenkephalin and leuenkephalin?
Tyr - Gly - Gly - Phe - Met/Leu
What are met and leu generated from?
Proenkephalin
What ratio of met to leu in proenkephalin?
4:1
All endogenous opioids feature…?
The same N terminal sequence of either metenkephalin or leuenkephalin
Which fibres are used to signal non-noxious mechanical stimuli?
A beta fibres
Which fibres are used to signal noxious mechanical stimuli?
A delta fibres
C fibres are used to transmit what sort of stimuli?
Noxious heat and chemical stimuli
Which types of fibres are nociceptive?
A delta and C fibres
What is coding of intensity?
Action potentials occur more frequently when a stimulus is more painful or increased and vice versa
what is coding of intensity recruitment?
More neurons are recruited in the presence of a more painful stimulus, leading to increased frequency of action potentials.
What is the endogenous descending control of nociception?
5HT neurons act on 5HT1A receptors to reduce activity of spinal projection neurons at a positive 5HT receptor to stimulate GABAergic neurons to also inhibit.
5HT can also bind to positive receptors on enkephalinergic interneurons to release metenkephalin and leuenkephalin to depress glutamate release from primary afferents and postsynaptically by activating K+ channels to hyper polarise - making it less like to have an EPSP.
What are the major sites of analgesic opioid action?
Periacqueductal Grey - opioid receptor activation causes activation of PAG projection neurons by inhibiting the ongoing synaptic inhibition they receive.
Presynaptic terminals of primary afferent nociceptors - depresses release of glutamate and thus synaptic excitation
What are the side effects of opioids?
Addiction, tolerance, sedation, itching, dry mouth, dizziness, nausea, vomiting, respirator depression and constipation.
Why does constipation occur during opioid use?
Opioid receptors are distributed throughout the GI tract. GI motility relies on fine balance between excitatory and inhibitory release of neurotransmitters by mesenteric neurons - this is redeuced by opioids leading to neuronal mediated blockade of secretomotor GI function - abnormal coordination of smooth muscle contraction and relaxation.
What is the solution to opioid-induced constipation?
Peripherally restricted mu opioid antagonists e.g. Alvimopan has low lipid solubility so doesn’t cross the BBB and is poorly absorbed so concentrated in the GI tract.
Why does overdose often happen in relapse?
Because opioid tolerance develops when you are taking the drugs, during withdrawal the tolerance reverses - but people may relapse and take the dose they used to, which can now kill them.
What is the pathway that leads to tolerance?
Phosphorylation > beta arrestin binding > endocytosis of receptor > tolerance
What is evidence that beta arresting is involved in the development of tolerance?
Beta arrestin knockout mice do not develop antinociceptive tolerance.
Why is fentanyl more potent in vivo than in vitro?
because it is very lipophilic, so crosses the blood brain barrier quickly.
