Pain and analgesics 2 Flashcards
Where does peripheral sensitisaiton occur?
The primary nociceptive neurons (in the skin etc)
Where in the spinal cord is the first synapse?
Most dorsal aspect (lamina 1 or lamina 2)
Which NTs is released from the nociceptive neurons in the spinal cord?
Mostly glutamate, also some substance P and a little amount of GCRP
What is CGRP?
Calcitonin gene related peptide
Which receptors does glutamate activate?
AMPA and NMDA
Which receptor does substance P activate?
NK-1 receptor
What type of receptor is NK-1?
GPCR
Why is a fast slow time course observed in glutamate transmission?
AMPA are fast bc and NMDA are slow
Which second messenger does NK-1 release?
Gq
What does Gq second messenger do regarding PIP2?
Breaks down PIP2 into Diacylglycerol (DAG) and inisitol triphosphate (IP3)
What does inositol triphosphate do?
Activates calcium stores which leads to an increase in intracellular Ca2+ concentrations
What does DAG do?
Activates protein kinase C
What does Gq second messenger do regarding ion channels?
Activate Na+, Ca2+ entry ion channels and inhibit K+ exit ion channels–> more depolarisation
What happens if there is a burst of activity from the presynaptic neuron in the spinal synapse part of the pain pathway?
The synapse increases in strength over time (i.e. after 11th AP the postsynaptic response is bigger than previous)
What is synaptic plasticity?
The strength of a synapse changes over time
Why does the spinal synapse become more sensitive over time?
NMDA receptors and NK-1 receptors
How is it known that NMDA receptors affect synaptic plasticity?
Synaptic plasticity does not occur with AP5 (NMDA agonist) present
How is it known that NK-1 receptors affect synaptic plasticity?
Synaptic plasticity does not occur with SP agonist(NK-1 agonist) present
Where in the nociceptive pathway do inhibitory interneurons attach?
The dorsal horn projection neuron
How are inhibitory interneurons activated in the pain pathway?
Offshoots of mechanoreceptors that are in the spinal cord can activate inhibitory interneurons
What type of neurons activate inhibitory interneurons in the pain pathway?
Glutamatergic
What is nursing the injury?
Touching an injured part of the body
Why do we “nurse an injury”?
Touching it activates mechanoreceptors which can cause inhibitory interneurons to be activated, thus inhibiting the pain
What is TENS?
Transcutaneous electrical nerve stimulation–>An electrical pack that stimulates touch receptors on the skin
Why does TENS work?
Activates mechanoreceptors which can cause inhibition of pain
Which two types of pathway can inhibit nociception?
Descending inhibitory pathway and ascending inhibitory pathway
What is the ascending inhibitory pathway?
Mechanoreceptors causing inhibition
What is the descending inhibitory pathway?
Parts of the brainstem, when stimulated, can inhibit pain
Which parts of the brain can cause descending inhibitory input?
Periaqueductal grey and raphe nuclei
Where does the periaqueductal grey project to in inhibitory input?
The raphe
Where does the raphe project to in inhibitory input?
The first synapse in the spinal cord
Where in the brain does the periaqueductal grey receive inputs from?
Hypothalamus, amygdala, cortex
Where does the nucleus reticularis paragigantocellularis project to?
Raphe nuclei
Where does the locus coeruleus project to?
Spinal cord
Where does the hypothalamic paraventricular nuclei project to?
Periaqueductal grey
Can the environment you are in affect the amount of pain you are in?
YEs
Why may your environment having an effect on how much pain you are in be beneficial?
Get injured while running away from predator–> still need to run away so pain is reduced
What effect does opioids have on nociceptive neurons?
Inhibit the free nerve endings, hyperpolarizing them and making them less likely to fire APs up pain pathway
How does the PAG act as an inhibitor of pain?
Sends input to the raphe which causes the raphe to fire inhibitory APs down the spinal cord
How does the raphe send inhibitory APs down the spinal cord?
Via release of 5HT
How does the locus coeruleus inhibit pain pathways in the spinal cord?
Via the release of noradrenaline
Effect of opioids on PAG?
Excitatory effect so more APs from PAG
Effect of opioids on nucleus reticularis paragigantocellularis?
Excitatory so more APs from the NRP onto the raphe nuclei
How do opioids inhibit pain?
Inhibit nociceptive neurons and the neurons in the spinal cord, and have an excitatory effect on PAG and NRP
Three different types of opioid receptor?
Mew delta and kappa
What are all of the endogenous agonists of opioid receptor?
Peptides
What is similar between the four endogenous agonists of opioid receptors?
Their first 4 AAs are the same
What are the four peptide opioid endogenous agonists?
Beta-endorphin, met-enkephalin, leu-enkephalin, dynorphin
Which endogenous opioid agonist binds well at all receptors?
beta-endorphin
Which opioid receptors are found in the brain (PAG)?
Mu
Which opioid receptors are found in the spine?
Mainly mew and delta, also kappa
Which opioid receptors are found in the nociceptive neurons?
Mu and kappa
What type of receptor are all of the opioid receptors?
GPCRs
What are the opioid receptors second messengers?
Gi/o
What does the Gi/o unit of the opioid receptor inhibit once an agonist had bound?
The conservation of adenyl cyclase to cyclic AMP
What is the effect of inhibiting the formation of cyclic AMP?
Less protein kinase A is formed
Other than AMP, what does Gi/o of opioid receptors inhibit?
Calcium channels, meaning less calcium can enter the neuron so less NTs will be released
What can the Gi/o of opioid receptors open?
Potassium channels, so more K+ leaves so neuron is hyperpolarized
How does opioid receptors cause more APs to be fired down the PAG to the raphe nucleus and thus to the spinal cord?
They inhibit the release of GABA meaning less inhibition from GABA goes to the synapse between the PAG and raphe nuclei
What is disinhibition?
Inhibiting something that is inhibitory
Net effect of disinhibition?
Excitation
What do the two branches of input from the raphe to the dorsal horn carry?
5HT to directly inhibit the synapse. The second one activates opioid interneurons neurons with enkephalins which also inhibit the synapse in the dorsal root
What is the effect of enkephalin on an action potential?
Shortens them and leads to a lower frequency due to opening K+ channels (neuron hyperpolarises more quickly
