Pain and Development Flashcards
Give three groups of people who tend to get undertreated for pain. (3)
What links these groups and their pain? (1)
- Babies/infants
- Elderly people with cognitive decline
- People with cognitive/learning disabilities
They all struggle to communicate their pain or communicate it in a different way.
True or false? Explain your answer if necessary. (1)
Neonates cannot consciously feel pain. Their reaction to a painful stimulus is a reflex mediated by the spinal cord.
False - Many clinicians thought this to be true until very recently. We now know that babies can consciously feel pain as it reaches their higher brain centres.
Fill the gaps relating to problems with infant pain. (5)
Knowledge of the developmental biology of pain, such as ……………………., …………………………, and ……………………. is increasing.
Additionally, improved care of pre-term neonates is leading to ……………………………….
However, there is an increasing need for a specialised approach to infant pain management. One factor impeding this is …………………………..
underlying synaptic development
pain pathways
central processing
increased survivability
a lack of well-designed analgesic trials, and difficulty testing pain in children
Fill the gaps relating to pain development. (4)
Changes to pain processing take place ……………………… the pain pathway, from birth to ……………………..
Some areas of the pain pathway are …………………….. in babies, and some are still ………………………… at birth.
a) all throughout / in certain places in
b) adolescence / adulthood
c) absent / more developed
d) in the early stages of development / relaying spontaneous pain signals
all throughout
adulthood
more developed
in the early stages of development
True or false? Explain your answer if necessary. (1)
Nociceptor expression and activity are different in neonates than in adults.
True
Describe how nociceptors are different in neonates and adults. (1)
Expression levels are different throughout development than in adulthood
Which two nociceptors are expressed more during embryonic life than early postnatal life? (2)
- TRPV1 (capsaicin)
- Cold-detecting nociceptors
Fill the gaps relating to nociceptors in neonates. (12)
Nociceptors detect noxious stimuli such as ………………., …………………, or …………………… stimuli.
They are distributed throughout most tissues such as ………………………., …………………………, and ………………………
Nociceptors are always expressed (located on) ……………………………..
We have a ……………………… system of receptors that are able to …………………………….., and expression levels …………………. throughout the stages of development.
This can be shown by looking at response of primary afferent neurones to different stimuli throughout development. Neurones respond ……………… to different types of stimuli at different stages of development, and this suggests that ……………………………………..
heat/cold
mechanical insults
chemicals (eg. acid)
skin
muscle
viscera
neurones that innervate that tissue
dynamic
transduce environmental stimuli
change
differently
the neurones contain different amounts of channels that respond to these stimuli
Briefly describe the predominant role of nociceptive peripheral nerves. (1)
Transmission of information regarding tissue damage to the central nervous system
At which stage of development is innervation of target tissues by peripheral nerves completed in normal, healthy babies? (1)
Describe the alterations that occur in this system after this time. (1)
Complete by birth
No alterations occur postnatally
At what point of development are A and C fibres specified? (2)
Both specified early in embryonic development (E12-E15 in rat)
Fill the gaps relating to peripheral sensory nerve development in babies. (4)
Innervation of target tissue is complete ……………….. in normal, healthy babies, and ……………………… postnatally.
However, central terminals in the spinal cord may appear ……………….., and are ……………….. in the postnatal period. This is especially true of Ab fibres.
by birth
is not altered
later
redistributed
How long is the gestation period in a rat? (1)
21.5 days
Choose the correct sentence relating to A and C fibre development in the embryo. (1)
- A and C fibres are born at the same time, in the same wave
- Cells are born in multiple waves - both cell types are born overlapping each other
- Cells are born in two waves - A cells before C cells
- Cells are born in two waves - C cells before A cells
- Cells are born in two waves - A cells before C cells
Out of the two populations of C fibres: peptidergic and non-peptidergic; which cells are born first? (1)
Peptidergic C fibres are born before non-peptidergic
Fill the gaps relating to development of peripheral sensory nerves. (5)
…………………………. produced by the skin and peripheral targets are important for the survival of neonatal sensory neurones.
Two examples of these are: ………………. and ………………….
These molecules may also determine ……………………..
An example of this process is ………………………….
Neurotrophic factors
NGF (nerve growth factor)
GDNF (glial-derived neurotrophic factor)
cell fate
sensitivity to different neurotrophic factors will determine whether a cell will become peptidergic or non-peptidergic
Name two neurotrophic factors which are thought to be important for survival or neonatal sensory neurones. (2)
- NGF (nerve growth factor)
- GDNF (glial-derived neurotrophic factor)
Sensory neurones enter which part of the spinal cord, by which root? (2)
Dorsal horn
Dorsal root
Fill the gaps relating to pain development and the spinal cord. (3)
Pain processing requires the formation of ………………… between nociceptors and second order neurones in the …………………….., in lamina/e ………………………
synapses
spinal dorsal horn
I and II
At what stages of development are peptidergic and non-peptidergic C fibre terminals present in the spinal dorsal horn? (2)
Peptidergic - before birth
Non-peptidergic - postnatal day 5 (P5)
At which stage of development are action potentials first evoked in the dorsal horn via C fibres? (1)
Postnatal day 10 (P10)
When we talk about developmental stages in pain, for example P10, why do we have to be careful when applying these developmental stages to humans? (2)
The studies are carried out in rats
and rat development does not occur on the same timescale as human development.
Roughly what age in a human does day P10 in rats equate to? (1)
key-stage 1 human child
Roughly what age in a human does a P0 rat equate to? (1)
Gestational week 28
Which sensory neurones are the first to enter the dorsal horn during development? (1)
Ab fibres
True or false? Explain your answer if necessary. (1)
During development, while some Ab fibres terminate in the superficial laminae of the DH and are then reorganised, other Ab fibres have characteristics similar to adult neurones and do not do this.
True
Describe the terminations of Ab fibres in the dorsal horn during development. (3)
Some Ab fibres extend terminals into superficial laminae I and II at first
However postnatal reorganisation of Ab innervation is considerable
and the terminals retreat to deeper termination zones later in development
Describe what drives postnatal reorganisation of Ab fibre terminations in the spinal dorsal horn. (2)
It is an activity-dependent process
so action potentials or activity are required in the neurones in order to retract.
True or false? Explain your answer if necessary. (1)
Infants who do not experience any pain early in life are better able to process pain later in life.
False - infants need to experience pain early in life to be able to process it properly later in life
Fill the gaps relating to pain processing. (2)
Noxious information is conveyed from the spinal cord to the …………….. via ……………………..
brain
ascending tracts
What are ascending tracts? (1)
Nerve tracts that travel up the spinal cord
Which ascending tract is a major ascending projection and conveys information to the thalamus, which passes information in turn to the cortex? (1)
Spinothalamic tract
Describe the role of the spinothalamic tract in pain. (1)
Conveys nociceptive information from the spinal cord to the thalamus, which in turn passes information to the cortex.
Which ascending tract conveys information from spinal cord to the midbrain and brainstem? (1)
Spinoparabrachial tract
What is the role of the spinoparabrachial tract in pain? (1)
Conveys information from the spinal cord to the midbrain and brainstem
Describe the development of the ascending tracts involved in pain, in terms of the following: (2)
a) when is neurogenesis of dorsal horn projection neurones complete in the rat?
b) when do the tracts of projection neurones reach the thalamus in the rat?
a) E16
b) E19 (just before birth)
Describe what information we get from rodent studies, and what they have taught us about the development and function of ascending pain pathways in early life. (2)
Information about the development of ascending pathways is purely visual
so we know little about whether these pathways are functional, and if so in what way, in early life
Fill the gaps relating to the brain and pain. (8)
The general role of the brain is to …………………. and ………………… to painful stimuli.
Areas such as the ……………………. and ………………… help locate the painful stimulus to an area of the body.
The …………………….., ………………………, and ………………….. brain areas are involved in the affective reaction to pain.
Structures in the ……………………….. region are involved in determining autonomic reactions to pain and modulating pain circuits in the spinal cord.
assess
react
sensory cortex
thalamus
cingulate cortex
amygdala
hypothalamus
brainstem
Describe the general developmental stage of the brain at 37 weeks gestation. (3)
Comment on the cerebral cortex, cerebellum, and brainstem.
- Fewer defined sulci and gyri (less development of cerebral cortex)
- Well-developed and recognisable cerebellum
- Well-developed and recognisable brainstem
Describe the general developmental stage of the brain at 26 weeks gestation. (3)
Comment on the cerebral cortex, cerebellum, and brainstem.
- Very little folding of the cortex
- Less well-defined cerebellum (slightly wilted-looking)
- Recognisable brainstem (can tell difference between midbrain, pons, and medulla)
Describe the general developmental stage of the brain at 21 weeks gestation. (3)
Comment on the cerebral cortex, cerebellum, and brainstem.
- Very smooth cortex
- Cerebellum poorly developed
- Brainstem poorly defined and developed
Briefly describe why babies born very prematurely (around 22 weeks gestation) may experience altered pain processing later in life. (3)
- Babies born this early experience a lot of pain in early life (in the NICU)
- Pain systems and the brain still have a long way to go in terms of maturation
- So this early pain may alter the maturation of pain systems
Fill the gaps relating to descending tracts and pain. (3)
Descending tracts are able to control ………………………..
They emanate from the ………………… and ………………….
spinal pain networks
brainstem
midbrain
True or false? Explain your answer if necessary. (1)
Descending tracts decrease the activity of neurones in the spinal cord, thereby decreasing the amount of painful information reaching the brain.
Technically true but also false:
- They do do this
- However they also increase the activity of neurones and amount of painful information reaching the brain
They work in a feedback loop.
Fill the gaps relating to the role and development of descending tracts in pain. (2)
Descending pathways are involved in the ………………………… of chronic pain states.
………………………… maturation of these pathways occurs ………………………
maintenance
considerable
postnatally
At what stage of development do descending tracts from brainstem nuclei grow down the spinal cord? (1)
Well before birth
At which stage of development (in rats) do brainstem nuclei differentiate? (1)
By which point are brainstem areas morphologically identifiable? (1)
Differentiate between E11-E16
Morphologically identifiable by E18
At what stage of development do descending tracts produce collaterals that innervate the superficial dorsal horn? (1)
Unclear
Give 12 simple noninvasive techniques or things that could be measured to measure pain in infants. (12)
- Heart rate
- Vagal tone
- Respiratory rate
- Metabolic responses
- Blood pressure
- Palmar sweating
- Skin blood flow
- Intracranial pressure
- Crying
- Facial expression
- Motor activity
- Composite measures (combining these parameters together)
Briefly describe how infrared light (or near infrared light) can help us measure infant pain physiology. (4)
- Use infrared transmitters and sensors
- Infrared light is absorbed by blood
- Transmit light to blood and measure light reflected
- So we can measure blood flow and therefore activity in different areas in response to pain
Describe what you would expect to see when measuring the cortical haemodynamic response to pain in babies using near infrared spectroscopy. (1)
What does this tell us about pain in babies? (1)
Increased blood flow to certain areas of the brain with pain
Babies consciously feel pain, as some cortical brain areas are activated.
True or false? Explain your answer if necessary. (1)
Supraspinal structures which are activated following noxious mechanical stimulation in infants barely overlap with that seen in adults.
False - the areas largely (but not totally) overlap with areas activated in adults
Name two brain areas that are activated in response to pain in adults, that are not in infants. (2)
- Amygdala
- Orbitofrontal cortex
Name three brain areas which are activated in response to pain in babies, but not in adults. (3)
- Hippocampus
- Auditory cortex
- Caudate
When looking at brain areas activated in response to pain in babies, we see bilateral activations, which we do not see in adults.
Suggest why these might be seen. (1)
Due to immature cortico-cortical and interhemispheric pathways.
Describe how you would expect functional connectivity in the descending pain modulatory system (DPMS) to correlate with brain activity in response to pain. (2)
Negative correlation
Stronger DPMS connectivity reduced noxious-evoked brain activity.
Describe how you would expect functional connectivity between the ACC and PAG to correlate with brain activity in response to pain. (2)
Draw a conclusion from this. (1)
Negative correlation
Stronger ACC/PAG connectivity reduced noxious-evoked brain activity
Conclusion: these areas work together to mediate pain signalling in the brain
Describe how functional connectivity of different brain regions involved in pain in children varies from that in adults. (1)
Patterns are very similar to what we would expect to see in adults.
Describe how the total EEG power of the brain differs with age at rest. (2)
It is not different.
The AUC and activity in specific EEG bands (alpha, beta, delta, gamma, theta) remain the same in both juveniles and adults when no stimulus is present.
Describe how EEG activity is different in juveniles and adults post-stimulus (painful stimulus). (2)
More activity in lower frequency bands in adults.
Activity distributed across the spectrum in juveniles.
True or false? Explain your answer if necessary. (1)
Brain activity after a painful stimulus is different in adults and juveniles. Although the same areas of the brain may respond to pain, neuronal firing and physiological measures (such as EEG) differ significantly.
True
Approximately what human age does a P3 rat equate to? (1)
28-30 weeks gestational age
At what age is a rat classed as a neonate? (1)
P7-P14 (second postnatal week)
At what age is a rat classed as a juvenile? (1)
P14-P21 (third postnatal week)
At what age in a rat is it thought to be reaching sexual maturity? So about the age of a teenager? (1)
P21
What age in a rat is considered to be adolescent? (1)
P21-P28 (fourth postnatal week)
What age in a rat is classed as an adult? (1)
Over P40
Describe how the age that a rat is classed as adult has changed from earlier to later pain studies. (2)
Used to be considered adult at P21 as this is when they get separated from mother.
Adult is now considered P40 and above.
Give two possible methods of determining individual synapse excitability in the spinal cord. (2)
Reflex arcs (measure muscle responses using EMG)
Directly measure DH activity using electrodes
When measuring dorsal horn excitability using withdrawal reflexes to nociceptive stimuli, why are these experiments usually done in rodents? (1)
It would be unethical to perform these experiments on humans
Describe the difference seen in the threshold required to evoke reflex withdrawals in P3 rats vs P21 rats (neonate vs ‘adult’). (1)
Threshold lower in P3 and higher in P21
Describe how EMG responses to painful stimuli are different in P3 rats vs P21 rats. (2)
Response amplitudes larger in P3
Response durations larger in P3
When measuring paw withdrawal responses in rats, which muscle would the EMG recording be taken from? (1)
Biceps femoris
Describe the general difference in individual synapse excitability in the spinal cord dorsal horn in neonates vs adults. (1)
The neonatal spinal cord is more excited than the adult spinal cord when looking at individual synapses.
Describe how we could compare the amplitude of withdrawal responses over a range of von Frey hairs in two separate groups of rats. (3)
Plot graph of vFh number on X axis, response amplitude on Y axis
Use the same vFh numbers for both experimental groups
Compare the area under the curve on both graphs
Describe the appropriateness of the response seen in neonates and adults when looking at reflex withdrawals. (3)
Neonates move their limb towards a stimulus more than adults (this is an inappropriate response)
This can be measured by ‘error rate’ - the error rate is much higher in neonates
Neonates also move their whole body in response to a stimulus - there is a lack of spatial precision
Why do newborn babies often move their whole body in response to a noxious stimulus instead of just the affected limb? (1)
They have not yet learnt the appropriate response
Describe how the whole body response seen in newborn babies to a noxious stimulus changes as the baby gets older. (2)
The same stimulus that produced a whole body response eventually produces a unilateral response
then eventually that stimulus will produce no response because thresholds increase.
Describe how sensory thresholds change as you move from distal sites to proximal sites in a baby. (1)
Thresholds increase moving proximally
Fill the gaps relating to neonatal responses to pain. (1)
Newborn babies often move their whole body in response to a noxious stimulus - this response is described as having a lack of …………………………..
spatial precision
Describe how stimulus encoding properties of A fibres change with age. (1)
Explain what this means. (1)
Stimulus encoding properties increase
this means that the action potential amplitude in response to a stimulus increases with age
Describe how the conduction velocities of A fibres changes with age. (1)
Conduction velocity increases with age
True or false? Explain your answer if necessary. (1)
Similar to what is seen in A fibres, there is a clear pattern of stimulus encoding properties and conduction velocities increasing with age in C fibres.
False - age dependent changes in C fibres are not as apparent, and neonatal conduction velocity appears to be higher than adults
Compare the conduction velocities of C fibres in neonates and adults. (1)
CV appears to be faster in neonates than in adults
Compare the refinement and reorganisation of A fibre and C fibre spinal cord terminations in the neonatal period. (2)
A fibre terminations undergo refinement and reorganisation (eg. Ab fibres)
This doesn’t really happen with C fibres
Describe how resting (non-evoked) activity across all laminae of the dorsal horn differs with age. (2)
Describe why this happens. (1)
Resting activity is lower in neonates, juveniles, and adolescents compared to young adults
So spontaneous activity increases with age
- Nobody really knows why this is
When recording dorsal horn responses across all laminae, are you looking at individual cell responses or responses of spinal networks? (1)
Spinal networks
Which specific cell type would you measure from to determine spinal cord neurone receptive fields in rats? (1)
Wide dynamic range neurones
When taking measurements from WDR neurones, describe how thresholds and receptive fields change with age. (2)
Threshold increases with age
Larger receptive fields in neonates, smaller receptive fields in adults
Describe a method that we could use to visualise activity throughout the dorsal horn in response to a series of nociceptive stimuli. (2)
Heat map
With superficial to deep layers and intensity of electrical stimulus on ‘axes’
Heat maps were produced which showed activity from all regions of the dorsal horn, to increasing stimulation amplitudes delivered to the foot of anaesthetised rats of different ages (neonatal to young adult).
Describe how the activity of the dorsal horn network changed with increasing age in response to pain. (2)
DH network activity increases with increasing age.
Neonatal and juvenile were much less excited at the network level.
True or false? Explain your answer if necessary. (1)
In the neonatal spinal cord, individual synapses are less excitable than the adult, but neuronal networks are much more excited.
False - individual synapses are more excitable in the neonate but network activity is reduced
Briefly describe two theories behind why the neonatal spinal cord is more excited at the cellular level but less excited at the population level. (2)
- There are populations of neurones in the adult dorsal horn which do not fire in the neonatal dorsal horn
- Inhibitory neurones are not firing early in life but are firing in the adult
Describe how inhibitory interneurones not being active in the neonatal spinal cord but becoming active later in development would lead to the conflicting results seen regarding cellular and network excitability in the neonatal dorsal horn. (4)
If inhibitory neurones are not firing early in life
individual synapses will be more excited
but the activity of inhibitory interneurones is not showing on the heat map or contributing to the overall activity in the spinal cord
however this is opposite in adults
When quantifying dorsal horn network activity in neonates vs adults, in which regions (superficial, intermediate, deep) is the biggest difference seen with age? (1)
Deep
Fill the gaps relating to pain development. (5)
……………….. activity of dorsal horn networks are lower, as is the network level response to …………………… in younger animals.
However WDR neurones are ………………….. excitable with …………………….. receptive fields and ……………………. thresholds to evoke firing.
Resting
stimulation
more
larger
lowered
Suggest an experimental design reason why single cell excitability in the dorsal horn decreases with age, but network excitability increases. (2)
Single cells are pre-selected and are not a random selection of all DH neurones
however network recordings are taken randomly.
Fill the gaps relating to pain processing and age. (3)
Network activity and response increases with age as network ………………….. and …………………… increase.
Whilst at a cellular level, excitable cells become less excitable with age as …………………… increases.
inhibition
connectivity
inhibition
Give one receptor which my be responsible for reduced inhibition and more excitation in the neonatal dorsal horn. (1)
GABAa receptor
Responses of neurones to GABA were recorded from lamina I of the dorsal horn.
Describe the differences between neonatal and adult response to GABA. (2)
Neonatal - a subpopulation of DH neurones depolarise in response to GABA (GABA acts as an excitatory neurotransmitter)
Adult - GABA is inhibitory (cells hyperpolarise)
True or false? Explain your answer if necessary. (1)
In neonates, GABA can be excitatory, however with age GABA becomes inhibitory. This can also be seen with glycine.
True
In a subpopulation of newborn dorsal horn neurones, GABA acts as an excitatory neurotransmitter.
Briefly explain why this might happen. (2)
Lower expression of KCC2
which reverses concentration gradient for chloride ions.
True or false? Explain your answer if necessary. (1)
With ageing, there are changes seen in neurones that are down to expression of key molecules such as KCC2. This is why individual neurones become more excitable with age but neuronal networks become less excitable.
False - the first sentence is correct, however individual neurones become LESS excitable with age and neuronal networks become MORE excitable
Describe the 2 mechanisms of inhibition in the spinal cord. (2)
- GABAergic and glycinergic interneurones
- Descending inhibition from higher brain centres (RVM)
Inhibitory interneurones in the spinal cord are likely to use which two neurotransmitters? (2)
- GABA
- Glycine
What would be the expected effect of stimulating the dorsal lateral funiculus on spinal nociceptive circuits in the neonate? (1)
What is the dorsal lateral funiculus? (1)
No inhibition of spinal nociceptive circuits
the descending tract from brain to spinal cord which would usually inhibit nociception
Describe how the effect of stimulating the dorsal lateral funiculus changes with age. (1)
With increasing age, more cells in the dorsal horn are inhibited with DLF stimulation.
Draw a conclusion from the fact that stimulating the descending tract (the dorsal lateral funiculus) in the neonate does not inhibit spinal circuits. (1)
Was this conclusion proven true or false in later experiments? (1)
There is no descending modulation from brain to spinal cord in neonates.
Proven false
Microinjection of kainate into the RVM destroys it.
Describe how. (1)
Via excitotoxicity
Describe the effect seen of destroying the RVM on vFh thresholds in neonates and adults. (2)
Write a conclusion about this. (2)
- In adults, thresholds decrease
- In neonates, thresholds increase
In adults, the RVM normally inhibits pain at rest,
but in neonates the RVM only facilitates pain.
True or false? Explain your answer if necessary. (1)
In neonates, there is no descending inhibition from the RVM to the spinal cord, however there is descending facilitation.
True
An experiment electrically stimulated the RVM at a range of intensities, and measured the dorsal horn response to vFhs (as area under curve).
Describe the effects seen of stimulating the RVM at a range of intensities in:
- neonates/babies (<P21)
- Adults (>P40)
(2)
P21 and earlier, area under curve always increased with RVM stimulation, so there was only descending facilitation from the RVM.
P40 and later, we see adult bi-phasic facilitation and inhibition (facilitation at low stimulation amplitudes, inhibition at high stimulation amplitudes).
Fill the gaps relating to descending control of the spinal cord by the RVM in neonates. (2)
In neonates, there is no descending ……………………, however there is descending …………………… from the RVM.
inhibition
facilitation
Describe the different results seen in young rats vs adult rats when DAMGO (MOR agonist) is injected into the RVM/PAG with regards to pain. (2)
Adult: dose-dependent inhibition of pain (decreased reflex excitability)
Young: dose-dependent facilitation (increased reflex excitability)
Fill the gaps relating to opioids and pain. (2)
In younger rats, mu opioid receptor activity is …………………………
However, in adult rats mu opioid receptor activity is ……………………..
Hint: both answers are either excitatory or inhibitory
excitatory
inhibitory
Describe why early pain studies referred to P21 rats as adults, however it was changed to refer to P40 as adults. (1)
Because descending inhibition does not occur until about P40, so this is when the nervous system has properly matured.
RVM neurones in juveniles and adults have different physiological properties.
Describe how the response speed differs between juveniles and adults, and also the reflex size. (2)
ON and OFF cells respond more quickly in juvenile rats
Reflexes greater in juvenile rats
Give five examples of neural systems where neuronal activity is required to regulate synaptic connections. (5)
- Visual system
- Auditory system
- Somatosensory pathways
- Olfaction
- Birdsong
Define ‘critical period’ in terms of development. (2)
A time window during which experience is essential for normal development
and permanently alters function if experience is perturbed during the critical period.
Give another term for the critical period during development. (1)
Experience or activity dependent plasticity/learning
Briefly describe an experiment and its results that demonstrate the critical period, not in relation to pain. (4)
- Sew eyes shut of animals at different points in life
- Eyes shut before critical period = no effect on development
- Eyes shut after critical period = no effect on development
- Eyes shut during critical period = major effects on development
Briefly describe an experiment to investigate how blocking opioid receptors during a critical period affects development. (4)
- Use osmotic mini pumps in brain
- Infuse naloxone (opioid block) over a week
- Do this for different weeks over different stages of development
- Test function as an adult and see how it has been affected
Osmotic mini pumps were used to infuse naloxone into the CNS over the third, fourth, or fifth postnatal week in rats.
As adults, these rats were then tested with regard to their RVM and whether this provided just descending facilitation, or descending inhibition as well. This was to see the development of their descending pain control systems.
Describe the results seen in weeks 3, 4, and 5. (3)
According to these results, when is the critical period for development of descending pain control? (1)
Week 3 = no effect on development of descending control
Week 4 = prevents normal maturation of RVM mediated descending control
Week 5 = no effect on development of descending control
So critical period is week 4
Osmotic mini pumps were used to infuse naloxone into the CNS over the third, fourth, or fifth postnatal week in rats.
As adults, these rats were then tested with regard to their RVM and whether this provided just descending facilitation, or descending inhibition as well. This was to see the development of their descending pain control systems.
Blockade of opioid receptors in week 4 affected normal development.
However, this was tested with naloxone hydrochloride and naloxone methiodide, and different results were seen with the two drugs.
Describe and explain the differences seen. (4)
Naloxone hydrochloride prevented normal development
because it crosses the BBB so blocks CNS mediated endogenous opioid signalling.
Naloxone methiodide has no effect on normal development
because it cannot cross the BBB so only blocks peripheral opioid receptors.
Fill the gaps relating to the critical period and development of descending control. (
In the ……………….. postnatal week, ……………………….. play a role in the maturation of the descending pain system. If these chemicals are blocked, ………………………. does not develop.
It has also been shown that giving ………………………… in early life speeds this maturation process up.
fourth
endogenous opioid peptides
descending inhibition
morphine
Describe how expression of the endogenous opioid peptide, enkephalin, changes in the dorsal horn as animals age. (1)
Increased expression as animals age
Describe how expression of the endogenous opioid peptides:
- enkephalin
- POMC
- mu opioid receptor
change in the vPAG as animals age. (3)
Enkephalin = no change
POMC = increases with age
MOR = no change
Complete the sentence relating to pain development in rats. (1)
Postnatal tuning of nociceptive reflexes requires ……………………..
tactile input
Briefly describe an experiment that could be used to show the effect of inhibiting tactile input on normal pain development. (4)
- Rat tail in tube
- Control = empty tube
- Experimental group = tube filled with local anaesthetic (EMLA)
- Measure nociceptive reflex errors
A study used local anaesthetic on rats’ tails during postnatal development. Then tested tail withdrawal reflex to a noxious stimulus.
Describe the results seen. (3)
- Normal function is delayed or completely prevented
- Use of the local anaesthetic prevents normal maturation of tail withdrawal
- So nociceptive reflex errors were seen for a prolonged period of time
Fill the gaps relating to pain development. (1)
The maturation of an appropriate pain response required …………………………….
nociceptive sensory input
Postnatal tuning of dorsal horn cell responses requires neural activity mediated by which receptor? (1)
NMDA
Describe the effects seen on dorsal horn cell responses if MK801 (an NMDA antagonist) is chronically applied during development. (3)
- Receptive fields do not get smaller
- Evoked responses remain bigger
- Threshold remains low
Briefly describe an experiment to show that NMDA-mediated neural activity is required for postnatal tuning of dorsal horn cell responses. (3)
- Use MK801 to block NMDA receptors
- Apply drug throughout development
- Examine dorsal horn connections 6 weeks later
What is required for postnatal tuning of NOCICEPTIVE REFLEXES? (1)
Tactile input
What is required for postnatal tuning of DORSAL HORN CELL RESPONSES? (1)
NMDA mediated neural activity
Which type of pain develops much later than other forms of pain? (1)
Neuropathic pain
Describe what you would expect to see after neuropathic injury (spinal nerve ligation) in neonatal and adult rats regarding pain. (2)
What conclusion can you make from this? (1)
Adult = hyperalgesia
Neonatal = no hyperalgesia
Babies do not get neuropathic pain
True or false? Explain your answer if necessary. (1)
Babies develop neuropathic pain to a higher degree than adults.
False = babies do not get neuropathic pain
Describe what you would expect to see after neuropathic injury (spinal nerve ligation) in neonatal and adult rats regarding microglial activation. (2)
What conclusion can you draw from this? (1)
Adult = microglial response seen in dorsal horn
Neonate = very weak microglial response
In adults, neuropathic pain relies on activation of microglia
Describe the difference in microglial response to neuropathic injury in neonates and adults. (2)
*The answer is not that microglia are not activated in neonates
Adults = microglia secrete pro-inflammatory molecules
Neonates = microglia secrete anti-inflammatory molecules
Fill the gaps relating to neuropathic injury in neonates. (6)
Neuropathic injury in early life does not result in increased expression of ……………………….. from microglia, like what is seen in adults. Two examples of these molecules are …………………. and …………………. However it does result in increased expression of …………………………., such as ………………. and ……………….
pro-inflammatory molecules
TNFa
BDNF
anti-inflammatory molecules
IL4
IL10
Describe why a system has evolved whereby microglia in neonates are more anti-inflammatory rather than pro-inflammatory. (2)
In neonates, many cells are dying as the nervous system is refined
and if this were to cause microglial inflammation than maturation would deviate from normal.
The actions of midazolam are significantly different in the perinatal period to the adult.
What is midazolam? (1)
A sedative and anxiolytic (benzodiazepine)
How does midazolam alter pain thresholds in the adult? (1)
Increases pain thresholds
Describe how the actions of midazolam are different in the neonate compared to the adult. (2)
Pain thresholds decreased (however thresholds are increased in adults)
Significantly reduced sedative properties in neonates
In general, how does neonatal injury affect pain in response to an injury later in life? (1)
Increases pain
Fill the gaps relating to pain development. (5)
If an animal is injured early in life, the pain usually ………………… over time.
However, if the animal is re-injured, they experience …………… pain than what would normally be expected.
This can be measured using …………………… and ………………….., and ……………………. indexes.
resolves
more
mechanical thresholds
thermal thresholds
hyperalgesic
Briefly describe a possible mechanism which could partly explain why animals that have experienced neonatal injury feel more pain when they then receive a later injury. (3)
Reprogramming of microglia.
Early injury changes the way that microglia mature
and they become hypersensitive to reinjury.
An experiment measured Iba1 immunofluorescence in the ipsilateral dorsal horn after just an adult injury, or after neonatal plus adult injury.
What would you expect to see? (1)
What does this mean? (1)
In rodents with neonatal plus adult incision, there is increased Iba1 fluorescence compared to just an adult incision alone.
So these animals show increased microglial reactivity after subsequent injury.
True or false? Explain your answer if necessary. (1)
Neonatal incision alters the maturation of descending pain control.
True
Describe how neonatal injury alters the actions of the RVM at rest. (1)
RVM always inhibits
Describe how you would expect the mechanical withdrawal thresholds and the thermal withdrawal latencies to change with RVM stimulation after a neonatal injury. (2)
All thresholds increase (hypoalgesia, descending inhibition)
Fill the gaps relating to neonatal injury and pain processing. (4)
In adults who have suffered neonatal injury, stimulating the RVM at rest provides …………………… at all frequencies, compared to the ……………. patten which is seen in adults without neonatal injury.
This can be shown by ………………………………. with RVM stimulation at rest.
However after a subsequent injury in adulthood, animals experience a ………………………
descending inhibition or hypoalgesia
biphasic (low frequency = facilitation; high frequency = inhibition)
increased mechanical and thermal thresholds
global hyperalgesia
Fill the gaps relating to neonatal injury and pain. (3)
Early life injury permanently alters ……………………….., which alter pain sensitivity across the whole body later in life.
After early life injury, the RVM did not produce any ………………… - it only produced …………………….
endogenous pain control mechanisms
facilitation
inhibition
