Physiology of pain 2 Flashcards by Suzi Tugnait

give three aspects of clinical pain

1) seen in clinics
2) associated with damage to tissues including the nervous system
3) mechanisms can be nociceptive and/or neuropathic

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what is pain that lasts

i) <3 months
ii) >3 months

i) acute pain

ii) chronic pain

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what pain is characterised by once the injury site has recovered the pain stops?

acute pain

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what is acute pain due to excitation of?

which molecules bind their receptors and allow this to happen? (2 molecules)

which spinal tract does this activate and what does it ultimately cause?

acute pain is due to direct excitation of nociceptors

molecules such as ATP and 5HT bind their receptors on nociceptors and activate them

this activates the spinothalamic tract which causes pain

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which receptors on nociceptors do
i) ATP
ii) H+ 
iii) serotonin 
bind?

i) ATP binds purinergic receptors
ii) H+ binds acid sensing receptors
iii) serotonin binds 5HT3 receptors

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PERIPHERAL SENSITISATION

i) is this an acute or chronic pain mechanism?
ii) what does it lead to? what is this?
iii) name three mediators that may be involved

i) acute
ii) leads to hyperalgesia which is an exaggerated pain response
iii) three mediators that are involved are bradykinin, NGF and prostaglandins

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which receptors do
i) bradykinin and NGF
ii) prostaglandins
work on and what effects do they have?

i) BK and NGF reduce the threshold for TRPV1 receptors by activating kinases that phosphorylate TRPV1 and reduce its threshold for activation
ii) PGs reduce threshold of activation for sodium channels - also activate kinases that phos Na+ channels and reduce threshold for activation

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what are prostaglandins made from (precursor and enzyme)

made from conversion of arachadonic acid by COX enzyme

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LOCAL ANAESTHESIA

i) give two examples of local anaesthetic drugs
ii) where can it be applied?
iii) what is the mechanism of action? how does this result in less pain being felt?

i) lidocaine and lignocaine
ii) can be applied topically
iii) mechanism of action is prevention of nociceptor firing by blocking sodium channels which results in the nociceptor being shut down therefore you feel less pain

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what are the sites of action of acute pain treatment? (3)

CNS, PNS or both

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NSAIDS

i) give two examples of NSAID drugs
ii) do they act centrally or peripherally?
iii) what is their mechanism of action and what does this result in?
iv) why do they produce this result? (ie what do prostaglandins normally do?)

I) ibuprofen and aspirin

ii) act peripherally
iii) they inhibit COX which will stop conversion of arachadonic acid to prostaglandins and this will prevent a lowering of sodium channel threshold for firing therefore reducing inflammation
iv) they produce this result as usually PGs bind their receptor and activate kinases which phos Na channels and increase their firing so blocking PGs will stop Na channels being phos and therefore decrease their sensitivity

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PARACETAMOL

i) is it an NSAID?
ii) does it act centrally or peripherally?
iii) which system may it act on

I) no

ii) centrally
iii) may inhibit COX and act on descending serotonergic pathways to decrease activation of the spinothalamic tract

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TOPICAL CAPSAICIN TREATMENT

i) what food is capsaicin found in?
ii) does it act centrally or peripherally?
iii) which receptor does it act on and what is its action here?
iv) what does this lead to? (mitochondria)
v) what sensation will it initially cause when applied to an injury site?

i) chili peppers
ii) acts peripherally
iii) binds TRPV1 and is an agonist which causes it to open
iv) opening the TRPV1 receptor will cause calcium overload and mitochondrial dysfunction which will inhibit the nociceptor
v) when applied to an injury site it will initially cause a burning sensation

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OPIOIDS

i) name three opioid drugs
ii) do they act centrally or peripherally?
iii) why are they not usually used in chronic pain?
iv) which pathway do they work on?

I) morphine, codeine and tramadol

ii) both
iii) not used in chronic pain as they are addictive
iv) work on the descending pain modulatory pathway

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MECH OF ACTION OF OPIOIDS

i) what do they agonise?
ii) which main areas do they bind their receptors?(2) and what does this cause?
iii) what other area do they bind? (which type of neuron) and what does this cause?
iv) what type of projections come from the RVM to the dorsal horn to inhibitory interneurons?

i) agonise the endogenous opioid pathway
ii) main areas they bind receptors is the periacqueductal grey matter and the rostral ventromedial medulla and this causes inhibition of inhibitory interneurons (disinhibition) and activation of the pain modulatory pathway
iii) they also bind second order neurons in the dorsal horn which causes them to be shut down therefore no pain information is conveyed up the spinothalamic tract
iv) serotonergic projections

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what is the action of opioids in the

i) brainstem
ii) spinal cord
iii) periphery

i) disinhibition and activation of the pain modulatory pathway
ii) bind second order neurons in the dorsal horn to shut them down therefore no info conveyed up the ST tract
iii) shut down of opioid receptors on nociceptors in the periphery

GATE CONTROL THEORY

i) what is the basis of this theory? (Ab fibres)
ii) what action activates the Ab fibres? (what do you do when something hurts)
iii) this is modulation of pain at what level?

i) pain evoked from nociceptors can be reduced by simultaneously activating Ab fibres at the injury site
ii) this can be activating by rubbing or blowing on the area
iii) this is modulation of pain at a spinal cord level

MECH OF GATE CONTROL THEORY

i) what does stimulation of Ab fibres at the site of injury activate and what does this cause?
ii) why does this reduce pain?

i) stimulation of Ab fibres will activate interneurons in the dorsal horn that are inhibitory which causes inhibition of spinothalamic neurons
ii) this reduces pain as the spinothalamic tract is shut down and this normally conveys pain

YOU JUST TOUCHED SOMETHING HOT. OUCH!

i) which fibres are activated?
ii) what does activation of these fibres cause?
iii) what does blowing on the site activate? which neurons are inhibited by this?
iv) where do Ab fibres usually ascend and where/what do they synapse onto?

i) activation of C fibres
ii) this causes inhibition of inhibitory interneurons (disinhibition) which causes activation of second order neurons and pain impulses are sent to the brain via the ST tract
iii) blowing on the site activates Ab fibres which activate the inhibitory interneurons which therefore inhibit the second order neurons in the DH and stop the pain message being conveyed
iv) Ab usually ascend in the dorsal horn and synapse onto inhibitory interneurons in the DH

in the gate control theory

i) what ‘opens the gate’
ii) what ‘closes the gate’

i) Activation of C fibres which INHIBIT inhibitory interneurons (which cause activation of second order neurons in the dorsal horn) opens the gate
ii) activating Ab fibres by blowing/rubbing on site will ACTIVATE inhibitory INs (inhibits second order neurons therefore inhibits pain info up ST tract) which close the gate

CHRONIC PAIN

i) how long does it last?
ii) what % of the population does it affect?
iii) is it nociceptive or neuropathic?

i) lasts for more than three months
ii) affects 20-50% of the population
iii) can be either nociceptive or neuropathic

NEUROPATHIC PAIN

i) what is this due to - give seven main examples
ii) what % of the population does it affect?
iii) does it involve central or peripheral mechanisms?
iv) give five symptoms of neuropathic pain

I) due to nerve injury - compression (carpal tunnel), traction (stretch), sever (trauma), hypoxia (stroke), demyelination (MS), tumour, neuroinflammation

ii) affects 8% of population
iii) involves both central and peripheral mechanisms
iv) stabbing, aching, burning, electric, shooting, hypersensitivity

what are two peripheral mechanisms of neuropathic pain and how do these work?

1) peripheral sensitisation = inflammatory sensitisation of the peripheral terminal of nociceptors
2) increased firing of primary afferents = spontaneous firing of damaged nociceptors

INCREASED FIRING OF PRIMARY AFFERENTS

i) do damage tips of nociceptors still fire?
ii) what happens in an intact nociceptor (ion channels)
iii) what happened in a severed nociceptor (ion channels)? what does thus cause?
iv) what mechanisms is this responsible for? (2)
v) what happens in phantom limb pain?

i) yes - they fire spontaneously despite damage
ii) in tact nociceptors - ion channels are synthesised at the cell body and transported to the terminal to be inserted into the membrane

iii) when severed - ion channels are still synth at cell body but accumulate in the nerve terminal and this increases excitation and pain impulses travelling up the ST tract
iv) this is responsible for spontaneous pain and phantom limb pain

v) in phantom limb pain the pain impulses going up the ST tract are perceived to come from the part of the limb that is no longer there

what are the two central mechanisms of neuropathic pain? and which is the main one out of these two?

1) central sensitisation within the spinal cord 2) changes in activation patterns and cortical remapping in the cortex (1) is the main one

CENTRAL SENSITISATION i) what is it? ii) which neurons are implicated in this? (type and location) iii) why do normal inputs produce abnormal responses? iv) what causes the signal amplification? v) are the changes easily reversed?

i) increase in the responsiveness of nociceptive neurons within the CNS ii) affects second order ST tract neurons found in the dorsal horn iii) normal inputs produce abnormal responses as the neurons in the ST tract are more responsive iv) signal amplification is caused by the reduced threshold for activation of second order neurons in the ST tract v) no the changes are not easily reversed

REDUCED THRESHOLD FOR ACTIVATION OF CNS NEURONS IN CENTRAL SENSITISATION I) what causes this? ii) involves release of which two transmitters? and what does binding to their receptors cause? iii) what does this result in in relation to NMDA receptors? iv) where are these NMDA receptors found? v) what does this ultimately lead to? vi) does this involve channel protein synthesis?

i) caused by constant firing of axons from peripheral nociceptors following injury ii) sustained release of glutamate and substance P - binding to their receptors causes prolonged depolarisation of the post synaptic membrane iii) prolonged depolarisation causes calcium channels to be kept open which causes a massive influx of calcium through NMDA receptors iv) these NMDA receptors are found in the dorsal horn second order neurons v) this ultimately leads to activation of kinases which phos NMDA and AMPA receptors which alters the kinetics and can also cause insertion of more channels and neurons fire more easily vi) yes this leads to channel protein synthesis

what two things cause reduced threshold for activation in central sensitisation? (in relation to ion channels)

1) altered kinetics of NMDA and AMPA receptors (they fire more easily) 2) channel protein synthesis (there are more channels)

CENTRAL HYPERALGESIA i) what does this occur after? ii) what is the mechanism of this? iii) what does this ultimately lead to?

i) occurs after central sensitisation ii) activation of nociceptors results in amplified spinal cord activation which increases signals passing uptake ST tract via second order neurons to the thalamus iii) leads to an exaggerated pain response

CENTRAL ALLODYNIA i) what causes this? ii) what happens in physiological conditions and what goes wrong following central sensitisation? iii) what pathway are these non noxious Ab fibres found in?

i) caused by non noxious afferents (Ab fibres) activating sensitised second order neurons therefore non painful stimuli are felt to be painful ii) in physiol conditions Ab fibres are not functional due to not enough stimulation for them to feel painful but following central sensitisation the second order neurons are more responsive and have a lower threshold for activation therefore non noxious stimuli active them causing pain iii) Ab fibres are found in the dorsal column medial lemniscal pathway and have branches that pass to the DH and synapses on 2nd order neurons

NEUROPATHIC PAIN TREATMENT i) name three types of drugs used to treat neuropathic pain ii) name one alternative therapy used to tear iii) name a psychological therapy iv) a surgical procedure - how does this work? (spinal cord) v) name two physical therapies

i) tricyclic antidepressants, anticonvulsants and topical capsaicin/lidocaine ii) acupuncture iii) CBT iv) spinal cord simulator - implant into patients and directly activate Ab fibres in the spinal cord therefore activate inhibitory interneurons to modulate pain pathway (same as gate control) v) manipulation of tissues to improve movement and pacing

TRICYCLIC ANTI-DEPRESSANTS i) name two ii) do they act centrally or peripherally? iii) what pathway do they act on? what do they do here? (in relation to transmitters) iv) what is the result of having more 5HT around? why does this help neuropathic pain?

i) amitriptyline and duloxetine ii) act centrally iii) they act on descending inhibitory pathways and inhibit the reuptake of 5HT and NA iv) If there is more 5HT there is more activation of inhibitory interneurons and therefore inhibition of pain moving up the ST tract

ANTI-CONVULSANTS i) name three ii) which has more side effects - pregabalin or gabapentin? which is licensed to treat neuropathic pain? iii) where do they act and what do they do here? iv) what channels does pregabalin block and what does this cause?

i) pregabalin, gabapentin and carbamazepine ii) gabapentin has more side effects than pregabalin and PG is licensed to treat neuropathic pain iii) act on the spinal cord and reduce excite by blocking calcium and sodium channels iv) pregabalin blocks pre synaptic VG calcium channels therefore prevents glutamate release and there is decreased excitation of pain pathways in the spinal cord

what are the NICE guidelines for first line treatment of NP pain? what is second line? what is third line?

first line is amitriptyline, duloxetine, pregabalin or gabapentin second line is to switch drugs or combine them third line is to refer patient to specialist pain service/oral tramadol/combine second line tx with topical lidocaine

how does placebo analgesia treat NP pain?

through subconscious activation of descending inhibitory pathways therefore reducing pain information ascending the ST tract

WHAT HAS GONE WRONG IN CHRONIC PAIN? i) in the peripheral terminals ii) in the nociceptor iii) in the DRG iv) in second order neurons in the dorsal horn v) what does peripheral firing drive?

i) sensitisation of peripheral terminals due to inflammation and tissue injury ii) increased and spontaneous firing of primary afferents (nociceptors) iii) changes in protein synthesis in the DRG iv) central sensitisation and amplification of second order neurons in the the DH v) peripheral firing drives central changes