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M202 > W22 Physiology and Pharmacology of Pain and Analgesics (RT) > Flashcards

W22 Physiology and Pharmacology of Pain and Analgesics (RT) Flashcards

1
Q

What is the definition of Pain?
Which cortex does pain exist in?

A

The subjective conscious appreciation of a stimulus that is causing, or threatening to cause, tissue damage. Pain exists in your cerebral cortex!

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2
Q

What is Nociception?
What are Nociceptors?

A
  • The physical process of detection and transmission of damaging or potentially damaging (noxious) stimuli
  • Structures/Receptors which detect noxious stimuli – peripheral tissues
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3
Q

What are the definitions of Algesia and Analgesia?

A

Algesia= The induction of a condition leading to nociception and pain (having pain sensation or perception)

Analgesia= Reduction or prevention of either nociception or pain without loss of consciousness

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4
Q

Types of pain:
What are the different durations? (2)

A
  • Acute= Short term
  • Local inflammatory changes, intensity affected by inflammatory mediators
  • Chronic= Progressive
  • Peripheral and central sensitization
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5
Q

Types of pain:
What are the processes/mechanisms for pain?(3)

A
  • Nociception (accounts for most acute) – often initial stimuli
  • Nociplastic (contributes to chronic)
    =Sensitization / altered function
  • Neuropathic (contributes to chronic)
    =Injury or disease affecting the peripheral nervous system or central nervous system reflects pathology in pathways
    =Long-term, may be unrelated to peripheral injury,
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6
Q

What are the 3 different levels that pain is processed at?

A
  1. Nociception= Peripheral activation and release of pain mediators
  2. Pain gating = Dorsal horn of the spinal cord
  3. Pain perception= The brain (thalamus, limbic and cortical systems)
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7
Q

Pain transmission: generalised pain pathways

What are the two routes for pain signal transmissions?

A
  • Ascending pathway: pathway that goes upward carrying sensory information from the body via the spinal cord towards the brain
    -Conveys pain stimuli from spinal cord to
    higher brain centres
  • Descending pathways: neural pathways that goes downward from the brain to the reflex organs via the spinal cord
    -Neurons that can affect or alter neuronal signals in ascending pathway
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8
Q

Receptors: Nociceptors
What are they stimulated by?
What are the sensitivity of these channels affected by?

A

Stimulated by:
* High mechanical stimulation,
* Thermal stimulation, Low pH
* Chemicals (often from inflammatory response)
-Released by tissue damage
- Bradykinin,
- histamine (itch)

  • Bradykinin (Inc)
  • Prostaglandins (Inc)
  • Opioids (Dec)
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9
Q

What are the steps involved in transduction of nociceptive stimuli?

A
  1. Noxious stimulus heat, cold, mechanical, chemical. (skin/viscera)
  2. Channel opening
  3. Change in membrane voltage (sensory receptor)
  4. Depolarization and action potential generation
  5. Transmitter release (primary afferent axon)
  6. Second order ascending neurone response
    (spinal cord- dorsal horn)

Primary afferent neurones convey information to spinal cord

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10
Q

What are the Two types/ speed of primary acute pain?

A

Fast/first pain – carried by small myelinated Adelta fibres
-Usually transient, a sensation of sharp, well localised pain
-Triggers reflex to move away from source of pain

Slow/second pain – carried by non-myelinated C fibres
-Less easily localised low conduction velocities cause a dull burning pain

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11
Q

Ascending pain pathways
Spinothalamic tract:
What is the order?

A
  • Sensory input from first order afferent neuron enters spinal cord via dorsal horn
  • Synapses with second order neuron
    (crosses)
  • Travels through medulla to thalamus
  • Synapses with third order neuron in thalamus
  • Third order neuron extends to primary somatosensory cortex
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12
Q

Sensitization- what are the 2 types?

A

Important in chronic pain development
1. Allodynia
* Pain to a non-noxious stimulus
2. Hyperalgesia
* Increased pain to a mildly noxious stimulus
-Peripheral sensitization
-Central facilitation

Allodynia Vs Hyperalgesia
Allodynia- pain due to a stimulus that does not usually provoke pain
Hyperalgesia- increased pain due to a stimulus that usually provokes pain

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13
Q

What is Peripheral sensitisation stimulated by? (2)

A

Stimulated by:
Release of (tissue damage and inflammation)
-Bradykinin
-Prostaglandins
They Increase sensitivity of nociceptors
* (linked to other channels)

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14
Q

Central: Transmission at nociceptor terminals
What is released from C-fibres? (2)
What binds to SP?

What is synaptic strengthening?

A
  • Substance P & CGRP (calcitonin gene related peptide), released from primary nociceptive afferents- c-fibres.
  • SP activated NK (neurokinin receptors)
    -leads to depolarisation of post-synaptic neurone

Synaptic strengthening:
Repeatedly activated fibres in periphery lead to the message being delivered at spine getting stronger

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15
Q

Central sensitisation (‘wind-up’) of nociception:
What does Stimulus number in first order neurone lead to?

A

Stimulus number in first order neurone leads to action potential in secondary neurone

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16
Q

What is Central facilitation/Wind-up?
What is it caused by? (2)
How can it be prevented?

A
  • Repeated stimulation increases the amplitude of the synaptic potential
    -Caused by NMDA glutamate receptors
    -Neurokinin receptors (C fibres)
  • Can be prevented by
    -Reducing peripheral stimulation
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17
Q

Afferent Pain gating at the spinal cord:

What do second-order neurons get excited by?

A
  • GATE THEORY OF PAIN
  • Some second order neurones are excited by c fibres AND non-pain sensory fibres (A-alpha
    or A-beta)
    -eg from mechano-receptors

Also connected via inhibitory interneuron
* Inhibited by pain fibre
-Pain transduction
* Excited by the sensory nerve fibre
-Can suppress nociceptive/pain signals

  • Mechanical stimulation inhibits nociceptive transmission
  • Transcutaneous electrical nerve stimulation
18
Q

Descending pain pathways:
The Periaqueductal grey (PAG) receives input from which different brain areas (HUB)?
What is the route?

A
  • Modulate ascending pain messages
  • Hypothalamus, cortex, somatosensory and insula, amygdala
  • Neurones descend through medulla to spinal cord
    -Can inhibit ascending pain pathway
  • Neurones from Locus coeruleus (pons)
    -To spinal cord
    -Also inhibit ascending pain pathway
  • ie when descending pathway is active it inhibits the ascending pathway
  • Can modulate these pathways to relieve pain!
19
Q

What is Neuropathic Pain?
Examples and Causes?

A
  • Pain often unrelated to peripheral nociception - pathological pain - serves no purpose
  • Thalamic stroke
  • Peripheral nerve damage
  • Spinal damage
  • Peripheral nerve terminal damage or infection
    -Spontaneous activity in damaged sensory neuron
20
Q

What is Nociplastic pain?

A
  • Persistent pain that arises from altered nociception
21
Q

What are the types of analgesics? (3)

A
  • NSAID (and related)
  • Opioid
  • Non-opioid, Non NSAID
    Act at different levels of pain transmitting pathways
22
Q

Recap:
What is sensitisation?
Where can it occur?
What is the gate keeper theory of pain?
What does the descending pain pathway do?

A
  1. Altered sensation of pain e.g. allodynia etc
  2. Peripherally or centrally
  3. Mechanical stimulation of non pain fibres can inhibit nociception at the dorsal horn of the spinal cord
  4. Activation of part of the descending pathway can inhibit (at the spinal cord) the ascending pain pathway so perception of pain is reduced.
23
Q

Peripheral analgesics

A

Non-opioid
* Aspirin
* Paracetamol (acetaminophen),
* NSAID : ibuprofen, naproxen, diclofenac –
* (All anti-pyretic – only NSAID and aspirin anti-
inflammatory)
* NSAID and aspirin
* Inhibit COX/COX2 (Catalyses generation of
PGE2 from arachidonic acid)
* Paracetamol less clear

24
Q

Peripheral modulation of nociception:

A
  • Peripheral analgesics modulate peripheral nociceptor
  • NSAIDS e.g. Aspirin inhibits generation of prostaglandins
  • When prostaglandins bind to the prostanoid receptor, inc chance of channels opening to allow + ions to move in and inc membrane potential and cause depolarisation
  • Prostaglandins generated at site of tissue injury, cause channels to open
25
Q

NSAIDs are COX inhibitors:
Synthesis:

A
  1. Phospholipid ( Phospholipase A2)
  2. Arachidonic acid (COX-1 or COX-2)
  3. Prostaglandin H2 (PGE synthase)
  4. Prostaglandin E2
  5. Prostanoid receptor

so inhibiting production of prostaglandins- dec agonistic activity at prostanoid receptor

26
Q

NSAID MoA

A
  • NSAIDs inhibit COX enzymes so that the prostaglandins are not synthesised and the prostanoid receptor is not stimulated.. so nociceptor is not stimulated
  • COX enzymes are induced at site of tissue injury
27
Q

Recap:
Where do NSAIDs have their function?
What enzymes do they inhibit?
What group of signalling molecules does this prevent being generated?
Why does this function in pain relief?

A
  1. On nociceptors in the periphery
  2. COX-1 and COX-2
  3. Prostaglandins
  4. Prostaglandins are not generated so they do not stimulate their receptors (prostanoid) which can therefore not sensitise the nociceptor
28
Q

What are the 3 main types of opioid receptors?

A

Mu, Kappa, Delta
All are GPCRs
* Gi/G0
-Inhibit adenylyl cyclase
-MAP kinase (ERK) activation
* Inhibit Ca++ or promote opening of K+

Natural ligands are endorphins

29
Q

Peripheral opioid inhibition of nociception

A
  • Opioids open K channels
  • K-efflux
    ohyperpolarisation
  • Opioids close Ca-channels
  • reduced Ca-signalling
  • reduced excitability

Where else might they act?
* Centrally: may act on inhibitory interneurons so cause disinhibition (ie they can activate pathways)

30
Q

What are the targets of opioids? (3)
How do they work?

A
  • Descending pathway (midbrain- periaquedactal grey)
  • Dorsal horn (spinal cord)
  • Periphery
  • Action:
  • Inhibit excitation in periphery
    -Inhibits ascending pathway
  • Inhibit transmission in Dorsal
    horn
  • Inhibits ascending pathway
  • Activates descending pathway
    -Inhibits ascending pathway
31
Q

What are examples of opioid drugs?

A

Opiates: Morphine and Codeine
Synthetic: Heroin, Oxycodone, Methadone, Pethidine, Pentazocine, Fentanyl, Buprenorphine (partial agonist)
Antagonist: Naloxone/naltrexone

32
Q

Opioid drugs and receptors

A
  • Opioids vary in receptor specificity and efficacy at different receptors
  • Complex!
  • Methadone- pure agonist
33
Q

Opioid Receptor Effects:
Where are mu receptors found? (3)

A
  • Different receptors – different effects
  • Different locations
  • Analgesia – mostly due to mu

Supraspinal - mostly mu receptors
* Forebrain –
o cerebral hemispheres (sedation, mood)
* Limbic system:
o Most receptors found in amygdala,
o probably do not exert analgesic action, may influence emotional behaviour
* Euphoria (Mu) v dysphoria (strong feeling of discomfort) (kappa)

Mid-brain -
o periaqueductal grey, nucleus raphe magnus,
* (inhibit ascending spinal transmission via descending iinhibition)

Spinal
* Dorsal horn of spinal cord
o mu, kappa & delta (mu dominant)
* terminals of primary afferents (opioids suppress release of SP & CGRP)

34
Q

Opioid receptor side effects?

A
  • Respiratory centre (medulla)
    o Respiratory Depression
    o Can occurs at therapeutic dose
  • GI Tract
    o Reduced motility
    o Constipation
  • Cough centre of medulla (anti-tussive)
    o Depression of cough reflex
  • Chemoreceptortrigger zone (medulla)
    o nausea, vomitting
    o Usually transient
  • Pupillary constriction
    o Occulomotor nucleus – pinpoint pupils
    o Diagnostic in induced coma
35
Q

Tolerance is an issue with opioid drugs:
What is tolerance?

A

Continued use requires increased doses for equivalent effect

  • Tolerance
    o Most pharmacological effects
  • Analgesia, emesis, euphoria, respiratory
    depression
    o Less
  • Constipation or pupil constriction
    o Desensitisation of opioid receptor
  • Changes in receptor density/GPCR coupling
36
Q

Pharmacokinetics of opioids:

A
  • Most morphine like drugs undergo considerable first pass metabolism
    o (less potent when taken orally)
    o Codeine has good oral bioavailablility
  • Plasma half lives
    o Morphine -2-3.5 h
    o Codeine -3 h
    o Fentanyl 1-6 h
  • Most morphine like drugs 3-6 h
    o Methadone 15-30 hr

Fentanyl
* Very potent
* Transdermal patch
-Pain relief 12-24 h
-Build up of subcutaneous reservoir
–Can persist after removal
* Morphine like drugs - Inactivation by hepatic metabolism normally by glucuronidation
* Excreted via kidneys
o Dose reduction in cases of renal failure
* Interactions - Benzodiazepines and opioids: risk of potentially fatal respiratory depression

37
Q
  • What type of receptors are the endogenous opioid receptors?
  • Which receptor is mostly responsible for the analgesic effect?
  • How do opioids function in terms of pain relief (ie how do they affect various parts of the pain pathways)
  • State an issue with fentanyl patches that is important to consider with subsequent medications
  • State a key side effect
  • What is an issue in taking opioids with benzodiazepines?
A
  1. Mu, kappa, delta (inhibitory GCPRs)
  2. Mu
  3. Inhibit peripheral nociceptors and enhance activity in the descending pain pathway
  4. Depots of drug may remain after patch has been removed
  5. Respiratory depression
  6. Both can cause respiratory depression- can lead to fatalities
38
Q

Non-opiod- noradrenaline

A

Noradrenaline
o NA: is the transmitter of the inhibitory pathway linking the locus coeruleus to the dorsal horn of the spinal cord
o TCAs: Inhibit NA reuptake (also 5HT) eg amitryptiline (SNRIs eg venlafaxane / duloxetine –similar mode of action)
o Tramadol HCl (opioid) weak mu agonist plus increased NA transmission (reduce monoamine reuptake)
* Effective neuropathic pain

39
Q

Non-opiods:
Anti-seizure medications

A
  • Na or Ca-channel blockade
  • Eg gabapentin, pregabalin (primarily Ca channel blockers)
  • Reduce primary afferent transmission
  • Neuropathic pain
  • May have other modes of action
40
Q

Non-Opioid:
Cannabinoid receptor agonists

A

– CB1 and CB2 receptors widespread
– Central and peripheral nociceptor
effects
– Neuropathic pain (esp. multiple
sclerosis)
» Sativex for MS
» Evidence weak for other types of
neuropathic pain

41
Q

Non-opioid:
Glutamate receptor blockers

A

– NMDA receptor antagonists?
– Ketamine? (only research)
– Block primary afferent transmission
– severe central side effects – psychosis
– May block central wind up

(Function at the spinal cord )

42
Q
  • What is the role of Noradrenaline just discussed?
  • How do TCAs contribute?
  • How does tramadol contribute?
  • How MIGHT NMDA receptor antagonists (in the future) contribute?
A
  1. Noradrenaline is the neurotransmitter in the pathway from the locus coeruleus to the spinal cord. If there is more NA this pathway is activated and it can inhibit the ascending pathway. (The ascending pathway takes pain messages to the higher centres of the brain where it may be interorered as pain)
  2. Inhibit the reuptake of NA
  3. Tramadol can reduce the reuptake of monoamines including noradrenaline. It, as an opiod also has some mu agonist activity so can work in the same way as other mu agonists.
  4. Reduce neurotransmission at the spinal cord- therefore they MAY reduce central wind up and sensitisation

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