Lecture 24 - Introduction to Pain Flashcards
Outline the various types of pain
- Nociceptive
• Triggered by brief injury
• Results in brief pain
• Nociceptors carry message to CNS where ‘pain’ is generated - Inflammatory
• Mediators in inflamed tissue activate nociceptors
• Results in persisting pain - Neuropathic
• Abnormal circuits in the CNS
• Can be triggered by non-noxious stimuli, e.g. feather
Give the IASP definition of ‘Pain’
“an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage…”
What is nociception?
Neural encoding and processing of noxious (painful) stimuli
What are nociceptors?
Free nerve endings in tissue (skin, bone) that are activated by noxious stimuli
List ways that nociceptors can become activated
- Mechanical stimuli
- Thermal stimuli
• Heat
• Cold
3. Chemical stimuli • H+ • ATP • Prostaglandin • Bradykinin • Caspaicin • Histamine
Describe nociception following tissue injury
1. Tissue injury results in release of: • Bradykinin • Prostaglandin (through inflammation and activation of COX2) • ATP • Acid
- These chemical activate receptors on nociceptors in damaged tissue
- Activated nociceptors release:
• Substance P
• CGRP - Substance P causes mast cell degranulation, releasing histamine, as well as increased vascular permeability (along with CGRP), resulting in tissue oedema
- Nociceptor conducts message to dorsal horn of spinal cord, where ‘pain’ experience is generated
How can prostaglandin synthesis be pharmacologically targeted?
NSAIDs, such as aspirin and ibuprofen
What is the effect of CGRP?
Where does it come from?
Released by activated nociceptors
Results in increased vascular permeability → tissue oedema
Define the following terms:
• Hyperalgesia
• Allodynia
Hyperalgesia:
• Increased sensation of pain to a stimulus of a given noxious intensity
• i.e. Less intense stimuli can result in pain that would normally be elicited by a very intense stimulus
e.g. pain of showering when sunburnt
Allodynia:
• Pathological response to non-noxious stimuli
• e.g. excruciating pain upon light touch
When does pain hypersensitivity occur?
Describe the mechanism
This occurs after tissue injury
Early inflammation:
• Amplification of chemical mediators that activate nocicpetors
Long terms changes:
• Transcription of ‘pain’ receptors, ion channels and neurotransmitters
• This is driven by cytokines and GFs
Define dermatome
Area of skin supplied by a given spinal nerve
Describe the axonal transport of somatic pain signals from the tissue to the CNS
- Nociceptor activated in tissue
- Action potential travels up axon
• Cell body in dorsal root ganglion - Synapse on neuron in dorsal horn of spinal cord
- Pain pathway projects to:
• Superior colliculus
• Periacqueductal grey (PAG) - Further projections to many areas in the brain
• Dopaminergic system
• Cardiovascular centre
etc.
Outline the different neuron types
Aα - motor and proprioception, heavily myelinated
Aβ - touch and pressure
Aγ - motor to muscle
Aδ - pain, temp., touch
B - preganglionic autonomic
C - pain, reflex, postganglionic autonomic
Which neurons detect pain?
Differentiate between them
Aδ:
• Sharp, prickling, acute pain
C:
• Slow, aching, throbbing, burning pain
Describe what happens to the sensation of pain in the spinal cord
- Modulation of the signal being transmitted by nociceptors
- Dampening aspects
- Interneurons, afferents etc. are interconnected
- Primary nociceptor neuron release glutamate
- Glutamate moves across synaptic cleft and acts on receptor on the post-synaptic neuron:
• NMDA
• AMPA
Attenuation of pain:
• Other neurons inhibit nociceptor neurons in the spinal cord - ‘gate control theory’
• Descending signals form the brain can inhibit nociception in the spinal cord (think about the soldiers tuning out the pain)
Describe Gate Control Theory
a. Interneurons in the spinal cord can release endorphins, which inhibit the neurons that are conducting the ‘pain’ signals
b. Furthermore, vibration stimuli detected by Aβ neurons, can inhibit ‘nociceptor’ neurons in the spinal cord and activate the inhibitory interneurons, thus attenuating pain
Nociceptors, on the other hand, activate neurons in the spinal cord that synapse with the pain centres
What effect do endorphins have on nociception?
Endorphins inhibit pain
Compare the neurotransmitters release by excitatory and inhibitory neurons
Excitatory:
• Glutamate
• Aspartate
Inhibitory:
• GABA
Which receptors does glutamate act on on the post-synaptic neuron?
Compare them
AMPA:
• Low activation threshold
NMDA:
• High activation threshold
Describe the NMDA receptor
Transmembrane pore plugged with Mg2+ in inactive state
Protracted nociceptor results in the displacement of the Mg2+
The receptor is now resistant to opioids
→ “Wind-up”
Describe the effects of opioids
Where do they predominantly act?
Pre-synaptically:
• Decrease neurotransmitter release
Post-synaptically:
• Hyperpolarisation of post synaptic neuron
Predominantly act in the spinal cord
What type of receptor is the opioid receptor?
GPCR
Where are nociceptors (ascending to the brain) located in the spinal cord?
Dorsal horn
Describe how descending pathways attenuate pain
How could this be exploited pharmacologically?
(think about the wounded soldiers)
Descending neural projections from the brain can inhibit Adelta and C fibres that are conducting pain signals through the spinal cord
Descending neurons release:
• Adrenaline
• Serotonin
Since these pain attenuating descending neurons are adrenergic and serotonergic, by mimicking this pharmacologically, one could block pain impulses
Describe the experiments with Amitryptyline
What is amitryptyline?
Amitryptyline:
• NA and serotonin reuptake inhibitor
• Tricyclic antidepressant
- Mice administered with Amitryptyline
- Mice subjected to pain protocol
• Tail placed in front of a heat source
• Frequency of moving the tail away from the heat recorded - Amitryptyline resulted in analgesia
• 70x more potent than aspirin
• Not as potent as morphine
Describe the TPRV1 receptor
What activates it?
This is a receptor on nocicpetors that is activated by noxious stimuli
Ligands:
• Heat
• Capsaicin
• H+
Describe the role of tricyclics antidepressants in central analgesia
Amitryptilline is a tricyclic antidepressant
Showed experimentally to produce a potent analgesic effect by actin on the spinal cord
List ways that transmission in the spinal cord can be pharmacological targeted
- Amitryptilline
• Inhibition of NA and serotonin reuptake
• Mimics the activity of the inhibitory neural projections from the brain - Gabapentin
• Inhibits subunit of Ca channel in spinal neurons
Describe the role of the ‘Periacquaductal grey’ area in the brain
How can this be therapeutically exploited?
PAG:
• Target of pain pathway projections from the spinal cord
Murine model:
• Stimulation of this area results in analgesia
Opioids stimulate this area
Therapy:
• Deep brain stimulation of this area for relief of chronic pain
Describe the effect of pain on the cardiovascular system
Pain pathways to the brain then project further to the cardiovascular centre in the brain
Results in:
• Tachycardia
• Hypertension
• Vasoconstriction
List the ‘levels’ upon which pain can be pharmacologically targeted
- Noxious stimuli
• e.g. Aspirin and Ibuprofen inhibit prostaglandin production - Nociceptor
• Ketamine inhibits NMDA receptor - Spinal cord
• Activation of descending neural projections that normally inhibit pain pathways in spinal cord:
- Amitryptilline (NA and serotonin reuptake inhibitor)
• Gabapentin: Ca2+ channel inhibitor
• Opioid: inhibition of neuronal transmission
• Lignocaine: inhibits neuronal transmission - Brain
• Deep brain stimulation of PAG
• Naraptriptan: serotonin agonist
Describe how imaging technology can investigate the effect of drugs on the brain
e.g. fMRI
• Measure brain activity during experience of noxious stimulus (e.g. heat on hand)
• Look at the areas that light up during pain
Testing the effect of the analgesic:
• Administer the patient a drug, and see if there is diminished activity of the pain centres in the brain
List ways that genetics can affect experience of pain
- Metabolism
• Neurotransmitter metabolism (COMT: dopamine metabolism)
• Drug metabolism (e.g. codeine metabolism) - Receptor genes
• ‘Stargazer’ gene
Describe the role of the COMT gene in pain
COMT: enzyme that metabolises pain
If the enzyme is under active, there is increased dopamine in the system
Endorphins have less time to act on receptors
The individual has an increased susceptibility to pain
What is the gold standard analgesic?
Morphine
What is the definition of chronic pain?
How does chronic pain occur?
In which situations does it occur?
Chronic pain:
Pain that continues to be present more than three months after surgery or an injury or from various disease or other causes
Mechanism:
Structural remodelling leading to abnormal hyper-excitability of pain responses
The pain signal becomes embedded in the system (i.e. not triggered by external events)
When?
• 15-20% develop chronic pain after traumatic injury
• Conditions such as shingles
• Limb amputation (phantom limb syndrome)
Describe the effect of sodium channel mutations in chronic pain
Sodium channel (Nav1.7) is key in the transmission of neural impulses in pain pathways
WT: no pain
PE disorder:
• Increased channel function mutation
• Painful hands and feet
• Autosomal dominant
PEPD disorder:
• Increased channel function mutation
• Ocular, mandibular and rectal pain
• Autosomal dominant
CIP disorder:
• Absent channel
• Absence of pain
• Autosomal recessive
List some genetic pain syndromes
- Familial hemiplegic syndrome
- Primary erythermyalgia (PE)
- Paroxysmal extreme pain disorder (PEPD)
- Channelopathy-associated Insensitivity to Pain (CIP)
Describe the ‘Stargazer’ mutation
‘Stargazer’ gene encodes ‘Stargazin’ protein
• A subunit of the AMPA receptor
• aka CACNG2
In this mutation, the protein is absent
Stargazer mice exhibit:
• Absence of seizures and ataxia
• Susceptible to neuropathic pain
Polymorphism of this gene in humans is associated with chronic pain
Describe the role of codeine metabolism in chronic pain
Codeine metabolism:
• Codeine → Morpheine or Norcodeine
• Metabolised in the liver by CYP2D6
CYP2D6 mutation:
• Can’t metabolise codeine into morphine
• Codeine is ineffective in bringing about analgesia
List analgesic medications
- Opioids
• Mainstay for severe to moderate pain - Paracetemol
- Aspirin
- NSAIDs
• e.g. Ibuprofen - Adjuvants
• Antidepressants
• NMDA antagonists
etc.
List side effects of morphine
• Ventilatory depression • Drowsiness • Sedation • Urinary retention etc.
Outline the strategies for pain management
1. Multimodal analgesia • Small doses of opioids + non-opioids • Targets pain transmission at multiple sites (receptors) • Synergistic analgesic effect • Reduces opioid requirement
- Pre-emptive analgesia
• Analgesia prior to injury (i.e. surgery)
• Theorectically: attenuates injury and neuroplastic response
• In practice, has little effect - Regional anaesthesia
• Targets nerve transmission
• ‘Nerve block’ - General anaesthesia
• Removes cognition: pain perception and transmission
• Enables surgical procedures
Define anaesthesia
Loss of sensation
Define analgesia
Reduction in pain
List limitations of analgesic drugs
- Individual response
- Inadequate pain control
- Administration
- Dependence, addiction
- Multiple adverse effects (e.g. Bex, phenacetin, chronic renal failure)
Describe pain and intervention in MI
Experienced pain:
• Crushing visceral pain
• Referred pain to arm and neck
Intervention:
• Aspirin in ambulance
• Morphine to relieve distress
• Glyceryl nitrate, thrombolysis
Describe pain and intervention with a child with a broken leg
Pain:
• Distressed child
Intervention:
• Intranasal opioid delivers rapid analgesia
Describe pain intervention with sports injury (e.g. shoulder reconstruction)
- Paracetamol
- NSAIDs
- Synthetic codeine
- Local anaesthetic
- Morphine if required
Describe pain intervention with migraine
What is the pathogenesis of migraine?
Pathogenesis:
• Cerebral vasodilation
Combined therapy:
1. Analgesics
• Aspirin
• Ibuprofen
- Vasoconstrictors
• Ergotamine
• Serotonin (5-HT) agonist
• CGRP antagonists
What drug is used for labour pain?
Inhalational NO
Morphine:
• Can not be used
• Crosses the placenta and harms to baby:
• Respiratory depression
Describe spinal anaesthesia
Injection into spinal canal (dorsal horn) delivers anaesthesia to lower body
Describe epidurals
Administer:
• Local anaesthetic
• Opioids
Into epidural space
Blocks nerves to uterus
Describe an instance where pain is not triggered by physical stimuli
Emotional pain: e.g. rejection by friend induces experience of pain
How do aspirin and ibuprofen act?
Inhibit production of prostaglandins
Prostaglandins activate receptors on nociceptor neurons
These neurons synapse on other neurons in the brain, generating the perception of pain
Describe the action of ketamine
Analgesic
Acts on the NMDA receptor to inhibit pain
Describe the action of cocaine
Local anaesthetic
Blocks neuronal transmission
