Physiology of pain Flashcards
Define pain
An unpleasant sensory experience associated with tissue damage
Accompanied with an emotional reaction
Consider the classifications of pain
What is a nociceptive pain? How are its receptors activated?
Nociceptive receptors physiologically respond to pain. They are primary sensory neurons. This means its cell body is in the dorsal ganglia and synapses in the dorsal horn.
Have free nerve endings in the periphery (skin, muscle, joints, viscera and meninges)
Activated by pressure, heat, cold, chemical and tissue damage/inflammation
Consider the classifications of pain
What is an inflammatory pain? How are is the inflammatory response accelerated as a result of nociceptor receptors?
Give an example
Pain in response to inflammation. CLINICAL PAIN
Activation of 1 branch of a nociceptor axon triggers release of Substance P and cGRP from another. This causes:
vasodilation -> increased permeability –> activation of mast cells –> release of histamine –> MORE INFLAMMATION
e.g. Rheumatoid arthritis
Consider inflammatory pain
Chemicals released as part of tissue damage activate or modulate nociceptors. State these chemicals with the receptor to which the bind, or where they are secreted from
Give a practical example of inflammatory pain
ATP- bind to purinergic receptors (P2X) H+ - bind to acid-sensing ion channels Serotonin- from platelets which bind to 5-HT3 receptors Histamine - from mast cells Bradykinin Prostaglandin Nerve growth factor
e.g in runners -lactic acid build up leads to tissue acidosis (increased H+)= activation of nociceptors= PAIN
Consider the classifications of pain
What is neuropathic pain?
Pain in response to injury to the NS e.g. compression, traction, sever, hypoxia, demyelination, tumour
CLINICAL PAIN
e.g. Carpal tunnel syndrome, spinal cord injury, thalamic stroke
NOTE: A nerve injury may not be obvious on examination
Consider afferent nerve fibre classification.
Describe A-alpha and A-beta nerve fibres
They DO NOT transmit pain
Myelinated (30-75m/sec)
Large diameter
Respond to Light touch and proprioception
Consider afferent nerve fibre classification.
Describe A-delta nerve fibres
THEY TRANSMIT PAIN
Thinly myelinated (5-30m/sec)
Medium diameter
Respond to light touch, proprioception, and NOCICEPTION
Consider afferent nerve fibre classification.
Describe C nerve fibres
THEY TRANSMIT PAIN
Unmyelinated (0.5-2m/sec)
Small diameter
Respond to temperature, NOCICEPTION
Most are polymodal- respond to pressure, temperature and chemical damage
What is the difference in pain characterisation when a nociceptors respond to A-delta and C fibres?
A-delta: sharp pricking pain - This is quickly transmitted -Well localised -Activates reflex arcs LACKING in visceral pain as they lack a-delta neurons
C: slow dull ache, burning pain
-Poorly localised
Consider pain transduction mechanisms
How does transduction differ between pressure and temperature stimulation?
PRESSURE
- Uses Mechanically sensitive ion channels
- Not yet identified in eukaryotes
TEMPERATURE -Uses Transient receptor potential (TRP) channels which detect different temperarutures: TRPV1- Hot, agonist: chilli (capsaicin) TRPM- Cold, agonst: menthol TRPA1- V Cold, agonist: cinnamon
Consider central pain pathways
Which tract is involved in pain transduction to the brain?
Describe the pathway the first, second and third order neurons take
Spinothalamic tract
FIRST ORDER NEURONS:
-Enter dorsal horn and form tract of Lissauer. They synapse in substantia gelatinosa- in dorsal horn (Lamina 1 and 2)
Glutamate and Substance P excite 2nd order neurons
SECOND ORDER NEURONS:
- Cross in dorsal horn at each level
- Ascend in anterolateral column to thalamus
THIRD ORDER NEURONS:
- Ascend to primary somatosensory cortex from thalamus
- Lower body to medial cortex and upper body to lateral cortex= sensory homunculus
- Encode the sensory components (where and modality)
CLINICAL APPLICATION
Consider central pain pathways
What is referred pain?
Give an example
Convergence of visceral and cutaneous nociceptors on same second order neurons in spinal cord. Brain perceieves pain as cutaneous
e.g. Angina perceived as pain in upper chest wall and left arm. Cutaneous nociceptors from skin over left arm and visceral nociceptors from heart synapse on same second order neuron
CLINICAL APPLICATION
Consider central pain pathways, specifically descending regulation of pain
What is the phenomena observed in batter victims? How does it come about?
Battle victims don’t feel pain from their injuries= Stress-induced analgesia
Pain experience is determined by factors such as behavior, emotions from past experiences
-Higher cortical regions can activate descending modulatory pathways
PAG neurons excite RVM neurons, which inhibit (or excite) the spinothalamic tract. Serotonergic projections act on dorsal horn inhibitory interneurons (in dorsal horn)
- Also parallel noradrenaline pathway
Consider central pain pathways, specifically descending regulation of pain
How is the spinothalamic tract modulated
Periaqueductal gray matter (PAG)
Rostral ventromedial medualla (RVM)
Cortical regions project to PAG in midbrain
PAG projects to RVM in medulla
RVM projects to dorsal horn
Describe the endogenous opioid system
Opioids play a role in descending inhibition of pain e.g. endorphins, enkepalins
Especially stress-induced analgesia
INHIBITORY (act on inhibitory metabotropic receptors)
Released from interneurons at multiple sites: midbrain (PAG); medulla (RVM), dorsal horn
How are nociceptors modulated?
Inflammation can cause pain hypersensitivity
Allodynia - non-noxious stimuli produce a painful response
Hyperalgesia- noxious stimuli produce an exaggerated pain response
What is the difference between peripheral and central sensitisation?
PERIPHERAL SENSITISATION
- Hyperalgesia- increase in responsiveness of the peripheral ends of nociceptors
- Driven by Inflammation/ tissue damage
CENTRAL SENSITISATION
- Hyperalgesia and allodynia
- In spinal cord
- Major mechanism in neuropathic pain
Consider the micromolecules involve din peripheral sensitisation.
How do bradykinin, NGF and Prostaglandin contribute to peripheral sensitisation?
Bradykinin and NGF reduce the threshold of heat activated channels (TRPV1)
Bradykinin binds to the metabotropic-Gcoupled protein, activation of protein kinase phosphorylaates TRPV1
Prostaglandin reduce the threshold of sodium channels
Clinical pain can be acute or chronic.
What is classified as acute clinical pain?
What is its mechanism?
Inflammatory or nociceptive pain lasting LESS than 3 months
e.g. following surgery, MSK injury, burn
Pain stimulus activates receptors which excite first order neurons. Activation of modulation of nociceptors e.g. macrophages, mast cell and neutrophils/granulocytes. Cell body in dorsal ganglion. Second-order neuron travels to brain
Once the injury site recovers, pain stops
Which micromolecules are involved in acute pain trandsuction?
Histamine Serotonin Bradykinin Prostaglandins ATP H+ Nerve growth factor TNFa Endothelins Interleukins
What is peripheral sensitisation?
Major mechanism of acute pain which leads to pain hypersensitivity (hyperalgesia)
- Reduction in the threshold of channels at the peripheral ends of nociceptors
- This decreases threshold potential of TRPV1 channels (by bradykinin, nerve GF); Na+ channels (by prostaglandins)
What is typical of treatment for acute pain?
How is this different to chronic pain treatment?
It is effective. Acts on PNS, CNS or both (site of injury)
Central changes are not easily reversible therefore chronic pain is difficult to treat. Acute pain treatments often don’t work. Instead pain management requires good individual patient management and it is important to manage primary condition and associated symptoms e.g. depression/sleep/fatigue
Consider treatment for acute pain.
LOCAL ANESTHETIC
Mode of administration?
Mechanism of action?
E.g.?
Topically applied to skin
Na+ channel blocker (preventing nociceptors firing as it inhibits upstroke)
e.g. Lidocaine
Consider treatment for acute pain.
TOPICAL CAPSAICIN TREATMENT
Class of drug?
Mechanism of action?
Component of chilli peppers
TRPV1 channel agonist: repeated use decreases nociceptor firing
It’s mechanism of action is unknown. May have someting to do with depletion of substance P. Causes peripheral terminals to die (Ca2+ overload causing mitochondrial dysfunction)
Consider treatment for acute pain.
Non-steroidal anti-inflammatory drugs (NSAIDS)
Mode of administration?
Mechanism of action?
E.g.?
Oral, topical application
MOA: Reduces inflammatory response by inhibiting prostaglandin synthesis
- PREVENTS PERIPHERAL SENSITISATION
COX inhibited –> Prostaglandin synthesis reduced –> Prevents decrease in Na+ channel threshold
e.g. Aspirin, ibuprofen
Consider treatment for acute pain.
PARACETAMOL/ACETOMINOPHEN
Mode of administration?
Mechanism of action?
Oral
Not NSAID
MOA: Inhibits COX enzymes (but doesn’t decrease inflammatory). Acts on descending serotonergic pathways
EXACT MECHANISM UNKNOWN
Consider treatment for acute pain.
OPIOIDS
Mechanism of action?
e.g?
Most effective but numerous side effects
MOA: Agonists of endogenous opioid system
Multiple sites of action: brainstem (disinhibition), spinal cord and periphery (inhibits channels on nociceptors)
e.g. morphine, codeine, tramadol
CLINICAL APPLICATION
Why does rubbing/blowing on painful area reduce pain sensation?
Gate control theory
Modulation of pain at the level of the spinal cord
Pain evoked by nociceptors can be reduced by simultaneous activation of low threshold mechanoreceptors (AB fibres)
Stimulation of AB fibres in vicinity of injury –> activates inhibitory interneurons in dorsal horn –> inhibits spinothalamic neurons = CLOSES Gate
!! C-fibres (nociceptive signals) inhibit inhibitory interneurons = OPENS GATE
Name 4 symptoms of neuropathic pain
- Shooting, burning, stabbing pain
- Tingling/numbness
- Spontaneous or evoked pain
- Chronic sensation of unpleasant feeling
- Difficulty sleeping/resting
- Emotional problems
ASYMPTOMATIC
Consider neuropathic pain mechanisms
What are the two PERIPHERAL mechanisms?
- Peripheral sensitisation
- Spontaneous firing of nociceptors- following peripheral nerve injury, increased axonal firing at the site due to the accumulation of ion channels and regeneration tip of axon-MORE EXCITABLE
Consider neuropathic pain mechanisms, specifically the CENTRAL mechanisms
WHAT IS CENTRAL SENSITISATION?
Central sensitisation (normal inputs cause abnormal responses in spinal cord) - increase in the responsiveness of nociceptive neurons within the CNS (due to decreased TP for activation of 2nd order neurons as in LTP)
Constant firing of axons from periphery –> sustained release of glutamate –> prolonged depolarisation of post-SN –> massive influx of Ca2+ VIA NMDA –> activation of kinases –> Phosphorylation of NMDA/AMPA receptors, channel protein synthesis
Ultimately alters kinetics of channels (increases efficiency) and causes insertion of more channels
Consider neuropathic pain mechanisms, specifically the CENTRAL mechanisms
What is the difference between the CENTRAL HYPERALGESIA MECHANISM and the CENTRAL ALLODYNIA MECHANISM?
Central hyperalgesia mechanism- following central sensitisation, activation of nociceptors results in amplified spinal cord activation
Central allodynia mechanism- non-noxious AB fibres also synapse onto 2nd order spinothalamic neurons which are normally non-functional. Post central sensitisation, non-noxious afferents activate sensitised 2nd order neurons.
Consider neuropathic pain mechanisms.
What other mechanisms are there other than those aforementioned?
- Altered synaptic connections: AB fibres form new sprouts that synapse onto spinothalamic tract neurons
- Loss of inhibitory interneurons e.g. GABA and glycine
Consider drug treatment for chronic pain.
TRICYCLIC ANTIDEPRESSANTS
Mechanism of action?
E.g?
Unclear MOA: act on descending inhibitory pathways and inhibit reuptake of serotonin (and noradrenaline)
e.g. amitriptyline
Consider drug treatment for chronic pain.
ANTICONVULSANTS
Mechanism of action?
E.g?
Unclear MOA: act in spinal cord to reduce excitability,
blocks Ca2+ channels (pregabalin/gabapentin)
-DONT ACT on GABAergic interneourons, block Pre-SN voltage-gated Ca2+ channels which prevents release of glutamate from nociceptors
or block Na+ channels (carbamazepine)
Consider drug treatment for chronic pain.
NMDA ANTAGONISTS
Mechanism of action?
E.g?
MOA: NMDA receptor antagonist (decrease glutamate influx)- prevents depolarisation of second order neuron
Adverse side effects e.g. hallucination, nightmares
Ketamine
CLINICAL APPLICATION
What do the NICE guidelines say regarding treatment of neuropathic pain?
1st line- amitriptyline or pregabalin
2nd line- switch drugs or combine
3rd line- refer to specialist pain service and consider oral tramadol (opioid) or in combination with 2nd line treatment consider topical lidocaine
Consider treatment for chronic pain.
Other than drugs, how else may chronic pain be treated?
- Physiotherapy - e.g. manipulation of tissues, pacing
- Psychological therapies - e.g. cognitive behavioural therapy
- Surgery - e.g. spinal cord stimulator
Consider treatment for chronic pain.
How do placebo/complimentary alternative therapies work?
Placebo analgesia has been shown to be effective in the treatment of neuropathic pain - due to activation of descending inhibitory pathway
Complementary alternative therapies include: acupuncture, message therapy, homeopathy, herbal medicine hypnosis
In conclusion, what are the 5 things wrong in chronic pain?
- Peripheral terminals experience peripheral sensitisation
- Axon-spontaneous firing of nociceptors
- DRG - synthesis of new ion channels
- Dorsal horn/spinal cord- central sensitisation
- Brain- changes in brain activation patterns
