08. Pain - Part 1 (Nocigenic Pain) Flashcards
1
Q
What is pain?
A
“An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.”
2
Q
What is nocigenic pain?
A
Pain occuring from painful stimuli acting on nociceptors
3
Q
What are the 5 Stages of pain response?
A
- Detect pain – Activate sensory receptors and nociceptors
- Spinal reflex, withdrawing from painful stimuli
- Signals to the brain that make you conscious of it
- Feel a slower throbbing pain
- Hop up and down
4
Q
What are the two types of pain receptors called?
A
- nociceptors
- high threshold mechanoreceptors
5
Q
What is the structure of nociceptors?
A
Just free nerve endings
6
Q
What stimuli do nociceptors detect?
A
- intense pressure
- stretching
- striking
- pinching
7
Q
How do nociceptors function?
A
When tissue is damaged, nociceptors are activated, sending signals to the spinal cord and then the brain.
8
Q
What stimuli do high threshold mechanoreceptors detect?
A
- heat
- acids -> damage
- capsaicin -> chilli pepper (detected by vanilloid receptor) & heat (detected by temperature-gated (TRP) channels)
- damage -> from ATP release (detected by purinergic receptors)
9
Q
How do high threshold mechanoreceptors function?
A
- Channels open, neuron depolarises - fires action potentials
10
Q
Two types of primary afferents
A
- Ad fibres: lightly myelinated, medium diameter
- They communicate the ‘first pain’: fast localisation of painful stimulus
- C fibres: unmyelinated, small diameter
- They communicate the ‘second pain’
- provide the continuing dull ache, poorly localised
11
Q
Two pathways into brain:
A
- to the somatosensory cortex via the thalamus
- encodes the sensory components
- allows for sensory discrimination (tells you “where” it hurts)
- to ‘emotional’ cortex (insula and cingulate) via the thalamus
- encodes the emotional components (unpleasantness & negative affect)
12
Q
How can pain be protective?
A
It allows us to heal through two processes:
- Peripheral sensitisation
- Central sensitisation
13
Q
What does peripheral sensitisation consist of?
A
- Inflammation in and around injured tissue
- Peripheral nerve endings (nociceptors) are more responsive to stimuli (lower threshold)
- Hyperalgesia (noxious stimuli produce exaggerated pain sensation)
- Allodynia (non-noxious stimuli produce pain sensation (e.g. touching sun-burnt skin))
14
Q
What does central sensitisation consist of?
A
- Changes in the central nervous system
- Neurons more excitable and responsive
- Persistent pain, nerve injury, or inflammation can lead to central sensitisation
15
Q
Peripheral Sensitisation and Inflammation
A
- Trigger: Inflammation, tissue damage, and exposure to irritants
- Mechanism: When tissue is damaged, chemicals (ATP, H+) are released as part of the inflammatory response. They directly activate and/or modulate ion channels in nociceptor terminals
- Then neuropeptides (substance P and CGRP (calcitonin gene related peptide)), are released from nociceptor neurons, triggering:
- vasodilation,
- plasma extravasation (leakage of proteins and fluid from capillaries)
- activation of Mast cells and neutrophils
16
Q
What is ‘inflammatory soup’?
A
The liquid that fills inflamed areas, which contains:
- Histamine (mast cells): they cause vasodilation (widening of blood vessels) and increased permeability, leading to swelling and redness
- Nerve Growth Factor (mast cells)
- Serotonin (platelets)
- Proteases: they cleave extracellular peptide to bradykinin (A peptide that sensitises nociceptors, making them more responsive to pain stimuli. )
- COX enzymes (cyclo-oxygenase) convert arachidonic acid (lipid) to prostaglandin (contribute to inflammation, pain, and fever)
- Neurotransmitters: Substance P and CGRP(released by nociceptors)
- Cytokines (IL-1β, TNF-α)
17
Q
How does pain modulation occur?
A
Components of the inflammatory soup (Bradykinin, NGF and Prostaglandin) feedback to their metabotropic receptors on the nociceptor neurons:
- VR1 receptor (vanilloid receptor 1) is phosphorylated & threshold changes occur so it opens at lower temperatures.
- A sensory nerve specific (SNS) Na+ channel is phosphorylated so threshold voltage for firing is decreased, making the nociceptor more excitable
- Nociceptors become hypersensitive to stimulation
- Causes peripheral sensitisation
18
Q
Why increase pain sensitivity?
A
- Prevents further damage to the area
- Prevents you touching the area
19
Q
Central sensitisation - “wind up pain”
A
- Nociceptor afferents release glutamate and substance P in spinal cord (activating the spinothalamic neurons)
- Repetitive firing causes neuroplastic changes in the spinal cord, strengthening the synapse (so less stimulation will create a larger signal)
- NMDA receptor activation leads to influx of Ca2+
- Substance P activates NK1 receptor (metabotropic)
- phosphorylation of NMDA and AMPA receptors
- receptors become more responsive to glutamate
- neurons more excitable (long term potentiation)
- Substance P diffuses to other synapses - so “wind up” can spread causing a generalized sensitisation to painful stimuli
20
Q
Maladaptive plasticity
A
Particularly intense tissue damage results in maladaptive plasticity:
- peripheral sensitisation in primary afferents
- central sensitisation in dorsal horn secondary afferents
- brain remodelling
Activation of peripheral nociceptors generates APs that are transmitted to secondary afferents in the dorsal horn, which then project to the brain for processing
21
Q
What is Gate control theory?
A
A distraction-based theory:
- Why do we blow on or rub the site of an injury / bite a finger to distract from pain in our legs?
- ∴ A different sensation can block out the transmission of pain
22
Q
Example of gate control theory
A
- When changing the dressings of burns patients, they experience extreme pain
- Must be done, and frequently
- Use of snowy environment-based virtual reality experiences lessens pain (by 30-50%, self-reported)
- Central process: Reduced activity in pain processing areas of brain when treatment in presence of virtual reality (VR)
- Areas: Somatosensory cortex, anterior cingulate and insula + thalamus.
23
Q
Stress induced analgesia
A
Another way to decrease pain:
- In stressful situations, pain is not felt
- Adaptive response
- Central mechanism: triggers descending regulation of pain circuitry to inhibit pain signals arriving in the brain
- Another mechanism: the release of endogenous opioids - naloxone challenge (opioid antagonist) blocks the analgesic effect
- E.g. soldiers escaping danger do not feel their wounds (until safe)
24
Q
Descending modulation of spinal neurotransmission
A
Pathway of transmission:
- somatosensory cortex via thalamus to midbrain and hypothalamus to midbrain
- midbrain to medulla
- medulla into spinal cord
- a variety of onward projections to dorsal horn of spinal cord (opioid peptide, serotonin, noradrenaline)
- modulation (“gating”) of transmission carried out by dorsal horn nociceptive neurons
25
What is "descending inhibitory pain modulation"?
- Summary: Brain overrides pain signals (switches them off in spinal cord)
- Key brain regions involved: periaqueductal grey (PAG) and rostral ventromedial medulla (RVM)
- Mechanism: brain regions activate the endogenous opioid system, which releases endorphins and other opioids that bind to receptors in the spinal cord, reducing pain transmission
26
How is the descending modulatory pain pathway made inactive?
When no pain modulation required, the GABAergic projection from PAG to Raphe fires tonically, keeping the system switched off
27
Mechanism of descending inhibitory pain modulation in detail:
- Opioids inhibit inhibitory neurons in the periaqueductal gray (PAG), allowing excitation.
- Disinhibited PAG neurons fire and activate serotonergic neurons from the raphe nuclei.
- Serotonergic neurons excite enkephalinergic neurons in the spinal cord.
- Enkephalin release acts on opioid receptors on the nociceptor terminal in the dorsal horn.
- Inhibits firing of spinothalamic neurons through pre- and postsynaptic effects.
28
Reducing pain:
Acute pain
- We know the biology so can target directly
- Potential sites of action for local anesthetics, NSAIDS, opiates, and cannabinoids to mediate analgesia
29
Reducing pain:
Desensitising pain receptors
- Capsaicin – active ingredient in chilli & agonist of TRP channels
- Repeated exposure to capsaicin desensitises pain receptors
- Possible mechanism:
- desensitises receptors (stop fluxing ions)
- massive release of Substance P in Spinal cord, depletion of substance (neuropeptides) and blocks central sensitisation
30
Opiates e.g. morphine, codeine, fentanyl
- Mechanism: agonists of the endogenous opioid system tap into body's own system of pain regulation
- Sites: peripherally, spinal cord, centrally
31
Methods of tapping into the endogenous (existing) opioid systems
- Electrical stimulation of PAG: clinically significant pain relief (stimulates release of opioids?)
- Acupuncture: relieves pain (~gate control theory), there is some evidence this can be blocked by naloxone implicating opioid system.
- Placebo: effects can be blocked with naloxone (opioid antagonist) (shows the power of suggestion)
- Non-opioid mechanisms (existing): there are multiple ways the brain can modulate pain signals (e.g. endocannabinoid system)
- Evidence: some stress induced analgesia is not blocked by naloxone
32
Cannabinoid system and stress induced analgesia
(Opioid independent mechanism)
- Endocannabinoids (2-arachidonoylglycerol (2-AG) & anandamide) act at CB1 receptor
- Levels of 2-AG and anandamide in PAG increase with stress
- Injection of CB1 agonist into PAG is analgesic (pain-relieving)
- Injection of CB1 antagonist into PAG blocks stress induced analgesia (Hohmann et al., 2005)
