HNS15 Pain Pathway And Mechanisms Of Pain Flashcards
Definition of pain
Unpleasant sensory and emotional experience associated with actual / potential tissue damage, or described in terms of such damage
Nociception vs Pain
Nociception:
Reception of signals in CNS evoked by activation of specialized sensory receptors (nociceptors) that provide information about tissue damage
Pain:
***Subjective perception of an aversive / unpleasant sensation that originates from a specific region of the body
—> an individual can have distinct responses to the same nociceptive stimulus at different times
—> have Affective + Emotional components
Types of pain
Classified based on site of origin:
- Somatic pain
- Superficial pain: Skin
—> Initial pain (fast/sharp)
—> Delayed pain (slow/dull)
- Deep pain: Connective tissues, bones, joints, muscles - Visceral pain: Gall and kidney stones, ulcers, appendicitis etc.
Nociceptors
- Non-specialised free nerve endings (NOT encapsulated)
- Widely distributed throughout body
- A few tissues lack pain endings (e.g. neural tissues of brain)
- Most are ***Non-adapting —> as long as pain stimulus present —> continue firing
- Majority: Multimodal (respond to multiple stimuli), some activated by specific stimuli
- 2 kinds of afferent nerve fibres:
—> Aδ (thinly myelinated, fast) and C (unmyelinated, slow) fibres
—> double pain sensation: sharp pain followed by dull pain
Sharp pain vs Dull pain
Sharp / First pain:
- larger amplitude
- lasts shorter
Dull / Second pain:
- lower amplitude
- lasts longer
Aδ fibres vs C fibres
Aδ fibres:
- Thinly myelinated, fast
- Stimuli (respond to ***single type of stimuli):
—> Mechanical
—> Thermal (extreme temperature: <5oC (TRPA1+TRPM8) / >45oC (TRPV3+TRPV1/M3)) (Transient receptor potential channels)
C fibres:
- Unmyelinated, slow
- Stimuli:
—> Polymodal (mechanical, temperature, chemicals e.g. pH, hypoxia, lactic acid, prostaglandins, bradykinin, histamine, electrolytes e.g. K leaking from damaged cells)
—> Silent nociceptors (in Viscera): normally not activated by noxious stimulus, but firing threshold largely ***reduced by inflammation
Pain transduction: Nociceptors to spinal cord
Enter spinal cord via dorsal horn (1st order neuron cell body in dorsal root ganglion)
—> synapse with 2nd order neuron in dorsal horn
—> cross the midline in spinal cord
—> ascend to brain on contralateral side
Dorsal horn grey matter:
- divided in 10 laminae (lamina I most lateral)
- Nociceptors: mainly connect to 2nd order neuron (projection neurons) in laminae I, V, VII (i.e. ***Lateral dorsal horn)
Neurotransmitter used by pain fibres: Aδ fibres + C fibres
- Aδ fibres: ***Glutamate
- C fibres: **Glutamate + **Substance P
—> Glutamate: small clear vesicles
—> Substance P: large dense vesicles (poor reuptake —> ***diffuse to other places to activate other 2nd order neurons —> more diffuse signaling than glutamate —> poor localisation of pain —> dull pain)
Pain sensitisation
Pain hypersensitivity after an injury —> helps healing by ensuring that contact with injured tissue is minimised until repair is complete
Allodynia: Normally innocuous (non-noxious) stimuli may be perceived as pain (e.g. sunburn —> skin touch becomes painful)
Hyperalgesia: Increased painful sensation to noxious stimuli
—> Areas not affected / damaged will also become sensitised
—> lower pain threshold
***Hyperalgesia due to peripheral sensitisation
- During inflammation
- Damaged cells —> **Prostaglandin + Bradykinin
- Activated mast cells —> **Histamine
—> Activate + Sensitise Nociceptors (by modulating ion channels) - Release of **Substance P + **CGRP (calcitonin gene-related peptide) from Nociceptor sensory endings
—> causes ***Neurogenic inflammation
—> plasma extravasation + dilation of blood vessels + swelling - Neurogenic inflammation further sensitises nociceptors (Vicious cycle)
—> making them far more sensitive to stimulation
—> Hyperalgesia - Hyperalgesia can be
- Primary (felt at site of stimulation)
- Secondary (cytokines / neuropeptides spread to a site remote from original injury)
***Hyperalgesia due to central sensitisation
Increased excitability of ***2nd order neuron in dorsal horn
Mast cells
—> release neurotrophic factors **NGF (nerve growth factor)
—> carried by nociceptor nerve endings
—> transported to cell body of 1st order neuron (retrograde transport)
—> increased transcription of **BDNF (brain-derived neurotrophic factor)
—> central release of BDNF to 2nd order neuron
—> central sensitisation (reduced threshold)
***3 major Ascending pain pathways
Anterolateral system:
3 major ascending pain pathways:
- Spinothalamic tract —> **Localisation + Discrimination (intensity, quality) of pain
- 2nd order neuron
—> **VPL, VPM nucleus
—> 3rd order neuron
—> project to ***Somatosensory cortex S-I, S-II (with well somatotopic organisation) - Spinoreticular tract —> **Emotion (Limbic system), **Autonomic reflex, Arousal
- 2nd order neuron
—> **Reticular formation
—> **Medial nuclei of Thalamus (3rd order neuron)
—> **Insula cortex + **Anterior cingulate cortex + ***Hypothalamus (autonomic response e.g. ↑HR) + (Somatosensory cortex) - Spinomesencephalic tract —> **Affective and Aversive behaviour associated with pain + **Descending pain modulation
- 2nd order neuron
—> **Midbrain (Periaqueductal gray, Reticular formation, Superior colliculus) + **Amygdala
Neuropathic pain
- Different from central pain sensitisation
- Injuries to afferent nerves in peripheral (e.g. nociceptors nerve endings) / central pathways
- Pain without stimulus
- Burning / Electrical sensation
- e.g. shingles
Thalamic pain syndrome (Dejerine-Roussy syndrome)
- Lesion in VP nucleus of thalamus due to stroke
—> Analgesia followed weeks/months later by Paraesthesia (burning/pickling pain)
Pain modulatory pathways
- Descending pain modulatory pathway
2. Gate control theory
***Descending pain modulatory pathway
Structures involved:
- Periaqueductal gray: Serotonin, Glutamate, Opioid neuropeptides
- Nucleus raphe magus: Serotonin
- Locus ceruleus: Norepinephrine
- Dorsal horn **interneuron: **Enkephalin
2 pathways:
1. Periaqueductal gray (midbrain) —(synapse)—> Nucleus raphe magus (medulla) —> Dorsal horn (interneuron)
- Noradrenergic locus ceruleus neurons (upper pons) —(through medulla)—> Dorsal horn (interneuron)
-
Enkephalin:
1. Bind to **Opioid receptor on **presynaptic **afferent nociceptor —> **inhibit release of **Glutamate + **Substance P from presynaptic afferent nociceptor
- Bind to **Opioid receptor on **postsynaptic **2nd order neuron —> **hyperpolarisation —> less likely to fire action potential
—> Overall effect: reduce transduction of pain signals to brain
Gate control theory
Occur locally in spinal cord
E.g. Bump knee into table leg —> Skin rubbing
- Activates Aβ mechanoreceptor (non-nociceptive mechanoreceptor)
—> activate interneuron (inhibitory neuron) in dorsal horn
—> inhibits 2nd order pain projection neuron in dorsal horn
(Aβ mechanoreceptor as a gate to close transmission of pain signals from nociceptor to 2nd order neuron)
Pain perception
Subjective interpretation of characteristics of noxious stimuli
- in terms of:
1. What (submodalities)
2. Where (spatial localisation) - Body reactions to pain
Submodalities of pain
- Sharp, pricking, tearing, crushing, burning, dull, soreness etc.
Basis of submodalities:
- ***2 classes of nociceptive afferents (Aδ fibres: sharp pain; C fibres: dull pain)
- Contribution by ***non-nociceptive modalities (needle hit skin activate mechanoreceptor as well —> feeling combination of pain + touch —> give varieties of pain perception)
- ***Psychological factors
- ***Learning and experience
Spatial coding of pain
- Localisation of pain depends on Topographical organisation + Projection
-
**Pain is poorly localised compared to touch due to:
1. **Low innervation density
2. **Wide receptive field of nociceptors / neurons in medial thalamic nucleus / anterior cingulate cortex / insula cortex (compared to neurons in somatosensory cortex)
3. **Coarse topographical representation of brain areas receiving pain signals (e.g. anterior cingulate cortex / insula cortex)
4. ***Branching and convergent ascending fibres (e.g. converging on same 2nd order from different nociceptors) - However, localisation can still be aided by contribution from non-nociceptive modalities (e.g. mechanoreception which is sharper)
- Errors in localisation:
—> Phantom limb
—> Referred pain
Phantom limb and Phantom pain
Phantom limb:
Sensation from amputated limb
—> due to ***Reorganisation of somatosensory cortex
—> regions originally receive input from amputated limb also becomes activated when other areas are stimulated
Phantom pain:
Pain from amputated limb
—> possible cause: **Increase in excitability of 2nd order neuron in dorsal horn (due to inflammation of amputated area) —> fire **spontaneously
Referred pain
- Excitation of visceral nociceptors sensed as originating from superficial sites
- Visceral pain referred to cutaneous dermatomes that share ***same dorsal root (e.g. MI, angina, acute appendicitis, gallstone colic, renal and ureteric colic)
- Cause:
Convergence-Projection:
1. Convergence of nociceptive **cutaneous and **visceral receptors onto ***same pool of 2nd / higher order neurons
2. Projection according to “learned” experience (經常刺激皮膚, 到heart attack都以為係皮膚痛)
Pain control
- Oral analgesics
- inhibition of production of pain-inducing substances e.g. Prostaglandins (sensitise nociceptors, increase excitability of 2nd order neuron)
- by inhibition of COX e.g. paracetamol, NSAID - Local / regional anaesthesia
- LA: lignocaine, xylocaine —> blockage of Na channel —> prevent axons from conducting action potential - Opioids / morphine-like drugs
- activate opioid receptor (in spinal cord, midbrain etc.) —> activate descending modulatory pathway for pain
- adverse effects: addictive - General anaesthesia
- loss of consciousness in addition to loss of sensation - Surgical treatment (anterolateral cordotomy)
- Transcutaneous electrical nerve stimulation (TENS)
- stimulation of Aβ fibres (gate control theory) - Acupuncture (possible modulate pain pathway)
