PAIN I Flashcards
Nociception
The neural encoding of a noxious stimulus
What is meant when we say that nociception is neurophysiological
The stronger the stimulus the higher the frequency of action potentials
Pain
An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage
the 2 Properties of pain
Salience and valence; applied to nociceptive signal to give us pain
Salience
Level of importance or ability to be noticed, ability to interrupt ongoing activity and behaviour
Valence
How pleasant or unpleasant it is perceived to be
Acute (first) pain is ___ (good or bad)
`Good pain’ serves biological purpose (protection from tissue injury)–to notice and remove yourself from painful stimuli
Bad pain
If Injury leads to inflammation causes chronic pain, carried by C-fibers (second pain)
Acute pain is carried by
A-delta fibers to the CNS (‘first’ pain)
First pain is ___ to stimulus
proportional
Acute pain
Nociceptive stimulus, e.g. stepping on a nail, causes acute pain via activation of nociceptive pathways
Chronic Pain Timeline
No set time for chronic pain–could be 1 month or a year
Is any stimulus-independent pain
Chronic pain is better described as
Stimulus independent pain
Subtypes of Chronic pain
- Mild, musculoskeletal pain
- Deep pain
- Neuropathic Pain
Mild, musculoskeletal pain –cause
Ongoing pain caused by release of bradykinin, histamine, acid metabolites and prostaglandins
Mild, musculoskeletal pain is ____ to stimulus intensity
not proportional
Is Mild, musculoskeletal pain protective?
Yes, allow healing
Mild, musculoskeletal pain–treatments
Treated with NSAIDs (non-steroidal anti-inflammatory drugs)
ex. aspirin (acetylsalicylic acid) or ibuprofen
Deep Pain–treatments
Treated with major analgesics (opioids) such as morphine
Deep pain–localization and def
Deep aching pain, deep to body surface, poorly localized
Deep Pain causes
Pain associated with major trauma, traffic accident, childbirth, some forms of post operative pain or disease such as heart attack or cancer
Is deep pain beneficial
Yes, still ‘good pain’ as it is protective. Allows healing process to progress
Neuropathic Pain-definition
pain induced by injury to or disease of the somatosensory system
Neuropathic pain results froom
injury to the nervous system
Examples of neuropathic pain
Herpes Zoster –> postherpetic neuralgia (shingles)
Phantom limb pain, trigeminal neuralgia, postherpetic, diabetic and HIV-related neuropathies, post-stroke pain, fibromyalgia
Timeline of neuropathic pain
Outlasts initial injury, slow onset (develops long after initial acute pain)
Is neuropathic pain beneficial
NO, has no obvious protective role
It is “bad pain”
Neuropathic pain is characterized by
Spontaneous shooting pain
Causalgia
Hyperalgesia
Allodynia
Hyperalgesia–definition
heightened pain sensitivity, same stimulus mode
increased sensitivity to painful stimuli
Allodynia–definition
painful response to innocuous stimulus, different stimulus mode, can be touch, cold or warmth
(pain to innocuous stimuli)
Pain perception has 2 components
Somatosensory component and Affective component
Somatosensory Component of pain
Specific pain pathways allow the localization, intensity and quality of pain–how pain is felt (how strong, where, what)
Affective component of pain
- Production of negative emotion
- Arousal
- Initiation of stress responses
- Interruption of ongoing procedures (i.e. waking due to pain)
- Learning (associating stimuli to pain)
- Stress, anxiety, anticipation make pain worse
Free nerve endings–what are they
primarily afferent nociceptors;
cutaneous nociceptors
Free nerve endings–role
Transduce mechanical, thermal, chemical or tissue damaging stimuli into trains of a.p.’s
Free nerve endings stronger stimulus…
stronger stimulus more a.p’s
Where are the cell bodies of free nerve endings
Cell bodies in DRG
Pathway of free nerve endings
receptors in the skin , cell bodies in DRG –> project to substantia gelatinosa, marginal zone and wide dynamic range neurons in dorsal horn of SC –> brainstem –> thalamus –> somatosensory cortex
Primary Afferent fibres
A-alpha and A-beta fibres
A-delta fibres
C-fibres
Properties of A-alpha and A-beta fibres
fast conducting (40-50 m/s)
thickly myelinated fibers
proprioception
touch sensors
A-delta fibers
myelinated slower conducting (~ 20m/s) high threshold mechanoreceptors--need strong stim (ex. pain stim) for stimulation
C-fibres
unmyelinated slow conducting (< 2m/s)
2 subtypes of C-fibres
Polymodal nociceptors (peptidergic) and non-peptidergic
Polymodal nociceptors
contain neuropeptides (SP and CGRP) and express TRPV1 channels
Non-peptidergic
“itch” fibres
bind isolectin B4 (IB4)
Damaged tissue or inflammation releases:
• NGF (nerve growth factor) • bradykinin (painful when applied) • ATP (leaked from damaged cells) • histamine (inflammatory) • Prostaglandin (from cell memb breakdown) • H+,K+ • 5-HT • Cytokines (IL-6 and IL-1b, TNF-alpha) CAUSES activation of C-fibres
TRPV1 Receptors
aka Vanilloid receptors
Ligand gated ion channels activated by: warmth etc.
TRPV1 Receptors activated by
- Capsaicin (why u sweat when u eat spicy food)
- Resiniferatoxin
- Moderate thermal stimuli (43 degrees C)
- H+
TRPA1 Receptor activated by
Noxious heat (> 52 degrees C) on A-delta cells
TRPM-8 receptor activated by
Noxious cold (8-28 degrees C) Menthol and icilin
Number of TRP channels
> 30
Are hot and cold channels on the same cells
sometimes!
different channels but can be expressed on same cells
Ionotropic Receptors
- 5HT3 Receptors
- P2X3
- ASIC
P2X3 receptors
iontropic receptor that is ATP-sensitive and found on sensory neurons
ASIC receptor
iontropic receptor that is acid sensitive
activated by H+
Metabotropic Receptors
- B2 bradykinin
- Eicosanoid (activated by prostaglandins)
- Histamine (mainly Hist 1)
- 5HT1 and 5HT2
- NK1 (atcivated by substance P)
Tyrosine kinase receptors
TrkA, TrkB, cytokine
Sensitization
Release of prostaglandins, interleukins, bradykinin, acid metabolites, nerve growth factor sensitize nociceptors beyond site of injury
Hyperalgesia is due to _____
sensitization; enhanced response to pain
Neurogenic inflammation cause
Axon reflex
C-fibre excitation causes release of substance P and calcitonin gene related peptide (CGRP) –> excite other C-fibres
Axon reflex
When C-fibres are activated –> CGRP release –> excites other C-fibres
Axon reflex b/c don’t need to be connected (use chemical messager–CGRP, substance P)
Signs of inflammation
Redness (rubor), swelling (tumor), heat (Calor), pain (dolor)
Neurogenic inflammation causes
Vasodilation –> rednesss
Extravasation of plasma proteins
Edema (as fluid follows proteins)–> swelling
In dorsal horn, pain fibers project to
Lamina II (substantia gelatinosa) Lamina I (marginal zone) Lamina IV
Lamina I projection neurons project to
brainstem, parabrachial nucleus (in hypothalamus), hypothalamus and thalamus
Local circuit interneurons allow
local withdrawal and autonomic reflexes
Pain fibres contact to ___ neurons in the lamina __ and __
The dendrites of Wide dynamic range neurons (WDR); lamina IV and V
WDR deferential firing to diff fibres
fire slowly with Ab fibre input (tactile stim= weak)
strongly with Ad fibre input (pain stim = strong)
Descending inputs
NA/5HT from rostroventral medulla, LC and raphe nucleus
Modulatory–how mood, etc. can alter pain
Primary afferent fibers release
Glutamate;
glut –> acts on NMDAR/AMPAR –> EPSCs
Release of P, CGRP and Neurokinin A
Generates slow EPSPs in dorsal horn cells
5HT release in dorsal horn
predominantly excitatory
NA release in dorsal horn
predominantly inhibitory
Transmission in the dorsal horn is modulated
GABA / glycine inhibitory interneurons
Sensitization of cutaneous nociceptors and repetitive discharge leads to
sensitization of dorsal horn neurons
Sensitization of dorsal horn neurons and plasticity has led to
the pre- emptive use of local anaesthetics (in addition to general anaesthetics) in surgery–to keep sensory nerves quiet to they don’t become sensitized and cause pain after surgery
Types of Pain
Acute (first) and chronic (second) pain
2nd pain types: Musculoskeletal, Deep pain, Neuropathic Pain
Peripheral Mechanisms
Vanilloid and other receptors role of inflammatory mediators in generating pain
Neurogenic inflammation/axon reflex
Dorsal Horn in pain
- Integration in substantia gelatinosa
- Inputs to laminae I, IV and V
- Descending modulation via 5-HT and NA pathways
