Pain Flashcards
3 classifications of pain
i) Nociceptive pain - adaptive
ii) Inflammatory pain - adaptive
iii) Pathological pain - maladaptive
Nociceptors
Specific peripheral primary sensory afferent neurones
Normally activated preferentially by intense stimuli (thermal, mechanical, chemical) that are noxious
Free nerve endings
FIRST ORDER NEURONES that relay information to second order neurones in the CNS
Nociceptive pain
> ADAPTIVE - serves as an early warning system to detect and minimise contact with damaging stimuli.
> HIGH THRESHOLD - provoked only by intense stimuli that activate nociceptors.
> OVERRIDES most other ongoing activities of the nervous system.
- withdrawal reflex
- extremely unpleasant
- engages adverse emotional componenets
> Serves to INSCRIBE MEMORIES that allow avoidance of harm in future
Inflammatory Pain
> ADAPTIVE & PROTECTIVE - caused by activation of the immune system in injury or infection.
> Causes pain hypersensitivity and allodynia (innocuous stimuli now illicit pain)
- LOW threshold pain
> Assists in healing of damaged body part
- discourages physical contact (wound)
- discourages movement (e.g. inflamed joint)
> Although adaptive, nonetheless requires reduction in ongoing inflammation (e.g. rheumatoid arthritis to alleviate suffering)
Allodynia
Innocuous stimuli now elicit pain.
Pathological Pain
> Maladaptive with no protective function - results from abnormal nervous system function
> May be neuropathic or dysfunctional
NEUROPATHIC
- neural lesion
peripheral nerve damage - positive and negative symptoms
–> spontaneous pain
pain hypersensitivity
DYSFUNCTIONAL
No neural lesion
No inflammation
Positive symptoms
ALL LEADING TO…
Maladaptive, LOW threshold pain
Disease state of nervous system
Fire alarm analogy
> Nociceptive pain – the system is working as intended and is only activated by intense heat
> Inflammatory pain – the system is activated by warm temperatures (lower threshold)
> Pathological pain – the system is malfunctioning and sounding false alarms
Congenital Insensitivity to Pain (CIP)
Vittangi, Sweden.
Results due to loss of function mutations (missense, in frame, deletions) in gene SC9A that encodes a particular voltage activated Na+ channel (nA 1.7)
Na 1.7 is highly expressed in nociceptive neurones
> Lip and tongue injury > Bruises and cuts > Multiple scars > Bone fractures > Joint deformity > Premature mortality due to multiple injuries/infections.
Subtypes of nociceptor
Aδ (alpha delta)
C fibres
Aδ (alpha delta) fibres
Mechanical/thermal nociceptors.
Thinly myelinated (FAST conduction) - 6-30 metres/sec
Respond to mechanical and thermal stimuli.
Mediate first (fast) pain.
Localised, stabbing pain
Types
Type I - activated by really extreme heat (53°C)
Type II - activated by a more modest heat threshold (43°C)
43°C at skin surface is precisely the temperature at which pleasant warmth becomes unpleasant and painful heat.
Termination
Terminate superficially in Laminae I, II & V of laminae of rexed.
C-fibres
UNmyelinated
SLOW conduction compared to Aδ fibres. (0.5 - 2 metres/sec)
Respond to ALL noxious stimuli - Polymodal
Mediate second (slow) pain.
Delay in registry of painful response - burning, throbbing, cramping, aching.
Terminate
C fibres terminate superficially in laminae I and II
Events leading to action potential to CNS
Noxious stimuli
–> Na+/Ca2+ influx
–> depolarised membrane (graded)
–> voltage gated Na+ channel activation
–> AP to CNS
Thermal stimuli receptor
Transient receptor potential family (TRP)
TRPV1 esp.
Activated by noxious heat
TRPV1 is greatly sensitised in inflammation to become active at body temperature
Chemical stimuli receptors
H+ activates acid sensing ion channels (ASICs) , ATP activates P2X and P2Y receptors
Bradykinin activates B2 receptors
Mechanical stimli receptors
Not fully understood
Piezo2- pressure/mechanosensitive ion channel.
How sensory neurones –> electrical activity
Sensory neurones terminals transduce a stimulus into electrical activity
Stimulus opens ion channels (cation selective) in nerve terminal to elicit a depolarising receptor (generator) potential
Amplitude of generator potential is graded and proportional to stimulus intensity.
Local current flow (Hermann currents) triggers “all or none” acton potentials at a frequency proportional to the amplitude of the receptor potential
i.e.
Intensity of stimulus is coded by the receptor potential, location potential and frequency of action potential discharge
Which horn of the spinal cord does pain travel to?
Dorsal horn.
Peptidergic Polymodal Nociceptors
Subset of C fibres.
Have afferent & efferent functions.
AFFERENT
- transmit nociceptive info to the CNS via release of glutamate and peptides (substance P, neurokinin A) within the dorsal horn.
EFFERENT
Release pro-inflammatory mediators from peripheral terminals - contributes to neurogenic inflammation (calcitonin gene related peptide CGRP, Substance P)
Noxious stimulation in the long term increases spinal excitability contributing to hyperalgesia and allodynia
Noxious stimulation in the long term does what>
Increases spinal excitability contributing to hyperalgesia and allodynia
Neurogenic inflammation
- Peptides (SP and CGRP) reeled from free nerve ending in peptidergic nociceptor
Due to tissue damage or inflammatory mediators,
- SP causes i) vasodilation and extravasation of plasma proteins
- promotes formation of bradykinin and prostaglandins
ii) Release of histamine from mast cells.
iii) sensitises surrounding nociceptors.
3. CGRP induces vasodilation
4. Primary and secondary hyperalgesia and allodynia ensue
Neurotransmission between the primary afferent and second order neurone in the dorsal horn
Presynaptic
AP –> Opening of voltage gated Ca2+ channels –> Ca2+ influx –> glutamate release
Postsynaptic
Activation of glutamate receptors –> Membrane depolarisation (epsp) –> opening of voltage gated Na+ channels –> AP
EPSP - excitatory post synaptic potential
Primary transmitter is glutamate producing a fast epsp and neuronal excitation by activating postsynaptic AMPA receptors with NMDA receptor participation
Peptides (Substance P and CGRP) also participate causing SLOW, PROLONGED e.p.s.p. that facilitates activation of NMDA receptors by relieving voltage dependent block by mg2+
When are NMDA receptors activated?
When there is intense afferent input.
Normally they do not conduct because they are blocked by extracellular Mg ions
Only in intense depolarisation does the Mg leave and allow NMDA receptors to respond.
Where are the primary afferent cell bodies located?
Dorsal root ganglia
Where does the primary afferent axon terminate?
Centrally in the dorsal horn of the spinal cord
In Laminae of Rexed
Laminae of Rexed
Where primary afferent axons terminate
Nociceptive specific cells
Synapse ONLY with C and Aδ fibres
WDR (Wide dynamic range) neurones
Receive input from ALL three types of fibre and this respond to a wide range of stimuli
Aδ, Aβ fibres DIRECTLY synapse at WDR
C fibres indirectly
(Aδ, Aβ and C fibres)
Aβ fibres
???
Second order neurones ascend the spinal cord in…
the anterolateral system comprising mainly:
- the spinothalamic tract (STT)
- the spinoreticular tract (SRT)
Spinothalamic Tract
> Projection neurones originating from lain I (fast fibre Aδ pain) terminate in posterior nucleus of the thalamus.
> Projection neurones originating from lamina V (WDR neurones) terminate in posterior and ventroposterior nucleus of the thalamus
> Pain perception (location, intensity) requires simultaneous firing in both pathways
Spinoreticular Tract (SRT)
> Largely transmits slow C-fibre pain
> Makes extensive connections with reticular nuclei in the brainstem [e.g. periaqueductal grey (PAG) and parabrachial nucleus (PBN)]
> Involved in autonomic responses to pain, arousal, emotional responses, fear of pain
