47. Pain Pathways Flashcards
Define pain
Pain is
‘an unpleasant sensory and
emotional experience associated
with actual or potential tissue damage’.
(IASP: International Association for the
Study of Pain)
Pain can be classified according to its chronicity:
> Acute
- Recent onset, limited duration
- Identifiable cause related to injury/disease
> Chronic
- Persists beyond time of healing or injury
- No clearly definable cause
It may also be classified according to its nature:
> Nociceptive:
noxious stimulation of nociceptors.
This may further be subdivided into:
• Superficial somatic pain (skin) –
well-localised, sharp pain
• Deep somatic pain
(ligaments, tendons, muscles) –
dull aching poorly localised pain
• Visceral pain (organs, viscera) –
cramping pain, varying localisation,
associated with referred pain and autonomic stimulation.
> Neuropathic: due to dysfunction of the nervous system.
Give a detailed description of the pain pathways that become activated if you prick your finger with a pin.
> Nociceptors respond to noxious stimuli, which may be thermal, mechanical or chemical.
> Tissue damage releases mediators,
which initiate and sensitise receptor stimulation.
> An action potential is generated
and propagated
along the primary afferent nerve fibres
(C & Aδ) to the dorsal horn of the spinal cord.
> Synaptic transmission with
secondary interneurones occurs
in Rexed’s laminae.
> Secondary interneurones decussate
and travel in the anterolateral
spinothalamic tracts through
the brainstem to the thalamus.
> From here,
tertiary afferents project
to the somatosensory cortex.
> Some spinal ascending fibres
transmit impulses to the reticular-activating
system, and to higher centres involved with affect, emotion and memory.
> Descending fibres from cortex,
thalamus and brainstem exert an
inhibitory influence on pain
transmission in the dorsal horn
> An immediate polysynaptic
withdrawal reflex occurs at the level of the
spinal cord as some inter neurones connect to motor neurones at many levels. This is a protective reflex.
Fig. 47.1 Schematic representation of pain pathways
Fig. 47.1 Schematic representation of pain pathways
What are nociceptors and how are they classified?
Pain receptors are unmyelinated
nerve endings that are
abundant in
skin and musculoskeletal tissue,
and that respond to thermal,
mechanical and
chemical stimuli.
They are classified according to their
sensitivity to the type of stimulus:
> Unimodal (thermo-mechanoreceptors)
respond to pinprick and sudden heat.
> Polymodal respond to pressure, heat, cold, chemicals and tissue damage.
How do noxious stimuli activate pain transmission?
> Chemical stimuli may be exogenous
(e.g. capsaicin) or endogenous.
> Tissue injury causes damage to cell membranes and release of endogenous chemicals, which stimulate nociceptors (bradykinin, histamine, serotonin, acetylcholine, H+ and K+ ions).
> Some chemical mediators
lower the threshold for receptor stimulation,
i.e. they sensitise nociceptors
(prostaglandins, leukotrienes, substance P,
neurokinin A and calcitonin gene-related peptide).
> Stimulation results in an influx of sodium and calcium ions, which causes depolarisation of the cell membrane and initiation of an action potential (AP).
> The AP is propagated along the nerve fibre
(via sodium and calcium channels)
to the dorsal root ganglion
and the dorsal horn.
The more heavily myelinated the
nerve fibre is,
the faster the impulse transmits.
> At the presynaptic terminal,
the influx of calcium causes release of
neurotransmitter into the synaptic cleft.
Which types of nerve fibres are involved?
> Three main types of fibres
relay sensory inputs from
the periphery
(Table 47.1).
> The cell bodies of all three
fibres lie in the dorsal root ganglia.
> The fibres terminate in the dorsal horn
of the spinal cord,
where they synapse with secondary
afferent neurones in Rexed’s laminae.
Table 47.1 Characteristics of different nerve fibres
Aβ Aδ C
Stimulus
Diameter (μm)
Myelin
Conduction
velocity (ms–1)
Type of pain
Dorsal horn
termination
(Rexed’s laminae)
What happens at the level of the dorsal horn?
> The dorsal horn is the area of synaptic transmission between primary and secondary afferent neurones in Rexed’s laminae.
> Laminae II and III are called
the substantia gelatinosa where extensive
modulation of pain occurs. It is the site of the ‘gate control’ theory of pain.
Describe the classes of second order neurones.
Table 47.2 Classes of second-order neurones
Class (NS) (WDR) Low-threshold
Location Superficial laminae Deeper laminae Laminae III and IV
Response to type of
stimulus
Specific noxious Non-specific Innocuous
Synapse with primary fibre
C & Aδ Aδ Some Aβ
Which neurotransmitters and receptors are involved?
> The main excitatory neurotransmitters
released by the primary afferent
terminals include
glutamate, aspartate and substance P
(‘glutamate and aspartate excitate!’).
These trigger various receptors on interneurones
and secondary afferent neurones, such as:
- N-Methyl-d-aspartate (NMDA)
- α-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)
- Neurokinin-1 (NK1)
- Adenosine (A1/A2)
> Inhibitory neurotransmitters released locally include:
- Enkephalins (MOP opioid receptors)
- Gamma-aminobutyric acid (GABA receptors).
Describe the path of the ascending
spinal tracts to higher centres.
There are multiple ascending tracts.
The most important ones are:
> Spinothalamic tracts (STT)
• Most secondary fibres decussate
and ascend as the anterolateral STT.
⚬ Anterior STT: light touch.
⚬ Lateral STT: pain and temperature.
• Fast (discriminatory)
and
slow (affective) fibres
travel together to the
brainstem where they separate
to end in different nuclei.
• Fast fibres pass through the brainstem
with no intermediary synapses
before terminating in the
ventral posterior nucleus of the thalamus.
From here, tertiary neurones
project to the somatosensory cortex
(parietal and frontal lobes).
They are responsible for conscious perception and memory of pain as well as its discrimination (location, intensity, quality).
• Slow (affective) fibres synapse in the brainstem’s reticular formation and in intralaminar nuclei of the thalamus before projecting to the hypothalamus, limbic system and autonomic centres.
• Tertiary fibres project to the cingulate gyrus in the cortex.
They are associated with the affective-arousal component of pain.
> Spinoreticular tracts
> Spinoreticular tracts
• Slow fibres may also ascend in the
spinoreticular tract, terminating in
the reticular formation and thalamus.
> Spinomesencephalic tracts
> Spinomesencephalic tracts
• These terminate in the
midbrain and periaqueductal grey (PAG).
> Dorsal columns
• Pressure, vibration and proprioception
carried by Aβ fibres from the
periphery ascend in the
dorsal columns ipsilaterally.
• They do not transmit pain sensation to higher centres.
Describe the descending
inhibitory pathways.
> Periaqueductal grey (PAG) in the midbrain.
> Periaqueductal grey (PAG) in the midbrain.
• This is the main descending pathway.
• It receives projections from the thalamus, hypothalamus, amygdala and cortex, and delivers projections to the nucleus raphe magnus (NRM) in the medulla, whose fibres synapse in the substantia gelatinosa of the dorsal horn.
• Its transmitters include
endorphins and enkephalins
(MOP opioid receptors)
and serotonin (5HT1 and 5HT3 receptors).
Describe the descending
inhibitory pathways.
Locus caeruleus (LC).
Locus caeruleus (LC). • An important brainstem nucleus projecting descending inhibitory pathways to the dorsal horn via noradrenaline (α-adrenergic receptors).
What do you understand by the
‘gate control’ theory of pain
modulation?
(Melzack and Wall 1965)
> This is one aspect of pain modulation,
reducing the response to nociceptive stimuli.
> It postulates that pain transmission
from primary to secondary afferents
is ‘gated’ by interneurones in the
substantia gelatinosa.
> Inhibition can be presynaptic on
primary afferents or postsynaptic on
secondary afferent neurones.
• Opening: The ‘gate’ is opened
presynaptically by C fibres via
substance P
(‘pushes’ the gate open)
and
post-synaptically by Aδ fibres,
which inhibit the action of
enkephalinergic interneurones
(which are inhibitory)
at the level of the substantia gelatinosa, thus allowing
transmission of pain signals.
• Closure: It is closed by descending inhibitory fibres,
peripheral Aβ fibres and indirectly
by the action of Aδ fibres on descending
pathways,
which result in reduced transmission of pain signals.
> Aβ fibres inhibit C fibre
input presynaptically via stimulation
of GABA receptors (which are inhibitory).
Aβ fibres are stimulated by touch/
pressure and explain how
‘rubbing it better’ and how high-frequency,
low-amplitude TENS may attenuate pain.
> Descending serotonergic
(PAG, NRM) and noradrenergic (LC) fibres
activate enkephalin-secreting interneurones,
which inhibit postsynaptic transmission.
This explains how antidepressants
(which block the
reuptake of serotonin and noradrenaline)
and opioids exert their effect.
> Aδ fibres ascend and stimulate the
PAG to exert its inhibitory action as
above.
This explains how acupuncture and
how low-frequency TENS
may attenuate pain.
Fig. 47.3 Sites of action of analgesics
Site of action Receptor Neurotransmitter
Fig. 47.3 Sites of action of analgesics
Site of action Receptor Neurotransmitter
Paracetamol
Site of action Receptor Neurotransmitter
Central
Peripheral
+ 5HT3
+ Cannabinoid
– COX
+ Serotonin
+ Endogenous cannabinoids
– Prostaglandins
NSAID
Nociceptor – COX – Prostaglandins
Opiate
DH (presynaptic afferents) Descending pathways: PAG (postsynaptic secondary afferents)
+ MOP opioid
– GABA
receptor
Reduced glutamate release from Aδ & C fibres (reduced nociceptive transmission) – GABA (increased anti-nociceptive transmission, i.e. GABAergic inhibition activates serotonergic and noradrenergic descending pathways
Tramadol/ Pethidine Tramadol/ Pethidine Tramadol
DH Descending pathways Descending pathways \+ MOP opioid \+ 5HT1 & 5HT3 \+ α-Adrenergic \+ 5HT1 & 5HT3 Reduced glutamate release from Aδ & C fibres Inhibition of reuptake of serotonin and noradrenaline \+ Presynaptic serotonin release
