Somatic Sensation and Pain Flashcards
Define asterognosia
Inability to identify objects by touch
What are the 4 types of cutaneous mechanoreceptor in glabrous skin?
Slowly adapting type 1 (SA1) afferents that end in Merkel cells
Rapidly adapting RAI afferents that end in Meissner’s corpuscles
Rapidly adapting RAII Pascinian corpuscles
Slowly adapting type 2 SAII afferents that end in Ruffini endings
Discuss pascinian corpuscles
Stim type they respond to
Depth in the skin
Sensitivity
Receptive field
Afferent
DensityRespond to object held in the hand, good at detecting successive quick events, not to detect ongoing stimulation (but does detect high freq stim)
Deepest
Very, respond to 10nm motion at 200Hz
Large, central zone of maximum sensitivity
RAII 1:1
350 in finger, 800 in palm
Discuss Meissner's corpuscles
Stim type they respond to
Depth in the skin
Sensitivity
Receptive field
Afferent
DensityLow frequency vibration, I.e. perception of slip used for feedback for grip
x
High: enhanced sensitivity, poor spatial resolution
Small 3-5mm
RAI
High, 150/cm2
Discuss Merkel cells
Stim type they respond to
Depth in the skin
Sensitivity
Receptive field
Afferent
Density
SizeIndentation: points/edges/curvature
x
Lower - higher spatial resolution. 10x more sensitive to dynamic stimuli.
Small, highly localised RF (0.5mm resolution)
SAI 20:1
Densely innervate skin
10s of micrometers
Discuss Ruffini endings
Stim type they respond to
Depth in the skin
Sensitivity
Receptive field
Afferent
Density
SizeHand shape and finger position, respond to stretching skin in a certain direction Deep x x SAII 1:1 x Few 100 micrometers
What does the lamellae of the pascinian corpuscle contribute and how do we know?
Know: peel then away
Find: when removed, they act like slowly adapting fibres. With lamella, in response to a stimulus onset or offset, the RP rises then decays quickly. Direct from the nerve ending, the stimulus triggers RP rising and then decaying slowly.
Define accessory structures
Structural components of sense organs which may play an important role in protection, conduction, concentration, analysis, sensitisation or inhibition, but that are not directly involved in the transduction process.
Name an accessory structure in somatosensation, proprioception, vision, auditory
Lamellae in PCs
Intrafusal muscle fibres
Eye structures
Basilar membrane
How can you detect vibration?
RA afferents
What is the evidence for the existence of 2 RA channels?
Altering the sensitivity of detection of vibration
Normally peak sensitivity Meissner’s 30Hz ish, Pascinian 300Hz (i.e. area at lowest threshold for dep)
Add local anaesthetic, increases threshold for Meissner’s as less deep in the skin
Stim for a while at high freq (for PC) or low freq (Meissner’s) –> adaptation of the relative frequency,
Which afferent is best at reading Braille? How do we know?
Merkel
Show on spatial event plots: AP evoked by Braille
What is the test of tactile acuity? What sets tactile acuity?
Two point limen
Receptive field size - if two points contacting the skin both stim the same receptive field, we have no information that two points on the skin were stimulated
Are there more warm or cold spots?
Cold, but different body areas have different proportions of cold and warm spots
What is the structure of thermoreceptors?
Unencapsulated nerve endings
What is spatial summation?
Many more receptors exist than there are responses, and it normally requires the simultaneous activation of many receptors to get the response
What are the different thermoreceptor channels? What are their afferents?
Hot = capsaicin/above 43 degrees channel Trpv1. Sub population of C fibres
Cold = menthol/below 25 degrees = Trpm8. Adelta and C fibres
There are more, overlapping to create a range
Explain paradoxical cold spots. What does this tell us?
When a heat stim of >45 degrees is applied to a single cold spot, feels cold.
Cold receptor has a parabola shaped sensitivity curve
Tells us that activity in the cold fibre is labelled line
Define labelled line
Activity in a fibre is experienced in the same way, irrespective of the physical nature of the stimulus
Our sensory experience is determined by the central connections of the neuron, not the stimulus that evoked the AP
What are nociceptors?
Pain fibres
Free nerve endings
How do you separate the different aspects of pain? Which fibres mediate each aspect?
- Early first pain - sharp. Adelta
2. Second dull pain - burning. C fibres
What do Adelta fibres mediate in sensation?
Cold, first component of pain
What do C fibres mediate in sensation?
Warm, cold, second component of pain
Most C fibres are polymodal and respond to thermal, strong mechanical and chemical stimuli (chilli peppers, acid)
Describe the different types of peripheral nerve
AalphaAbeta: 40-80m/s, myelinated large. Touch, proprioception
Adelta: 5-30m/s, thinly myelinated. Cold, stabbing pain
C: 0.5-2m/s unmyelinated. Warmth, itch, burning pain
What is a compound action potential?
A sum of all fo the action potentials in a nerve
Which kinds of nerve fibres do anoxia and local anaesthetic affect?
Anoxia = large
Local anaesthesia = small unmyelinated shallow
Where are the spinal cord enlargements and what causes them?
Cervical and lumbar
Where the limbs join
Define dermatome
Area of skin innervated by a single dorsal root. They overlap as several roots can innervate a peripheral nerve.
What splits the spinal cord in half?
Dorsal median sulcus and ventral median fissure
What is the grey matter divided into?
Rexed's laminae I- VI dorsal horn VII intermediate zone VIII IX ventral horn X ventral commissure
What is the main ascending pathway for touch and proprioception?
DC-ML dorsal column medial lemniscal
Describe the DC-ML pathway
- Primary sensory axons enter spinal cord
- Primary afferent bifurcates
- Small branch enters dorsal horn, large branch enters dorsal columns
- Large branch below mid-thoracic = ascend in fasciculus gracilis gracile nucleus
- Large branch above mid-thoracic = ascend in fasciculus cuneatus cuneate nucleus
- Leave dorsal column nuclei (these in lower medulla) as second order neurons
- Sensory decussation: cross brainstem
- Ascend in fast-conducting medial lemniscus to thalamus
- In ventral posterior nucleus of the thalamus, synapse on third order neurons
- Internal capsule
- Primary somatosensory cortex in postcentral gyrus of the parietal lobe
How are the dorsal column nuclei organised
Dorsal column nuclei somatotopically organised with leg medially and arm laterally
What does the DCML carry?
Tactile, vibratory, proprioceptive
What are the major ascending nociceptive pathways?
Spinothalamic tract/Anterolateral system
Spinoreticular
Spinomesencephalic
Describe the spinothalamic pathway
- Primary sensory axons enter spinal cord
- Bifurcate into short ascending and descending branches that run for about a spinal segment in Lissauer’s tract
- Branches terminate in the superficial part of the spinal cord dorsal horn: substantia gelatinosa
- One local synaptic relay in superficial dorsal horn
- Second order neurons arise on IPSILATERAL SIDE
- Neurons in layers I and V-VII of dorsal horn
i. V = tactile system via wide dynamic range neurons too
ii. I = nociception specific - These second order neurons cross ventral commissure to contralateral anterolateral white matter
- Ascend in this lateral column
- Synapse in thalamus. VMPO post part ventromedial nucleus
- Third order neurons ascend via internal capsule
- Project to SI, also anterior cingulate cortex and insula
Where is the spinoreticular tract to and from?
From laminae VII and VIII
Terminates in reticular formation and thalamus
Some ipsilateral
Influences level of arousal through actions on sympathetic system and other ascending systems.
Where is the spinomesencephalic tract to and from?
Laminae I and V
Anterolateral quadrant of spinal cord
Mesencephalic reticular formation and periaqueductal gray
Periaqueductal gray modulates anterolateral ascending system (a descending pathway)
What are the two extra cell groups found in the thoracic cord?
Intermediolateral nucleus: sympathetic pre ganglionic neurons, with axons that run in the sympathetic chain
Clarke’s nucleus: relay cells for proprioception of the lower limbs
Describe the shape of the spinal cord at each level?
Cervical: oval, large, thick white matter
Thoracic and upper lumbar: circular, thin H profile of grey matter
Lumbosacral: Circular, expanded grey matter, white matter thinning out
Lower sacral: circular, little white matter
What is the substantia gelatinosa?
Rexed’s lamina: Layer II
Processing of noxious information - allows modulation and gating of pain processing e.g. through actions of endogenous opioid peptides.
Consists of unmyelinated fibres, fine cell processes, very small cell bodies
Pale, jelly-like appearance
What is Lissauer’s tract?
Contains incoming axons carrying pain or temperature information
Axons travel up or down the cord to an adjacent segment before entering the dorsal horn
What do layers IV and V do?
Contain relay neurons with many axons that cross the midline in the ventral commissure to ascend in the anterolateral column
What does lamina VII do?
Centre of spinal cord
Spinal interneurons concerned with local processing e.g. reflexes
How many neurons are involved in the dorsal column pathway?
3
Explain referred pain
Pain from internal organs being felt in a more superficial region
Signals from an inflamed visceral organ converge on projection neurons at the dorsal horn of the spinal cord.
Sensory input from a distant somatic structure converges on the same neurons
CNS cannot distinguish between superficial and deep pain, and failure results in incorrect assignment of pain to the healthy somatic area
Where is angina pectoris pain referred to?
Chest and left arm
Describe Brown-Sequard syndrome
Consequence of a spinal hemi-section
Affects both spinothalamic and DC-ML
As DC-ML ascends on ipsilateral, affects ipsilateral touch/proprioception
Spinothalamic ascends contralateral, so affects contralateral pain/temperature sensation
both BELOW the lesion
Describe infarction of the inferior cerebellar arteries
DCML and anterolateral system still separate through medulla, so a similar separation of tactile and nocicipetive sensation can follow damage here
Infarction ICA can damage laterally located anterolateral system: tactile system intact. Could sense contralateral pin prick as a gentle touch
Describe syringomelia
Central canal expands
Damages crossing anterolateral axons (pain and temp) crossing ventral commissure
Cape like distribution of loss of pain and temperature sensation in upper limbs and trunk but preservation of touch and pressure sensation
Describe tabes dorsalis
Posterior column syndrome
In late stages of syphilis
Causes a degeneration of central projections from the dorsal root ganglia esp in fasciculus gracilis and cuneatus.
Bilateral loss of touch below level of lesion, and also loss of proprioceptive feedback leading to a characteristic stamping gait.
What are spinal dural arteriovenous fistulae?
Relatively rare vascular malformations due to an abnormal connection between a meningeal branch of a segmental artery that normally supplies the dura, and the intradural radicomedullary vein that normally drains the spine. Lesion –> high pressure blood flows retrograde into the coronal venous plexus of the spinal cord, leading to venous congestion, oedema, and spinal cord injury.
Present with sensory disturbances due to dorsal location, but if left untreated, progress to cause motor weakness.
Treat by dividing abnormal connection.
What can vitamin B12 deficiency lead to?
Anaemia
Dorsal column demyelination
What is trigeminal neuralgia?
Neural condition where gentle stroking of the face or mouth provokes massive stabbing pain
What is allodynia?
Central pain sensitisation following painful, often repeated stimulation e.g. trigeminal neuralgia
What are the nuclei for trigeminal sensation?
Principal sensory nucleus = tactile
Spinal trigeminal nucleus = nociception and thermoception
What is lateral inhibition?
When stimulating two adjacent points of skin, lateral inhibition suppresses excitation of the neurons between the two points, sharpening the focus of the two points
Which thalamic nucleus do DCML neurons terminate in?
Ventral posterior nucleus
Where in the thalamus do anterolateral neurons terminate?
VMPO ventral medial nucleus posterior part
What can be found in the VMPO?
Temperature specific neurons either inhibited or excited by heat/cold
Explain gate-control
Failure of one input unmasks the presence of inputs ordinarily suppressed by inhibitory mechanisms. Shows sensory systems aren’t 1:1
Where is S1?
Immediately posterior to the central sulcus in the post-central gyrus
How is S1 organised?
Columns 300-600micrometers, all same modality and from same location
Which layer of S1 do thalamic afferents terminate in?
Layer IV
Which layer of S1 do thalamic efferents begin in?
Layer VI
In which layer of S1 do subcortical efferents begin?
V
To basal ganglia, brain stem, spinal cord
Which layer of S1 do cortical efferents begin?
II, III
To ipsilateral SII, contralateral SI, posterior parietal cortex and motor cortex
What is the map of somatosensory inputs to the cortex called?
Homunculus
What is the most common artery to be affected in stroke?
MCA so stroke mostly affects upper limb and head
Where is the insula? What does it do?
Buried cortex deep to lateral fissure - relay for processing noxious stimuli
Function of insula is to process information on the internal state of the body, so contributes to the autonomic component of the overall pain response
Where is the anterior part of the cingulate gyrus? What does it do?
Medial part of frontal lobe inside the longitudinal fissure - important for affective aspects of pain sensation
What are the bumps on the dorsal and ventral surface of the brainstem?
Dorsal = colliculi Ventral = mammillary bodies
What is the evidence that attention can alter the responses of cortical neurons in SII?
Responses of a single neuron in SII to a tactile stimulus when performing a tactile task or a visual task. Response is greatly diminished when performing the visual task (in this case the detection of a dimming light). The tactile task was to indicate whether the orientation of the bars were the same or different.
Give some experiments showing cortical plasticity
EXPERIMENT 2: Monkey trained to maintain contact with a rotating disk in order to get a reward. Cortical hand representation of the monkey, following 20 weeks of daily training, showed a marked expansion of the representations of the distal aspects of digits 2 and 3
Also musicians who play stringed instruments have a greater than normal cortical representation for the highly stimulated fingers on their left hand
Phantom limb
Describe the function of the thalamus
Relay from sensory systems (except olfactory) to the cortex
Part of motor system: modulating connections from cerebellum and basal ganglia internal globus pallidus to the motor cortex
Not just a relay: involved in processing of noxious and thermal stimuli (VMPO)
Describe phantom limb
Phantom limb: Many amputees have a sense of their missing limb – the representation of the body’s surface is altered in cases of amputation, I.e. map the missing hand onto the face and upper arm (sensory input from these areas is now innervating the hand area of the somatosensory thalamus or cortex).
Which parts of the cortex respond to pain?
- SI
- Anterior cingulate cortex
- Insula
What is the evidence for cingulate involvement in pain?
Single neuron recordings in ACC of human patients undergoing cingulotomy
Responded to heat stimuli in the noxious range
Identified 44 and 46 degrees as warm, then 48 as painful. The 46< failed to activate the unit.
Responded more vigorously to receiving pain than watching it.
Define pain
The unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage
What does layer V of the dorsal horn respond to?
Innocuous stimuli at low intensity, and noxious stimuli at high intensities, so known as wide dynamic range neurons
What is the TENS machine?
Transcutaneous electrical nerve stimulation
Based on gate-control hypothesis
Theory that different sensory afferents are ‘competing’ to go up the spinal cord, so less pain will ascend if more tactile information is
Draw the gate-control diagram
Small diameter nerve fibres stimulated by injury
O second excitatory input
Low-threshold myelinated afferents Abeta fibres
Inhibitory interneuron
Descending systems of pain modification
Wide dynamic range transmission neuron
Can’t find this anatomically
Explain what is meant by the intensity theory and the specificity theory of pain
Intensity: wide dynamic range nuclei can signal changes in stimulus intensity by increases in spike discharge rate over a wide range of intensities
Specificity theory: different neurons needed to signal changes in stimulus intensities over a limited range of amplitudes
Both types observed: specific lamina I, WDR lamina V
What are the descending pain modulation systems?
Periaqueductal gray of midbrain
Raphe nuclei (serotonergic)
Other nuclei rostral medulla
Descend through dorsolateral funiculus/Lissauer’s tract
What is the evidence for descending pain modulation systems existing in the PAG?
Electrical stim of PAG produces sufficient analgaesia to perform abdominal surgery
Morphine induced analgaesia blocked by injection of naloxone (opiate antagonist) into PAG
Somatotopic organisation of PAG found as stimulation of different areas produced analgesia in different cutaneous regions.
Define placebo effect
Administration of a non-analgaesic produces an analgaesic effect when the subject is told it is a pain killer
What is the evidence for the placebo effect?
Volunteers had capsaicin applied to the distal region of all four limbs, asked to report the magnitude of pain felt at each site.
Topical application of placebo cream, told it was a powerful local anaesthetic. Placebo analgesia only occurred on the treated part. Spatially specific placebo response abolished with naloxone, suggesting it was mediated by an endogenous opioid system.
Think endogenous opioids distributed specifically by attentional mechanisms.
What does Lissauer’s tract look like relative to the rest of the white matter?
Paler
What are the inputs to the PAG?
Ascending anterolateral pathway
Hypothalamus (potentially stress induced analgesia, or analgesia during motivated actions)
Where do PAG fibres terminate?
Raphe nuclei in medulla
What do the raphe nuclei do?
Source of serotonin
Project to spinal dorsal horn
Raphe magnus is major raphe nucleus
Small so unlikely to see them in brain sections
Midline
Activate opioid containing interneurons in substantia gelatinosa
Release of opioids depresses transmission from nociceptors, at least some of which is via presynaptic inhibition
Could also involve tactile Abeta fibres, via gate control
What are the branches of the anterolateral system and what is their aim?
Branch to medulla: reticular formation, activation of sympathetic reflexes
Branch to midbrain: reticular formation concerned with arousal and descending analgaesia via periaqueductal gray
What level is the sensory decussation?
Medulla
Above the motor decussation
What is the ventral groove on the pons?
Groove for the basilar artery
Where are the medial lemnisci in the brainstem?
Sensory decussation medulla midline
Upper pons more lateral
Lower midbrain even more lateral
What would the effect of a unilateral medial leminscal loss? What could cause this?
E.g. pontine artery infarction
Contralateral loss of touch, proprioception
What are the 3 parts of the CN V nucleus?
- Mesencephalic = proprioception. Small midbrain nucleus
- Pontine/chief = discriminative sensation and light touch
- Spinal trigeminal nucleus = deep touch, pain, temperature
How do proprioceptors get to the cerebellum?
Lower limb via Clarke’s column
Upper limb via cuneate nucleus unconsciously and via thalamus and cortex consciously
Define nociception
The neural process of encoding noxious stimuli
What is the effect of anaesthesia on nociception?
Local anaesthetics stop local nociception
General anaesthetics don’t affect nociception, just pain
Define nociceptor
A high-threshold sensory receptor, capable of transducing and encoding noxious stimuli
Where are the cell bodies of nociceptors?
DRGanglia and trigeminal ganglia
What are the steps of nociceptor activation?
- Ion channels activated by distinct stimuli at the peripheral terminals
- Receptor potential
- If RP great enough, VGSC opens
- AP propagates along axon to presynaptic terminals in the spinal cord
- Open VGCC
- Ca2+ influx release NT onto postsynaptic terminals in spinal cord
How do you measure nociceptor activation?
Isolate nociceptor cell bodies from DRG/TG, culture, patch-clamp, measure current
Use cell body as a model of the neuron
Define sensitisation
When a stimulus is great enough to cause tissue damage, the response to subsequent stimuli increases - stimuli that usually cause pain now cause more pain (hyperalesia) and stimuli that didn’t cause pain now do (allodynia)
Give examples of internal factors that are potent excitatory agents to nociceptors
ATP
Bradykinin
Acid
Give examples of sensitising agents
Enhance responses to excitatory agents
Prostaglandins
Nerve growth factor
Give examples of agents that are both excitatory and sensitising agents
Bradykinin
ATP
H+
What is the effect of PGE2?
EP4 Gs Acts on nociceptors to cause excitatory stimuli to have a greater effect
Also
Bronchial/smooth muscle contraction EP1 Gq
Vasodil/bronchodil EP2 Gs
Write out the EP4 signalling cascade that results in sensitisation
EP4 Gs AC cAMP PKA phos NaV1.8 reduces its activation threshold, smaller dep is able to evoke AP firing
What is neuropathic pain?
Pain resulting from peripheral nerve damage that often outlasts the initial injury E.g. Phantom limb Infectious diseases Diabetic neuropathy Trigeminal neuralgia Postherpetic neuralgia
Which prostaglandins are powerful vasodilators?
PGE2 PGI2
How do NSAIDs work?
Block PGE2 synthesis so reduced nociceptor sensitisation
Maybe act centrally where PGs are thought to facilitate nociceptor neurotransmission
Etoricoxib
COX2 selective NSAID
Treat osteoarthritis and RA
Only advised in patients where conventional NSAIDs pose a significant GI risk and after assessment of cardiovascular risk
Define opioid
Substance producing morphine-like effects reversed by antagonists like naloxone
Define opiate
Substance found in opium poppy
What are the 4 opioid receptors? What is their coupling?
mu
kappa
delta
ORL1
Effects largely mu mediated
All Gi/Go
Beta gamma subunit opens – GIRKS (inwardly rectifying potassium channels)
Hyperpolarisation
Neuronal firing less likely
- Also inhibit CaV N-type
Decreased Ca entry, decreased NT release
- Also decrease AC which counteracts the sensitising effects of PGs
What chemically makes the opioids agonists or antagonists?
Agonists: hydroxyl on benzene ring and N linked by 2C to the benzene ring
Antagonist: bulky substitution of N
How do opioids act normally?
Act presynapticlaly on nociceptors to decrease NT release, and postsynaptically to reduce dorsal horn neuronal excitability
How do opioids work supraspinally?
PAG: evokes activation of endogenous inhibitory systems
Affective: ability to evoke euphoria
both mu mediated
Give examples of opioids
Morphine
Diamorphine (heroin) - prodrug for morphine, higher lipid solublity, so higher BBB permeability so faster acting than morphine
Codeine - more reliably absorbed orally but less analgesic. Prodrug
Buprenoprhine - partial agonist that dissociates slowly. So can antagonise other opioids. Moderate analgaesia and less respiratory depression
Etorphine - 1000x more potent than morphine
Give an example of an opioid antagonist
Naloxone
Used to reverse opioid-induced respiratory depression after overdose and in newborn baby after use of opioid analgesia during labour
What are the side effects of opioids?
Respiratory depression (mu) Nausea/vomiting (delta/mu) Constipation (mu, kappa, delta)
List classes of analgesic
- NSAID: ibuprofen, aspirin
- Opioid: morphine, heroin, codeine, buprenorphine, etorphine
- Antidepressant: amitriptyline, duloxetine SNRI
- Gabapentin
- NaV inhibitor Lidocaine, lamotrigine, carbamazepine
- Ziconotide
Duloxetine
SNRI serotonin-noradrenaline reuptake inhibitors (SSRI like fluoxetine not efficacious)
Relief in neuropathic pain, probably due to descending inhibitory modulation of pain system from locus coeruleus involving NA
Amitriptyline
Tricyclic antidepressant also blocks serotonin and noradrenaline reuptake
Relief in neuropathic pain, probably due to descending inhibitory modulation of pain system from locus coeruleus involving NA
Gabapentin/pregabalin
GABA analogue with no activity at GABA receptors
Some patients works against neuropathic pain, no effect on acute pain
Decreases cell surface localisation of CaV alpha2delta1 subunit, which usually causes an increase in CaV current density (and so increased spinal cord NT release) and is upregulated in some forms of neuropathic pain.
Lidocaine
Local anaesthetic, blocks NaV so provides analgesia when applied topically
Carbamazepine
NaV blocker
anti epileptic
treat neuropathic pain
Lamotrigine
Blcok NaV
Anti epileptic
treat neuropathic pain
Ziconotide
Synthetic analogue of N-type CaV blocker w-conotoxin MVIIA. must administer intrathecally (into spinal cord)
What are the steps of the pain ladder?
- non-opioid e.g. NSAID + adjuvant (weak pain killer like tricyclic antidepressant)
- weak opioid e.g. codeine + non opioid + adjuvant
- strong opioid e.g. morphine + non opioid + adjuvant
Tanezumab
Anti NGF MAb
Reports of increased osteonecrosis so ongoing trials
What is NK1?
The substance P receptor
Antagonists efficacious in animals but not humans
What is the problem with using TRPV1 antagonists?
Common side effect of hyperthermia
Which drugs are used to treat neuropathic pain?
NaV inhibitors: lamotrigine, carbamazepine
Antidepressants: amitriptyline, duloxetine
GABApentin
List all the causes of somatosensory damage to spinal cord
- Brown Sequard
- Syringomelia
- Tabes dorsalis
- Hemisection
- Posterior Inferior cerebral artery infarct
- B12 deficiency –> anaemia –> post column demyelination
- Arterio-venous fistulae
- Pontine artery infarct –> ML damage
