S3C2 (2.0) Flashcards
What is a dermatome?
an area of skin that is mainly supplied by afferent nerve fibers from a single dorsal root of spinal nerve which forms a part of a spinal nerve
What innervates muscles?
Myotomes - a single ventral root
What are most muscles innervated by?
Axons from two spinal segments
What muscles are unsegmentally innervated?
Intrinsic muscles of the hand
When do muscles share innervation by the same spinal segment?
When they have a common primary action
What is the innervation for muscles with opposing action? Example?
They are supplied in sequence
i.e. C5/C6 bicep flexors
C7/C8 triceps extensors
What does complete sensory loss mean?
More than one spinal root must be damaged as there are functional overlap at boundaries between dermatomes/myotomes
When does the notochord appear in the medoserm?
3rd week
When are dermatomes formed?
3rd week - the tri-laminar disc has been established and the middle layer (mesoderm) has differentiated into its different types
What is directly adjacent to the neural tube?
Paraxial mesoderm
What does the paraxial mesoderm differentiate into?
44 somites
How many somites are formed? How many break down? How many are left?
44 formed
13 broken down
31 somites left
What does the ventral portion of somites contain?
Sclerotome, the precursor to the ribs and vertebral column.
What does the dorsal portion of somites contain?
Dermomyotome
How can spinal cord cells be classified?
Interneurons
Projection neurons
What % of spinal cord cells are interneurons?
97%
What is the role of interneurons?
Involved in modulating sensory input and motor output and make local connections with other cells in the spinal cord
What can interneurons be subdivided into?
Inhibitory and excitatory
What is the role of inhibitory neurones?
Limit receptive field size or activity of other neurones
What neurotransmitters do inhibitory neurones use?
GABA
glycine
enkephalin
{others}
What neurotransmitters do excitatory neurones use?
Glutamate
various neuropeptides
What is the role of excitatory neurones?
Their stimulation evokes action potentials in other cells
What % of spinal cord cells are projection neurons?
3%
What can projection neurons be subdivided into?
Axons of the ascending pathways (1%) Motor neurones (2%) - project from the spinal cord to innervate skeletal muscle and others
Describe A-alpha fibres
Myelinated Afferent - muscle spindles Efferent - alpha motorneurons Very fast conduction (60-120 m/s) Large (15 µm)
Describe A-beta fibres
Myelinated
Afferent - skin mechanoreceptors
Fast (30-60 m/s)
Medium sized (8 µm)
Describe A-gamma fibres
Myelinated
Efferent - muscle spindles
Slower (2-30 m/s)
Medium sized (5 µm)
Describe A-delta fibres
Myelinated Afferent - pain -free nerve endings -responsible for withdrawal reflex to pain Slower (2-30 m/s) Small (3 µm)
Describe C fibres
Unmyelinated
Afferent - pain
Slowest (0.24-1.5 m/s)
Small (1 µm)
What are low-threshold mechanoreceptors innervated by?
A-beta
What is Merkel’s disks good for?
highest spatial resolution, allows them to resolve tiny spatial details. Ideal for processing
What is the role of meisenner corpuscle?
40% of hand machinosensory information. Efficient in processing information about low-frequency vibration that occurs when objects move across the skin
What are ruffini endings essential for?
Internally generated stimuli
What is the role of pacinian corpuscle?
Detecting vibrations transmitted through objects that contact the hand
Where can muscle spindles be found?
Skeletal muscle
What do muscle spindles consist of?
4-8 specialised intrafusal muscle fibres surrounded by a capsule of connective tissue
How are intrafusal fibres distributed?
Distributed among the extrafusal fibres of skeletal muscle in a parallel arrangement
How are nuclei arranged in the largest intrafusal fibres?
In the largest of intrafusal fibres, the nuclei are collected in an expanded region named the nuclear bag fibres
How are nuclei arranged in the smaller intrafusal fibres?
Lined up single file - called nuclear chain fibres
What type of neurons are first order neurons?
Pseudo-unipolar neurons which have cell bodies within the dorsal root ganglion
Where are the cell bodies of second order neurons found?
In the rexed laminae of the spinal cords, or in the nuclei of the cranial nerves within the brainstem
Where are the cell bodies of third order neurons found?
Thalamus
Where do third order neurons project?
Ipsilateral postcentral gyrus
How are neurons in the sensory tracts arranged?
According to 3 anatomical principles:
Sensory modality
Somatotopic
Medial-lateral rule
What is the medial-lateral rule of neurons?
Sensory neurons that enter a low level of the spinal cord are more medial within the spinal cord
Sensory neurons that enter at a higher level are more lateral
What sensory information does the Dorsal column tract supply?
Proprioception
Fine touch
Pressure
What sensory information does the Spinothalamic tract supply?
Lateral - pain and temperature
Anterior - crude touch and pressure
What sensory information does the Spinocerebellar tract supply?
Proprioception
What sensory information does the Spinorecticular tract supply?
Arousal
Emotional aspects of pain
What fibres are used in the Dorsal column tract?
A-beta
Describe the first order neuron in the Dorsal column tract
Located in dorsal root ganglion
A-Beta fibres enter spinal column and ascend uncrossed in dorsal columns
F.gracilis up to T6
F.cuneatus after T6
Describe the second order neuron in the Dorsal column tract
Located in n.gracilis and n.cuneatus in lower medulla
Decussation: cross midline at medulla and form medial lemniscus
Describe the third order neuron in the Dorsal column tract
Ventral posterolateral nucleus in thalamus
Projects to somatosensory cortex
Where is the final destination of the Dorsal column tract
Post central gyrus in parietal lobe
What fibres are used in the anterior spinothalamic tract?
A-beta/A-delta SA fibres
Describe the first order neuron in the anterior spinothalamic tract
Located in dorsal root ganglion
Fibres enter spinal cord and project to lamina I and II
Describe the second order neuron in the anterior spinothalamic tract
Neurons in dorsal horn generate bilateral output fibres
Decussation: ascend in anterolateral fasciculus to terminate in thalamus
Describe the third order neuron in the anterior spinothalamic tract
VPL nucleus in thalamus
Projects to somatosensory cortex
Where is the final destination in the anterior spinothalamic tract?
Postcentral gyrus in parietal lobe
What fibres are used in the lateral spinothalamic tract?
A-delta SA fibres
Describe the first order neuron in the lateral spinothalamic tract
Located in dorsal root ganglion
Fibres enter spinal column and project to lamina II
Describe the second order neuron in the lateral spinothalamic tract
Lamina I and V neurons collect edited signals from lamina II
Decussation: cross midline at spinal segment, ascends in anterolateral fasciculus to terminate in thalamus
Describe the third order neuron in the lateral spinothalamic tract
VPL nucleus in thalamus
Projects to somatosensory cortex
Where is the final destination in the lateral spinothalamic tract?
Postcentral gyrus in parietal lobe
Define Malinering
The conscious fabrication of symptoms to achieve some form of benefits such as attention, to be relieved of undesirable activities, to obtain prescription medication, or to qualify for disability compensation.
Define pain behaviours
Non-conscious modes of communicating pain and distress and unlike cases of symptom magnification and malingering are not produced intentionally.
Define catastrophising
Extremely negative thoughts about one’s plight, even with minor problems being interpreted as major catastrophes. Catastrophising and consequently adaptive coping strategies are important in determining one’s reaction to pain.
What are important psychological predictors of chronic back pain?
Greater catastrophising and feeling a lower sense of control are among the most important predictors of chronic back pain.
What are the different types of pain?
Acute nociceptive
Inflammatory
Neuropathic
What stimuli can produce acute nociceptive pain?
Thermal
Mechanical
Chemical
What evokes acute nociceptive pain?
High-threshold stimulus-dependent pain
evoked in a graded response by appropriate high intensity (noxious stimuli)
What evokes inflammatory pain?
Active inflammation
Evoked by low (innocuous) and noxious stimuli
What causes neuropathic pain?
A lesion or disease of the somatosensory nervous system
Marked neuroimmune component
What are the features of neuropathic pain?
Maladaptive Persistent Hyperalgesia Allodynia Abnormal amplification
What is hyperalgesia?
Enhanced pain evoked by a noxious thermal or mechanical stimulus
What is allodynia?
pained evoked by a normally innocuous stimulus
How is neuropathic pain described?
Spontaneous pain: often described as a burning tightness accompanied with paresthesias, tingling, shooting or stabbing pains
What is neuropathic pain associated with?
Co-morbidities such as anxiety, depression and sleep-disturbance
What are the different causes of neuropathic pain? (with examples)
Trauma - nerve entrapment Central - spinal injury Neurotoxic - neuropathy Infections - post-herpatic neuralgia Metabolic - diabetic neuropathy Idiopathic
What is the mechanism of neuropathic pain?
Increased inflammatory cells and mediators in PNS and CNS
Altered nociceptor activity (receptor/ion channel expression)
Altered spinal processing: sensitisation, synaptic reorganisation
Altered central procession, descending inhibition
What are the four stages of acute pain?
Transduction
Transmission
Perception
Modulation
What happens during transduction in acute pain?
Injury results in the release of inflammatory mediators which bind to nociceptors converting thermal, mechanical or chemical insult into an electrical signa
What happens during transmission in acute pain?
Travels up:
Spinothalamic tract
Spinoreticular tract
Spinomesencephalic tract
What happens during perception in acute pain?
Nociceptive traffic is filtered through the individuals genetics, cognition, affect, environment and previous pain experiences
What happens during modulation in acute pain?
Nociceptive traffic is modulated by excitatory and inhibitory effects on the somatosensory system
What is the mechanism of modulation in acute pain?
Cortical/subcortical impulses
Impulses to the periaqueductal matter
Locus coeruleus (noradrenergic inhibitory system)
Raphé nucleus (serotonergic inhibitory system)
Inhibitory synapses in the dorsal horn
Ascending spinothalamic tract
Motor neuron reflex
What is post-herpatic neuralgia?
The pain that persists after shingles has cleared
What % of patients with PHN have mechanical allodynia?
> 75%
What % of patients with PHN have thermal hyperalgesia?
40%
What % of patients with PHN report pain improvement with pregabalin
35%
What neurotransmitter is used for pain afferents?
Glutamate
What does the release of glutamate evoke?
Fast synaptic potentials in dorsal horn neurons by activating the AMPA-type glutamate receptors
What is substance P required for?
The mediation of synaptic transmission for moderate to intense pain
Where is substance P stored?
Contained within storage granules in the axon terminals
How is substance P released?
Can be released by high-frequency trains of action potentials in C fibres
What is peripheral sensitisation?
A reduction in threshold and an increase in responsiveness of the peripheral ends of the nociceptor (high-threshold pain receptors) results from the interaction of nociceptors with the inflammatory chemicals at the site of tissue damage of inflammation
What effect does peripheral sensitisation have?
Protect the injured area - a result of painful perceptions produced by ordinary stimuli close to the site of damage
Promote healing and guard against infection - such as increased blood flow and the migration of white blood cells to the site
What is central sensitisation?
An increase in the excitability of neurons within the CNS, so that normal inputs begin to produce abnormal responses
What are the products of tissue damage substances?
ATP
Bradykinin
Prostaglandins
Substance P
How does ATP assist in tissue damage?
Directly depolarises nociceptors
How does bradykinin assist in tissue damage?
Directly depolarises nociceptors Stimulates long-lasting intracellular changes that make heat-activated ion channels more sensitive
How do prostaglandins assist in tissue damage?
Generated by enzymatic breakdown of the lipid membrane of cells
Do not elicit overt pain
Increase the sensitivity of nociceptors to other stimuli
What does substance P release cause?
Vasodilation and release of histamine from mast cells
Sensitisation of other nociceptors around the site of injury
What is primary hyperalgesia?
Increased sensitivity to pain within the area of damaged tissue
What is secondary hyperalgesia?
Increased to pain in the tissues surrounding a damaged area
What is the gate control theory?
That the spinal cord may either block pain signals or allow them to pass on to the brain
Pain signals are blocked when the gate is closed
Pain signals pass from the spinal cords to the brain when the gate is open
According to the gate control theory, we can be distracted from the pain by the release of endorphins (neurotransmitters)
How can the pain gate be closed?
A-beta fibre activation
What can be done to activate A-beta fibres to close the pain gate?
Massage
Acupuncture
TENS
What is cocodamol?
An opioid analgesic derived from morphine but less potent, less sedative and less toxic
Why is cocodamol less likely to cause dependence?
Causes little to no euphoria
What is the main side effect of cocodamol?
Constipation
What is the MOA for cocodamol?
Selective agonist for mu opioid receptor
What is the primary action of NSAIDs?
Inhibition of arachidonic acid oxidation by COX enzymes
This inhibits production of prostaglandins and thromboxanes
What is COX-2 inhibition linked to?
Anti-inflammatory and analgesic actions
What is COX-1 inhibition linked to?
The unwanted side effects, particularly those linking to GI tract
What are the 3 main therapeutic effects of NSAIDs?
Anti-inflam
Analgesic
Antipyretic (lower temp)
How do NSAIDs cause an anti inflammatory response?
Occurs as a result of decrease in prostaglandin E2 and prostacyclin
Reduces vasodilation and oedema
Accumulation of inflammatory cells is not reduced
How do NSAIDs cause an analgesic response?
§ Decrease in the production of prostaglandins that sensitise nociceptors (ORL1) to inflammatory mediators such as bradykinin
NSAIDS are effective in all conditions that are associated with increased local prostaglandin synthesis
How do NSAIDs cause an antipyretic response?
IL-1 releases prostaglandins in the CNS, where they elevate the hypothalamic set point for temperature control causing fever
NSAIDs prevent this
What are the side effects of NSAIDs?
GI disturbance
Rash
Prolonged bleeding due to decreased thromboxanes
Increased likelihood of thrombotic events (i.e. MI) by inhibiting PG12 synthesis
Bronchospasm
Liver disorders
What is Ibuprofen?
NSAID
weakly Cox-1 selective
Shortlived antiplatelet activity
What is Paracetamol?
Selective weak COX-2 inhibitor
No GI side effects
What are some examples of TCAs?
Imipramine, desipramine, amitriptyline, nortriptyline, clomipramine
What can TCAs be used to treat?
Depression in big doses
Neuropathic pain in small
How do TCAs treat depression?
Inhibit noradrenaline and 5-HT reuptake but have much less effect on dopamine reuptake
Improvement of emotional symptoms reflects an enhancement of 5-HT mediated transmission
How do TCAs treat Neuropathic pain?
Inhibit noradrenaline and 5-HT reuptake but have much less effect on dopamine reuptake
Improvement of biological symptoms results from the facilitation of noradrenergic transmission
What is the MOA of TCAs?
Block the reuptake of amines by nerve terminals by competition for the binding site of the amine transporter
What are the side effects of TCAs?
Antimuscarinic Sedation Confusion Motor incoordination Dry mouth Postural hypotension Increased risk of sudden cardiac death
What is gabapentin used to treat?
Anticonvulsant drug used to treat neuropathic pain including peripheral neuropathy
What is the MOA of gabapentin?
Interacts with cortical neurons at auxiliary subunits of voltage-sensitive calcium channels
It increases the synpatic concentration of GABA, enhances GABA responses at non-synaptic sites in neuronal tissues and reduces the release of mono-amine neurotransmitters (catecholamines)
What are the side effects of gabapentin?
GI disturbance
Dizzy
Drowsy
How do opioids relieve pain?
Raising pain mechanisms
Change in pain perception
How do opioids change pain perception?
Patients still experience pain consciously but do not attach negative emotional reactions to it.
This effect is mediated primarily via the limbic system which has the highest concentration of opioid receptors in the brain.
What in the brain has the highest concentration of opioid receptors?
Limbic system
Name endogenous opioids (produced in body)
Beta-endorphin
Enkephalin
Dynorphin
What are natural opioids?
Alkaloids derived from the opium poppy, also referred to as opiates
i.e. morphine and codeine
Name semi-synthetic opioids
Diamorphine (heroin)
Buprenorphine
Name synthetic opioids
Methadone
Fentanyl
What is an opioid receptor?
a group of G-protein coupled receptors with opioids as ligands
What does binding of an opioid receptor agonist cause?
Reduction of synaptic transmission
Closes presynaptic Ca2+ channels - hyperpolarises - reduced acetylcholine, noradrenaline, serotonin, glutamate, nitric oxide, and substance P released
Opens postsynaptic K+ channels - hyperpolarises
What are the 3 types of opioid receptor?
Mu
Delta
Kappa
What are Mu receptors responsible for?
Responsible for most of the analgesic effects of opioids and have some major unwanted effects
Located in the brain, spinal cord, Peripheral sensory neurons and intestinal tract
Strong analgesia
What does activation of Mu receptor 1 cause?
μ1 - analgesia, physical dependence
Chronic use of opioids produce tolerance
Negative physical withdrawal symptoms result from abrupt discontinuation or reduction
What does activation of Mu receptor 2 cause?
Respiratory depression, miosis, euphoria, reduced GI mobility, physical dependence
What does activation of Mu receptor 3 cause?
Vasodilation
What are delta receptors responsible for?
Result in analgesia
proconvulsant
Located in brain and peripheral sensory neurons
What does activation of delta receptors 1+2 cause?
Analgesia, respiratory depression, tolerance, strong addictive potential
Where are kappa receptors?
Located at the spinal cord, brain and peripheral sensory neurons
What does activation of kappa receptors 1,2+3 cause?
Analgesia, sedation, dysphoria and constipations
Do not contribute to dependence
What is Naloxone?
Opioid receptor antagonist
rapid onset, short duration (1–2 hours) → preferred for treatment of acute opioid intoxication
What is Naltrexone?
Opioid receptor antagonist long duration (24–48 hours) → used for withdrawal treatment after acute detoxification
What are the clinical features of opioid intoxication?
Altered mental state - can range from euphoria to apathy, impaired consciousness or seemingly normal mental state Bilateral miosis Respiratory depression Haemorrhagic lung oedema Seizures Decreased bowel sounds Decreased heart rate, blood pressure Hypothermia Rhabdomyolysis - breakdown of skeletal muscle tissue
What is the acute management of opioid intoxication?
Airway management
IV naloxone
Neutralisation of opioid effects
Restoration of ventilation
Slow administration to prevent acute withdrawal
Management of complications such as seizures
What are the clinical features of opioid withdrawal?
Flu-like symptoms: rhinorrhoea, chills, piloerection, myalgia, arthralgia, leg cramps
Gastrointestinal complaints: nausea, vomiting, abdominal pain, diarrhoea, hyperactive bowel sounds
Features of sympathetic hyperactivity: mydriasis, tachycardia, hypertension, hyperreflexia
Features of CNS stimulation: insomnia, yawning, irritability, anxiety, agitation, aggression
What is the treatment for opioid withdrawal?
Buprenorphine/naloxone is taken sublingually
Buprenorphine has a mild opioid effect after sublingual administration, while naloxone is hardly absorbed.
Naloxone prevents drug abuse by antagonizing the effects of buprenorphine if it is injected intravenously to achieve a stronger effect.
What is the cost of class A drug use in the UK?
£15.5 billion
How many hospital admission with primary diagnosis of a drug-related mental health problem?
6640
How many hospital admission with primary diagnosis of poisoning by drugs?
12586
How many deaths due to class A overdose in one year?
1784
Define drug abuse
substance used in a manner that does not conform to social norms. Can abuse drugs without being dependent or addicted
Define drug dependence
Physical - individual depends on drug for normal physiological functioning. Abstinence produces physical withdrawal reactions
Psychological - acquiring and using drug are strong motivators of behaviour. Compulsive use.
Where are the sites of rewarding brain stimulation?
Dorsal pons Septal area Lateral hypothalamus Medial forebrain bundle Ventral tegmental area
What do all drugs of abuse do?
Increase dopamine levels in nucleus accumbens
What is the management of opiate detoxification?
Detoxification
Reverse neuroadaptation from chronic use
Promote long term changes leading to lifestyle changes
Relapse prevention
Agonist maintenance (methadone)
Partial agonist maintenance (buprenorphine)
Antagonist maintenance (naltrexone)
Lifestyle and behaviour change
What does water and lipids show as on T1 MRI?
Water appears dark, fatty tissues appear bright
CSF appears dark
Grey matter is grey (higher water content)
White matter is white (higher lipid content)
What does water and lipids show as on T2 MRI?
Water appears bright and lipids appear dark
What is an issue with T2 MRI when scanning the brain?
Bright CSF can obscure pathology located in the parenchyma adjacent to ventricles or pia
Describe the somatic motor pathway
Upper motor neuron arises in primary motor cortex
Decussates in brainstem/spinal cord
Lower motor neuron arises in spinal cord
axon projects to skeletal muscle
What are the 3 subnuclei of the trigeminal sensory nucleus?
Chief - touch and pressure
Spinal - pain and temperature
Mesencephalic - proprioception
What CN is innervated contralaterally?
CN XII
Hypoglossal
What is an agonist?
Substance which stimulate the receptors and mimic the natural ligand
What is an antagonist?
Substance which block the receptors and stop the effect of the natural ligand
What is an ionotropic receptor?
Part of a ligand-gated ion channel protein and activation results in ion conduction changes
Opening by transmitter to allow Na+ (excitatory) or K+/Cl- (inhibitory) in
Involved in fast transmission
What is a metabotropic receptor?
Coupled to effector mechanism via G-proteins
agonist molecule combines with receptor and causes activation of membrane-associated proteins
