Week 7 Flashcards
What are different types of pain?
Acute thermal and mechanical pain Inflammatory Hyperalgesia Spontaneous pain Neuropathic Allodynia Chemotherapy-induced Allodynia Visceral pain/hypersensitivity
What are two approaches of nociception?
Top-down approach
Bottom- up approach
What is top-down approach?
Start with patients
Look at rare conditions
Look at genetics
How the condition arises through use of preclinical modules
What is bottom up approach?
Looking at taking preclinical models and looking generally at sensory function
Apply back to patients
Understand biology
What is case 1?
Debilitating upper body pain
Triggered by fasting/fatigue
Colombian family - 4 generation of pedigree
Linkage analysis: chromosome 8
Sequence region
Identify particular mutation within gene (TRPA1)
Patients: familial episodic pain syndrome
What are TRP channel?
Group of non-selective cation channel
They pass sodium, potassium, calcium
Tetramer of 6 transmembrane domain regions
Activated by stimuli
TRP channels
Key transducer channels for modulating neuronal excitability
What does TRPA1 have?
Multiple anchoring repeats on N terminus
What does TRPA1 have a role in?
Irritant defection
Inflammation
Cold sensor
What is TRPA1 activated by?
Series of irritant chemicals
What are examples of flavours?
Horseradish
Mustard
Garlic
Onion
What is the role of Allyl isothiocyanite and Cinnamaldehdye?
Directly and selectively activate TRPA1
What is quantitative sensory testing?
A quantitative way of testing response to heat and pressure and touch
What happens when you apply mustard oil to the forearms of patient with episodic pain syndrome?
Small flare around application
Area of Hyperalgesia and Allodynia surrounding that
What did the mutation lead to?
Substitution
Amino acid 885 in TRPA1 gene
What is Heterologous gene expression?
Take TRPA1 gene into a plasmid
Apply cell of interest
mRNA expression
Introduce specific point mutation into gene
What are other methods used?
Electrophysiology
Calcium imaging
What happens when you apply cinnamaldehyde?
Large current passing through the channel
What is case 2?
Loss of pain
Patients unable to feel acute or inflammatory pain
Present with mutilation to lips or cornea
Damage to fingers or toes (repeated infection)
What do patients with loss of pain have?
Normal neurological function
Normal sensitivity to light touch, vibration
Ability to sense their position in space
What do patients with congenital sensitivity to pain have?
Complete absence of nerve fibres within that layer of skin
What are epigenetic regulators?
Regulators of genome that don’t cause direct changes in the sequence of genome but regulate expression in a way that can be passed down generations and a number of different mechanisms
What is PRDM12?
A modifier of Histone
What is PRDM12?
Key role in neurogenedjd
Specific transcription factor involved in nociceptors development
