Analgesics Flashcards
What is somatosensation?
Our sense of touch, pressure and vibration against the skin
What is propriosensation?
Our sense of where our body parts are (a subtype of somatosensation)
What is nociception?
Our sense of tissue damage and the neural processes of encoding and processing noxious stimuli
What is pain?
Our perception of nociception that is in the brain (the sensory input)
Is pain made up of peripheral or central elements?
BOTH
Pain is the result of damaging processes and our interpretation of them
What are the four types of nocicpetor?
- Thermal
- Mechanical
- Polymodal
- Silent
What do thermal nocicpetors detect?
- 45 degree (painful heat)
- 10-15 degree (painful cold)
What do mechanical nociceptors detect?
- Squeezing, streching or penetrating the skin
- Sharp, intense pain
What do polymodal nocicpetors detect?
Dull, diffuse burning pain type
Where are silent nocicpetors found and what do they detect?
- Found in the viscera
- Respond to (over) distension/swelling
- Intense poorly localised pain
What do mechanical alpha delta fibres respond to?
- Do not respond to strong pressure from a blunt probe
- If equal pressure is applied all over a small area (pin prick, causing damage) they show a robust response
- Increased by pinching (damaging) a larger area
What is the nociceptor receptor family called?
TRP
How many heat sensing alpha delta TRP’s are there?
6 that cover a range of temperature sensing thermal nociception
Which two thermal TRP’s are activated at normal temperatures (more somatosensory than nocicpetive)?
- TRPv3
-TRPv4
What TRP is activated by chemicals such as garlic and radish?
TRPA1
Which TRP is active to menthol?
TRPM8
Which TRP is active to camphor?
TRPV3
Which TRP is active to capsaicin (chilli)?
TRPV1
Which chemical causes the spreading of local projections away from the site of injury?
Histamine
Which two chemicals are involved in exacerbating the nocicpetive response locally?
- Bradykinin
- Prostaglandin
What does substance P do?
- Dilates the blood vessel
- Can cause histamine release to potentiate the response
What is mechanical hyperaglesia?
The hyper-sensing of pain due to the spreading effect
What are prostaglandins produced by?
COX enzymes
What are the two neurotransmitters which project up the spinal cord?
- Glutamate
co-localised with - Substance P
Where are glutamate and substance P stored in the spinal cord?
In vesicles in dorsal route ganglion cells
How does Substance P act on glutamate?
- Causes depolarisation as it slows and prolongs the action of glutamate
- As it is not easily broken down, it can also act on neighbouring neurons (paracrine)
Why does substance P make it hard to localise some pain?
- Because it activates neighbouring synapses (paracrine)
- Regions in the spinal cord are being activated so the damage seems to spread out as there are other inputs and over estimation
Which type of nociceptive fibre causes a wind up effect?
Repetative activation of C but NOT alpha delta
What is the wind-up effect (steps)?
- Activation which projects to neurons in the spinal cord
- Second order neurons
- Input from C fibres and alpha delta fibres
- As alpha delta fibres are myelinated, the signal jumps across the nodes
- Because C fibres are un-myelinated, the signal has to be regenerated
- The initial reaction is the A volley because the AD fiibres get the information the quickest
- The A volley remains steady throughout
- Later on, the C volley starts earlier and lasts longer on every stimulus because there is priming input from the AD fibre
- When the C input comes along, there is plasticity from the C fibre and this increases the response of the neuron to the C fibre
What are the two second order neurons in the dorsal horn called?
- A-Volley from alpha delta
- C-Volley from C fibre
What receptors do glutamate and substance P bind to?
NK1, NMDA and AMPA
Why is AMPA the primary glutamate receptor in nocicpetive transmission?
The A fibre alone is not enough to release the Mg molecule from the NMDA receptor
How does the wind-up from the C fibre increase the firing at the synapse?
- The increased input the receptor receives means there is enough depolarisation for the NMDA to displace the Mg molecule
- Lots of calcium then enters
- This can cause the post-synaptic ion channels more likely to fire
- This then causes more C fibre response
Which axons make up most of the spinothalamic tract?
- Alpha delta fibres
- C fibres
- Alpha beta fibre (mechanoreceptor)
What layers of the spinal cord do the alpha delta and c fibres project into?
Layers 1 and 5
How does gating pain at the spinal cord level work?
- If drive the alpha beta mechanoreceptors by rubbing the area, they drive interneurons to become more active
- This increases the inhibition and reduces the excitability of the inhibitory neurons
- This reduces the projection neuron action the the C fibre
What is the cause of referred pain?
Due to poor localisation, particularly in the viscera
What is an example of referred pain?
Pain from a myocardial infarction can be felt away from the heart such as in the jaw
Where does the nocicpetive tract synapse at the supraspinal level?
- Thalamic level
- Then project to the other cortices
When does nociceptive decussation occur?
As soon as information enters te spine
What is the spinoreticular transmission system?
- Runs to the reticular formation from the spinal cord
- Then into the medulla and PONS
- Next into the thalamus and the cortex
- Lastly into the periaqueductal grey
Which regions of the brain project into the periaqueductal grey (PAG)?
- Insula
- Hypothalamus
- Amygdala
What are three bits of evidence that there is top-down modulation of pain?
- Electrical stimulation of the PAG
- Effect of opioids
- PAG through locus coereleus and raphe
What neurotransmitters do the locus coerleus and the Raphe use?
Noradrenaline (second order projection) and serotonin (projection neurons)
How do the pontine and 5HT neurons top-down regulate?
- They drive the interneuron which contains an endogenous opioid
- This decreases the excitability by reducing calcium entry and reduces activity
- This will turn off the synapse, reducing the nocicpetive information flowing into the brain
Which centre drives the LC and Raphe?
PAG
What mutations cause insensitivity to pain?
Autosomal recessive mutations
What can individuals with congenital pain sensitivity not detect?
Severe damage such as broken bones, burns, or even self inflicted injuries such as biting off the tip of their tongue
What does the gene SCN9A code for?
Voltage gated socium channel Nav1.7
What does the sodium channel Nav1.7 do?
Plays an important role in the dorsal route ganglion nociceptive neurons
What is the gene FAAH-OUT associated with?
The endocannabinoid system
What can long-term uncontrolled diabetes lead to?
Neuropahthy (nerve damage) with the legs and feet often the first tissues affected
What is parasthesia?
Pins and needles sensation
What are the steps to prostaglandin synthesis?
- Tissue damage to the cell membranes
- Arachidonic acid is converted to prostaglandin
- Leaves prostaglandin H2 and G2
- These are converted into a various group of compounds (icodomoids) such as prostaglandin E2
Where do the NSAID drugs act on prostaglandin synthesis?
When arachidonic acid is converted to prostaglandin G2 and H2 by targetting cyclooxygenases
What are three types of cyclooxygenases and when are they expressed?
- COX-1: constitutively expressed
- COX-2: Induced in damaged/infected cells
- COX-3: (splice varient of COX-1)
Which COX is the best target for the NSAIDs?
COX-2
What are the main therpeutic roles of NSAIDS (3)?
- Antipyretic (lower body temp)
- Analgesic (reduce pain)
- Anti-inflammatory
What does NSAIDS stand for
Non-steroidal anti-inflammatory drugs
What needs to happen when the core temperature is too low?
- Increase heat conservation- vasoconstriction (piloerection)
- Increase heat production- shivering, exercise
What needs to happen when the core temperature is too high?
- Increase heat loss- vasodilation, sweating
- Decrease heat production
Outline pyresis (fever)
CAUSE
Body thermostat is raised (hypothalamus is too high because of inflammatory response)
Core temp is sensed as too low
EFFECT
Increase heat gain/conservation
SYMPTOMS
Feel cold
WHY
Because prostaglandin E2 has been released in the periphery and this has an effect on increasing the set point of the thermostat
What is hyperthermia?
- Thermostat is not increased
- Too much heat production
- Feel hot
What is the area in the hypothalamus involves with heat?
Preoptic area hypothalamus