Pain Flashcards
Define pain
An unpleasant sensory or emotional experience associated with actual or potential tissue damage - is subjective and personal
How is pain defined?
- Source - somatic, neurogenic, psychological
- Severity - assessed by clinician
- Quality - sharp, dull, aching
- Extent - localised or diffuse
- Duration - intermittent, acute, persistent, chronic
What is the function of pain?
To signal injury/inflammation to promote guarding/resting or learned avoidance
When can pain be pathological?
When it relates to an underlying malignancy and so has no utility
How is peripheral pain detected?
Through noicireceptors which have many subtypes e.g thermal, mechanical and ‘silent’ (only responsive after inflammation!) - DISTINCT NEURON TYPE
Describe the process of pain signalling due to damage of the skin
- Noicireceptor firing projects through spinal cord to cortex
- Inflammatory release of H+, K+, ATP, leukokines and prostoglandins causing sensitization
- Release of substance P and histamine from mast cells cause further sensitization
- Retrograde transport furthers sensitization
What are the fibres that transmit pain?
A delta fibres - sharp, shooting pain (first pain)
C fibres - dull, aching, burning pain (secondary pain)
What is the stucture of the A delta fibers?
- Lightly myelinated
- Small axons
- Conduction of 5-30ms
What is the structure of the C fibers?
- No myelination
- Small diameter
- slow conduction of 0.5-2ms
How can pain perception change following the initial pain?
- Noicireceptors can fire more easily
- “hyperalgesia” where pain becomes more painful
- Allondynia- non-painful stimulus becomes painful
- “silent” nocireceptors become actibe
What is the organisation of the spinal cord?
- Dorsal and ventral roots
- Sensory input goes to dorsal root
- White matter are axon projections, grey matter are cell bodies
- Divided into laminae 1-10 where 1 is dorsal
Where do noicireceptors project into the spinal cord?
- A delta project to laminae 2-3
- C fibres to laminae 1-2
- Laminae 2 is important as it is where first and second pain converges (substantia gelatinosa)
How does the transmission of noicireceptor information differ to other sensory transmission?
- Sends short projections rostrally and caudally in the zone of lissar ipsilaterally
- Then synapse on to zone 2 (substantia gelatinosa) on to second order projection neurons which cross beneath the central canal and ascend contralaterally up the spinal cord (SPINOTHALAMIC TRACT)
Describe the neurochemistry of nocireceptors?
- Release substance P early after injury and glutamate for a fast response at the dorsal horn peripheral laminae (shown with antibodies raised against it)
- Substance P binds to post-synaptic tachykinin receptors (most importantly tachykinin1)
What is the ultrastructure of noiceptor neurons?
2 types of synaptic vesicle
- Large dense core vesicles (LDCV) contain peptides, require more Ca to be released and therefore more action potentials
- Small synaptic vesicles (SSV) contain glutamate
Therefore there is a co-release of substance P and glutamate
How does noiciceptive synapse release change?
- Neurokinin A only released after sensitization
- NOS and NO are also upregulated during pain
What is ‘wind up’ dorsal pain?
- Persistent repetitive activation of C-fibres causes response of dorsal horn to increase progressively
- Dependent however on NMDA activation by glutamate
- CENTRAL SENSITIZATION
What is gate control?
- Mechanosensory stimulation can decrease sensation of pain
- C fibres share tract with A alpha and A beta mechanosensory neurons which activate their own projection neurons and also inhibitory interneurons to the C fibres
What are the different classes of second order neurons within the spinothalamic tract?
Class I - thermal and mechanical stimuli
Class II - have a wide dynamic range
Class III - noiciceptive specific
What is endogenous pain control?
- Mitigates conflict between pain sensation and ability to escape
- Done through PAG located in the midbrain which is activated during excessive pain and sends activation through raphe nuclei to dorsal horn
- Releases enkephalin and endorphins which bind presyaptically to noiciceptors inhibiting Ca2+ and reducing AP length, and post synaptically to dorsal projection neurons to induce hyperpolarisation
What are drugs that control pain referred to as?
Analgesics
What are the classes of analgesics?
- Non-steroidal anti-inflammatory (aspirin)
- Morphine-like drugs (opiods)
- Local anaesthetics (lidocaine/benzocaine)
- Centrally acting non-opiod drugs e.g antidepressants and cannabinoids
note: 95% constitute first 2 categories
How was aspirin discovered?
- Chewing on bark of salix alba had pain relieving properties - contains salicylic acid
- Then synthesis in pure form of acetylsalicyclic acid called aspirin
How does aspirin work?
Targets inflammatory components
- Derived from arachidonic acid which is broken down by COX-1 constantly to produce housekeeping prostoglandins and COX-2 to produce inflammatory prostoglandins
- Aspirin blocks COX-2 (but also a bit of COX-1 and reduces platelet aggregation)
Why is ibuprofen more potent than aspirin?
- Higher affinity for COX-2
- Less affinity for COX-1
How do CNS acting analgesics (opiums) work?
- Bind to endogenous opiod-like receptors - endorphins and enkephalin
- These are usually released by local interneurons in the dorsal horn and from projections in the brainstem
What are the properties of dimorphine (heroin)?
- Converted into morephine in the body
- Lipid-souble so can pass through lipid membrane quickly
What is codeine?
- 20% as potent as morphine
- Can be absorbed orally
- Non addictive
What is pethidine?
- Can lead to dependency and euphoria
- Used for labour as its short acting
- However can cause drowsiness in newborn for several days
What is fentanyl?
- Short lasting opiod
- Used in patient controlled infusion systems to control pain
What is methodone?
- Used as a heroin substitute in recovering addicts
- Use S-enantiomer which is an antagonist at NMDARs
What are the endogenous opiates?
Opioid peptides (endorphine) include beta-endorphin, met-enkephalin, leu-enkephalin and dynorphin
- Widely distributed in the brain
- In the spinal cord dynorphin is present mainly in interneurons, enkephalins also in interneurons and long descending projections
What are the opioid receptor subtypes?
- u opioid receptors thought to be responsible for most effects
- delta receptors also contribute to to aanalgesia at the spinal levesl
- All can activate AC which opens K channels and inhibits Ca channels
What are neurosteroids?
- Modulate GABAa recpetors which have many binding sites for different sunstances (bind to allosteric site)
- Synthesized from peripherally derived progesterone/cholesterol in the neurons and glial cells
- Only has effect when this and GABA binds to produce prolongation of inhibition
What are endocannabinoids?
Lipids syntehsised from membrane phospholipids ‘on demand’ by neurons
Give an example of an important endocannabinoid
Arandemide
- Broken down by fatty acid amide hydrolase (FAAH)
- Womean who doesn’t feel pain has mutation on FAAH gene therefore potential drug interest
How do cone snails catch their prey?
- Extend probasis with sting which causes paralysis in fish
- Venom comes from bulb filled with peptides, this travels down the duct and is stored in the radular sac go be shot out by non-hydrostatic explosion
- Tooth has barbs allowing fish to be retracted and eaten
Why are the cone snails a target for pharmacology?
Each species has a venom containing 100s of neuropeptides, unique database for pharmacology
How have the neuropeptides of the cone snail been classified?
- Injecting isolated peptides into mice
- Each belongs to a super family based on which channel they affect and the number of cysteine residues
What is the lighting cabal?
Cone snail uses delta-conotoxin blocking Na channels so fish cannot escape and also K channels to induce tetanic shock
What is the motor cabal?
Uses alpha-conotoxin to block nAChRs and u-conotoxin to black Na channels
What is zicotonide?
- Used in the treatment of chronic pain
- is a w-conotoxin MVIIA (targets Ca channels)
- Synthetic version has identical structure
How does zicotonide work?
- Acts on Ca channels within dorsal horn
- Rises in Ca levels usually triggers release of glutamate and substance P
- Blocks N-type Ca channels to stop neurotransmitter release
(note: these channels are also found at the NMJ and hippocampus)
How is zicotonide administered?
- Injected into cerebrospinal fluid into the brain as it is a large molecule
- Must be placed carefully so that it does not spread too far
- Only used as a last resort for chronic pain
What are the side effects of zicotinide?
- Diziness and confusion
- At high doses can lead to psychosis and depression
