Peripheral and Central sensitization Flashcards
What are 5 risk factors for developing chronic pain conditions?
- Gender - women are more likely to develop chronic pain
- Age - older age can be a risk factor or can be protective
- Genetics: Genotype and epigenetics
- Environment - high exposure to stress, unemployment, injury or exposure to infection/injury at critical development stages
- Personality - tendency to catastrophize, depressive illness, pessimism, reward bias, anxiety
How might epigenetic mechanisms might confer risk for chronic pain?
They may function as a type of molecular memory. Epigenetic modulation of histones or DNA and that drugs targeting epigenetic processes can modify pain processing.
Examples:
- Histone deacetylases and possibly DNA methyltransferase inhibitors may have analgesic effects
- Back pain and lumbar degeneration are associated with altered DNA methylation at SPARC and PARK2 genes respectively
- MECP2 (binds to methylated CpGs) has been shown to be downregulated after nerve injury
(All from Pain vulnerability, Denk 2014)
What are the key genetic modulators of chronic pain?
SN polymoprhisms in COMT and SERT have both been associated with altered pain processing. They are involved in NA and 5HT metabolism respectively. Both effect PFC processing of pain and are also associated with affective disorders comorbid with chronic pain conditions. NA and 5HT are also both released by descending inhibitory control networks to cause antinocioception at the dorsal horn.
TRKa gene (NGF-TRKa interactions implicated in nocioceptive sensitisation) loss of function mutation is associated with congenital pain insensitivity
Sodium channel gene mutations (Nav1.7 is in 80% of nocioceptors). Mutations can cause sensitivity or insensitivity.
Homosynaptic potentiation
Refers to LTP - a use dependent facilitation of a synpase, caused by repetitive activation of that synapse.
Homosynpatic potentiation between c-fibres and projection neurones mechanistically explains hyperalgesia.
Heterosynaptic potentiation
Occurs when activity in one synpase potentiates other unactivated synpases, essentially sensitising the whole neuron.
This phenomenon explains the expansion of nocioceptive fields and recruitment of innocuous fibres that occurs during central sensitisation.
The precise mechanisms underlying homosynaptic potentiation are not clear - could relate to the ‘synaptic tagging’ hypothesis?
What are the three main features of a neuron in central sensitisation?
Increased sensitivity to noxious stimuli
Enlargement of receptive fields
Recruitment of non-nocioceptive fibres
Define primary hyperalgesia
A noxious stimilu creates a heightened response, specifically where a nocioceptor within the projection neurons ‘normal’ field of receptivity activates the projection neuron more powerfully than before
Define secondary hyperalgesia
When a nocioceptor outside of the receptive field of the projection neuron is sufficient to activate it
Define mechanical alloydynia
Activation of AB fibres by innocuous stimli activate projection neurons through disinhibition of a polysynaptic pathway from lamina III to II.
what is ‘priming’ in hyperalgesia?
Where early or previous life experiences (stress, viral infection, injury) cause long term changes to aspects of pain systems such that hypersensitivity is maintained.
Examples of insults include maternal seperation, chronic neonatal foot shock, injection of inflammatory agents (PGE2, NGF, 5HT) into the periphery
Examples of mechanisms fall into changes to peripheral afferents (NGF induced plasticity, changes to opioid system, increased axonal sprouting, involvement of the HPA axis)
Other changes involve microglial activation.
what is the reward network?
medial prefrontal cortex, ventrolateral prefrontal cortex, nucleus accumbens, hippocampus and the VTA.
How might the reward network be involved in chronic pain?
Greater functional connectivity between NAc and PFC predicts pain persistence by 80%.
Dispositional pessimism is a key trait factor in chronic pain - increased NAc activity distinguishes pessimists from optimists
Dopaminergic traits are also associated with chronic pain conditions
What is the descending pain modulatory system?
- *dorsolateral prefrontal cortex -> anterior cingulate cortices -> amygdala and hypothalamus -> PAG -> RVM
- > dorsal horn**
dlPFC, ACC, amygdala and hypothalamus are the means by which cognitive and emotional varibles interact with nocioceptive processing
How might the descending pain modulatory system confer risk factors in chronic pain?
The DPMS can exert bidirectional control of pain transmission at th dorsal horn - it is a balance between descending inhibitory and facilitatory inputs.
At certain critical stages in development (shown in rats and adolescence), the RVM switches from being primarily facilitatory to inhibitory. Insults during this stage may alter the ‘set point’ of the DPMS to cause vulnerability to pain in later life.
how may personality traits confer risk to chronic pain states?
Certain brain regions such as the PFC and the ACC show differential regulation in anxiety, and for personality traits such as neurotisicm and tendency to catastrophise. These brain regions are involed in the descending pain modultatory system. Changes may alter the salience of pain stimuli.
