PAIN MECHANISMS Flashcards
PAIN: definition& characteristics
= Unpleasant sensory & emotional experience associated with or resembling associated with actual or potential tissue damage
- Pain always personal experience influenced to varying degrees by biological, psychological & social factors
- Pain & nociception= different phenomena. Pain cannot be inferred solely from activity in sensory neurons
- Through their life experiences, individuals learn concept of pain - Person’s report of experience as pain respected
- Although pain usually serves adaptive role, have adverse effects on function, social & psychological well-being
- Verbal description only one of several behaviors to express pain; inability to communicate does not negate possibility human or nonhuman animal experiences pain
SENSATION vs EXPERIENCE
Sensation : location, quality, quantity, duration
Experience : daily life activities, work & social
Cognitive & affective dimension of pain
Cognitive (thoughts):cultural background, previous pain, beliefs & associations
Affective (emotion): emotional context at time of injury, catastrophizing, anxiety & social support
EXPERIENCE OF PAIN
Schema
MATUR ORGANISM MODEL: def, characteristics & adaptative vs maladaptative
= One example of didactic model
- Younglings : “naïve” organism model - Pain experience
* affected thoughts (cognitive aspect) * altered emotions (affective aspect) - Gives credit to experience
- Changes in output
- Changes in behavior
* Adaptive / maladaptive
(Tableau)
NEUROMATRIX: def & neurotags characteristics
Neurosignatures / neurotags
- Brain considered as mass of neural networks
* Distributed processing : brain cells work in parallel & form networks across multiple brain area
- Neural network evoking specific output : neurosignature/neurotag
* Neurotags work in collaboration or in competition * Influence other & influenced by other
* Action neurotags: influence beyond brain
* Modulation neurotags: influence within brain
- Same thing applies to spinal cord : spinal neurotags
Neurotags: Brain cells / neuroimmune unit multitask
- Can contribute to infinite number of neurotags
Neurotags strength influenced by:
- Neuronal mass: size of neurotag
- Synaptic efficiency:
* How quickly & how efficiently post-synaptic cell activated by pre-synaptic cell
* How quickly synapse return to “ready” state
Neurotag precision
- Probability that on cell will activate & not its neighbouring cell - Probability modulated in real-time
≠ types of pain mechanisms
Nociceptive pain
Nociplastic pain
Neuropathic pain
NOCICEPTIVE PAIN: def & characteristics
= Pain that arising from actual or threatened damage to non- neural tissue & due to activation of nociceptors
- Term used to describe pain occurring with normally functioning somatosensory nervous system to contrast with abnormal function seen in neuropathic pain
Normally functioning Somatosensory nervous system
- Is sensory nervous system’s response to certain harmful or potentially harmful stimuli
* Produces action potentials Thant can be interpreted by brain * Brain interpret or not info as pain
* Pain =/= nociception
- Nociceptors
* Free nerve ending
* High threshold sensory receptors: mechanical, temperature, chemical or polymodal
NOCICEPTIVE PAIN: ≠ phases of nociception
Transduction, transmission, modulation & perception
TRASNDUCTION: defintion & concept
D: Noxious stimulus converted into electrical impulse
C: It’s magic
- Convert mechanical stimulus into electrochemical activity
- Stimulation causes sensitives ion channel to open & produce transduction current changing membrane potential of cell
TRANSMISSION: definition & concept
D: Action potential conducted by nervous fibres (mainly Aδ & C fibers)
- Peripheral transmission
- Synaptic transmission
- Central transmission
C: It’s magic
- Connected to ion channel
- If stimulus high enough, nociceptors open ion channels
* Influx of positive charges in neurons
* Generates action potential
- Different types of ion channels
* Voltage-driven
* Thermal & chemical sensitive (Transient Receptor Potential) * Mechanically sensitive
* Ligand
Type of nervous fibres
- Difference in both diameter & in thickness of myelin sheath
- Bigger diameter & thickness of myelin sheath influence speed of action potential
- A-delta fibers conduct ”fast pain” : acute, specific pain
* Goes away rather quickly
- C-fibers conduct “slow pain” : dull, diffuse pain
* Takes more time
*70% of all nociceptive fibers
Signal input to spinal cord
- Primary nociceptors: terminate in dorsal horn at level they enter AND up to two level up & down
* Lamina I : Projecting neurons receive A-delta & C fibers info * Lamina II : Projecting neurons receive input from C fibers & relay it to other laminae
* Lamina III : Projecting neurons receive input from A- beta fibers * Lamina V (wide-dynamic range neurons) receive A- delta, C & A-beta (low threshold mechanoceptors) fibers information
- Cells from lamina II make synaptic connections in layers IV to VII. Cells, especially in laminae I and VII of dorsal horn, give rise to ascending spinothalamic tracts
MODULATION: defintion & concept
D: Afferent & efferent pathways for modulation of signal
C: PAG - RVM
- Pain-modulation system mediates analgesic action of opioids & recruited by internal & environmental challenges
- Intensity of pain varies among individuals & depends on circumstances (soldier wounded, athlete injured, during stress)
- Stimulation of PAG or RVM produces antinociception & inhibition of noxious-evoked activity of dorsal horn neurons
- RVM implicated in hyperalgesia & allodynia associated with inflammation, nerve injury
- PAG-RVM viewed as “pain-modulation system” that enhance or inhibit nociception under different conditions
Descending inhibition
- Periaqueductal gray (PAG), locus coeruleus (LC), nucleus raphe magnus (NRM), rostral ventromedial medulla (RVM) contributes to descending pathways inhibition
- At spinal level, opiate receptors located at presynaptic ends of nocineurons & at interneural level layers IV to VII in dorsal horn
- Activation of receptors hyperpolarizes neurons resulting in inhibition of firing & inhibition of release of substance P
* Suppression of release of excitatory neurotransmitters
* Suppression of post-synaptic response
- Catastrophizing, avoidance, somatization prevent effective descending inhibition & activate descending facilitation
- Affects both noxious & non-noxious stimuli
- Mainly due to RVM which facilitate & inhibit pain
- Key neurotransmitter: 5-HT
* High dose produces inhibition of AMPA/kainite-receptor-mediated excitatory postsynaptic current (EPSC)
* Low dose (or selective 5-HT2 receptor agonist) facilitate EPSC * Affects presynaptic et postsynaptic receptors
PERCEPTION: definition & concept
D: Noxious event consciously recognize as pain
C: Brain’s interpretation
- All pain in brain
* Brain produce pain without nociception & vice versa
- Brain produce pain by activating circuitry
* Thalamus
Sends incoming message to other brain regions
Thalamus activates periaqueductal grey which inhibits thalamus * Somatosensory cortex (Primary and secondary)
Responsible for identifying location of pain
Amount of activity correlates with pain
More attention one pays to pain, more activity observed
* Amygdala
Key role in negative emotions & pain-related memories Facilitator of chronic pain
Show less activity during pain delivery in case of positive treatment expectation
* Brain stem
Orchestrates top-down inhibition
Mesencephalic pontine reticular formation shows increased activity in CS -> increased
descending facilitation ?
Periaqueductal Grey : top-down endogenous analgesia
Different class of neurons in ventromedial medulla : ON-cells promote nociception ; OFF-cells suppress
* Anterior cingulate cortex
Affective & attentional concomitants of pain sensation
Social exclusion
• Activation of dorsal anterior cingulate cortex
• Further regulation by ventrolateral prefrontal cortex
• Broken heart pain
* Prefrontal Cortex
Pain anticipation & attention (vigilance) : pain memories (with amygdala and hippocampus
Dorsolateral part involved in nociceptive inhibition & endogenous analgesia
* Insula
Emotional component of pain sensation
Sensory-discriminative aspect of pain
NEUROPATHIC PAIN: definition, major condition, minor lesion, pressure, location, mechanisms & consequences
D: Pain caused by lesion or disease of somatosensory nervous system
= clinical description (not diagnosis) requiring demonstrable lesion or disease satisfing established neurological diagnostic criteria
MC: Neuropraxia
- Interruption of conduction
- No axonal lesion (no Wallerian degeneration) - Biochemical lesion
- Due to compression
- Function reversible in 6 to 8 weeks Axonotmesis
- Loss of continuity -> Wallerian degeneration
- Perineurium & epineurium intact Neurotmesis
- Axon + epineurium + perineurium lesion Regeneration
- Proximal 2 to 3 mm per day
- Distal 1,5 mm per day
ML: - No functional deficit
- Nervi
* Inflammation in epineurium: Cytokines and NGF & Allodynia + hyperalgesia
* Microvascular condition: Constriction injury model & Tourniquet effect : compression -> vascular dilatation -> nerve compression -> edema -> less oxygenated blood -> hypoxia
P: pT<pV<pF<pC<pA
Tunnel < Vein < Fasciculus < Capillaries < Artery
- 50mmHg for 2 hours: epineurial edema
- Whithin 8.5 hours of compression : motor function changes, Schwann cells necrosis & axon injury
L: - Peripherally generated: Trauma, entrapment, spinal nerve root
- Centrally generated: stroke, multiple sclerosis, spinal cord injury
Need to have proof of lesion or disease
Symptoms are neuroanatomically logical: burning, shooting, pricking
M: - Ectopic impulses: nerve generate impulses on their own - Neuroma(sprouting): fine nerve sprouts(grows)
* Increased mechanosensitivity
- Crosstalk
C: - Allodynia: Pain due to stimulus that does not normally provoke pain
- Hyperalgesia: Increased pain from stimulus that normally provokes pain * Neuroanatomical distribution
* Burning / sharp / shooting / electric shock-like
- Can cause constant pain
- Can cause impulses to not be contained within one fiber anymore
=> Whole system can be alive without even one external stimulus
NOCIPLASTIC PAIN: definition, description, plasticity & consequences
D: Pain arising from altered nociception despite no clear evidence of actual or threatened tissue damage causing activation of peripheral nociceptors or evidence for disease or lesion of somatosensory system causing pain
- Patients can have combination of nociceptive & nociplastic pain
D: - Neuroplastic pain central or peripheral * No biological purpose
- Neuroplasticity very important learning process
* Response more efficient when facing known stimulus * Not really good thing when talking about pain
=> Super-highway for painful stimuli to brain
P: - Ionotropic glutamate receptors (iGluRs) *AMPA receptors
* NMDA receptors
•Mg2+ block
•High voltage dependent
- Glutamate release from presynaptic opens AMPA receptors facilitating activation of NMDA receptors by removing Mg2+ block - Plasticity of nervous system by synthesis of gene products originating from second-messenger pathway from NMDA receptors * Increase of synaptic strength
- Leads to long-term potentiation = pathway to central sensitization
- Excessive activation of afferent pathways
* Wind-up effect
*Long Term potentiation
•Previously inactive receptors become active •2nd order cell produces more receptors •Activation of new synapses
C: Changes in inhibitory descending pathways - Impaired pain inhibition
- Conditioned pain modulation
- Exercised induced analgesia
- Cognitive emotional sensitization
Cortical modifications
- Reduced grey matter
- Augmented cortical pain response
Tissues NOT origin of pain
- Central pain need to be treated “centrally”
CNS sensitivity maintained by - Ongoing input from periphery - Psychometrics factors
- Plasticity of CNS
Pain literally becomes part of you
