Mechanisms Of Pain Flashcards
pain definition
unpleasant sensory and emotional experiences associated with actual or potential tissue damge
pain is essential for
survival and health of animal
perception of pain is
subjective, affected by emotion and experience and environment
acute pain generally elicits
strong activation of autonomic reflexes with noticeable change in heart rate and blood pressure; vomiting also common with visceral pain
behavioral responses to pain
avoidance response or aggression towards subjects inflicting pain often observed
chronic pain can manifest as
changes in mood, appetite loss, depression
pain sensation is a
- complex neurological process of both peripheral and central nervous systems, pain scale, and efficacy of analgesics vary from patient to patient
- extent of pain experience dependent
pain classified into 3 different types based on mechanisms
- nociceptive pain
- inflammatory pain
c. pathologic pain
nociception
one of somatosensory modalities; critical for detection and avoidance of noxious stimuli
nociception threshold
high threshold pain activated in presence of intense stimuli playing role in early warning physiological protective system
nociceptive pain clinically
easily localized not clinically a problem bc anesthetics and analgesics can reduce unpleasant feeling
nociceptive stimuli include
- extreem heat
- extreem cold
- chemical irritants
- intense mechanical force
nociceptive input is not
always perceived as pain even when noxious stimuli exist bc could be overwritten by other brain activities such as emotions or experience
inflammatory pain
- upon tissue injury cells of innate immune system migrate toward site of injury and release proinflam cytokines and small moelecues
- can be spontaneous pain
- pain hypersensitivity
- different inflammatory mediators= sensed by different receptors, inflammatory mediators= trigger for pain sensation
“inflammatory soup” fx
activate receptors on nociceptor neurons which either evoke action potentials to elicit pain signaling or modulates ion channel properties (often making nociceptors more excitable)
inflammatory pain fx
protect injured area (persistent warning system)
inflammatory pain threshold
low threshold pain
inflammatory pain treatment
NSAIDs often suppress it
chronic pain
- unnecessarily-prolonged inflammatory pain can become debilitating chronic pain (ex rheumatoid arthritis, lower back pain, sever injury); this is v hard to treat
- pathologic pain is debilitating type chronic pain
pathological pain function
there isn’t one it isn’t protective
pathological pain subclassifications
- dysfuncitonal
- neuropathic pain
dysfunctional pain
substantial pain w/o noxious stimulus or peripheral inflammatory pathogens
dysfunctional pain conditions
- fibromyalgia
- IBS
- tension type headache
- TMJ dx
- interstitial cystitis
neuropathic pain cause
neurons themselves are injured and pain hypersensitivity becomes persistant; generally caused by nerve injury
- (ex. back pain, neck pain, migraine, pain after limb amputation)
neuropathic pain can occur
spontaneously and duration and amplitude of its response to noxious stimuli are amplified and often irreversible (neuropathic pain = autonomous dx state of nervous system)
mechanism neuropathic pain
unclear
examples neuropathic pain vet species
- pain from lumbosacral lesions
- intervertebral disc herniation
- other spinal cord injuries
- discospondylitis
- vertebral osteomyelitis
- polyradiculoneuritis
- feline orofacial pain syndrome
painpathway
- transduction
- transmission
- projeciton
- perception
- modulation
transduction
noxious stimuli recognized by nociceptors
transmission
nociceptive signals propagate as action potentials
projection
signals from nociceptors relayed to neurons in DH spinal cord -> transmitted to brainstem and thalamus
perception
thalamic nuclei relay nociceptive info to cerebral cortex, perception pain regulated by non-nociceptive afferent fibers
modulation
pain pathway plastic and modulated at many places in pain pathway can -> hypalgesia or analgesia
nociceptors types
- As= thinly myelinated (conduction speed 5-30m/s)
- C fibers- unmyelinated (conduction speed 1m/s)
speed nociceptors
slower conduction than touch or proprioception
nociceptor structure
- free nerve endings in skin, muscle, jt, bone, viscera
- cell bodies at DRG or trigeminal ganglia
- pseudo unipolar
- central and peripheral terminals emanate from common axonal stalk
signal transduction direction nociceptor
bidirectional signal transduction made possible by majority of proteins synthesized in nociceptor neurons distributed to central and peripheral terminals
types nociceptors
- thermal nociceptors
- mcechnaicla nociceptors
- polymodal nociceptors
- silent nociceptors
thermal nociceptors
- activated >45 C <5C
- As fibers
mechanical nociceptors
- intense pressure activated
- As
polymodal nociceptors
- activated by high intensity mechanical, chemical, or thermal stimuli
- C fibers
silent nociceptors
- usually not responsive to noxious stimuli
- responsive upon inflammation and various chemical agents in viscera
- C fibers
primary neurotransmitter of primary sensory neurons
glutamate
cot transmitters of nociceptors
neuropeptides released as cotransmitters by many nociceptors
neuropeptides vs neurotransmitters
no efficient mechanism peptide reuptake so neuropeptides diffuse greater distances than glutamate which can -> poorly localized character of many pain conditions
molecular sensors detecting noxious stimuli location
expressed in peripheral terminals of nociceptors
molecular sensors for detecting noxious stimuli are often
nonselective cation channels whose activation leads to membrane depolarization, a voltage change called “generator potential” or “receptor potential”
steps molecular sensors for detecting noxious stimuli
- Nonselective cation channels activated -> membrane depolarization (voltage change called generator potential or receptor potential)
- Voltage-gated Na+ channels
- action potential
each nociceptor tends to express
one class transduction receptors; segregation of diff molecular transducers into distinct subclasses sensory fibers allow peripheral nervous system to elicit specific types pain sensation = helps shape specific avoidance responses
ion channels sense different
noxious stimuli
what sense noxious stimuli
- Thermal sensors
- Chemical sensors
- Mechanical sensors
Thermal sensors
- thermal stimuli sensed by transient receptor potential (TRP) channels
- open and close at different temperatures ranging from 0-60C
- opening TRP allow cations to flow in -> action potential
thermal sensors respond to
- diff temperatuers
- natural products (capsaicin, menthol)
- membrane stretch
- they are versatile sensors for all 3 types noxious stimuli)
birds thermal sensors
relatively insensitive TRPV1 channels so more tolerant to high temperature and capsaicin
chemical sensors
nociceptors can sense
- pungent chemicals (methol capsaicin)
- cellular components (ATP, signaling peptides like calcitonin gene-related peptide), or acid
- chemical sensors are diff ligand gated channels that sense different stimuli
- at peripheral nerve sites chemicals bind to receptors -> action potential; can have modulators modulate excitability of channel
chemical sensors include
- TRP channels
- Acid-sensing ion channels (ASICs)
- ionotropic purinergic receptors (P2X receptors)
- receptor tyrosine kinases (ex. TrKA)
- GPCRs
activation TRP channels and ligand-gated ion channels
directly evokes generator potentials
activation of receptor tyrosine kinases and GPCRs
do not directly trigger action potential but modulate ion channels in nociceptor neurons
mechanical sensors
- mechanosensing mechanisms poorly understood; some ion channels demonstrated to sense mechanical stimuli (not necisarrily painful stimuli) including:
- TRP channels
- candidate mechanosensors= 2 pore K+ channels (K2P), Mac-Like mechanosensitive channels, epithelial Na+ channels (ENaC/DEG), Piezo channels
nociceptor input and central nociceptive pathways
nociceptor input can trigger prolonged increase in excitability and synaptic efficacy of neurons in central nociceptive pathways (pain sensitization including hyperalgesia, allodynia, and wind up)
- PNS and CNS cause pain sensation
abnormal sensitization of pain can ->
maladaptive chronic pain
hyperalgesia
- increased pain sensitivity
- primary hyperalgesia st site injury peripheral and central sensitization mechanisms involved
- secondary hyperalgesia- area adjacent to or remote to site injury this is solely due to changes in central processing NOT sensitization nociceptive nerve endings
allodynia
- pain in response innocuous stimulis
- occurs when pain pathway hijacked by other sensory pathway via nerve rewiring
- generally pain evoked by AB fibers
pain wind up
- in response to repetitive stimulation primary afferent C-fibers
- in absence of intention inflammation, trauma, nerve injury
- underlying mechanism unclear
peripheral sensitization
- reduced threshold and increased responsiveness of nociceptor evoked by set of inflammatory mediators released from injured and inflammatory cells
- broad range inducers (usually inflammatory get intracellular cascade of kinases that up regulate signals)
- multiple intracellular signal transduction pathways are involved (mechanotropic receptors turn on intracell signals that indirectly up regulate channels)
- usually inflammatory pain
central sensitization
- process that establishes state of hyper-excitability established in CNS -> enhanced processing nociceptive (pain) messages
- C fiber -> interneuron -> brain -> pain
- increase activity Ca2+ channels, increase neurotransmitter please
- kinases can up regulate receptors
mechanisms implicated in central sensitization
- alteration in glutamatergic neurotransmission/ NMDA receptor-mediated hypersensitivity
- Loss of tonic inhibitory controls (disinhibition)
- Glial-neuronal interactions
nerve termini of sensitized nociceptors release
substance P and calcitonin gene-related peptide (CGRP) which triggers release of inducers from immune cells in peripheral sensitization
can have unpleasant stimuli
that isn’t perceived as pain
protective pain
- acute nociceptive pain
- acute inflammatory pain
debilitating pain
- chronic inflammatory pain
- chronic pathologic pain (neuropathic/ dysfunctional)
site of moduation
synapses; mainly glutaminergic in sensory system
neuropathic pain main points
- normally caused by nerve injury
- low-threshold pain
- pain hypersensiitivy
- abnormal central processing
- spontaneous pain
- no appropriate treatments yet
- chronic pain (debilitating and devastating)
inflammatory pain main points
- low threshold pain
- pain hypersenstiivty
- spontaneous pain
- fairly effective treatments available (NSAIDs)
- persistence warning system (protective) OR
- chronic pain (debilatating)
central sensitization inhibitory interneuron
can inhibit this then inhibition inhibited -> increase sensitization
central sensitization microglial activation
have membrane proteins that release cytokines which activate receptors; multiple mechanisms can -> similar symptoms
touch pathway in allodynia
goes through sensitized pain pathway and touch is then felt as pain
