Nociception-pain-temp Flashcards
Structure of pain and temp axon
bifurcates with one receptor branch and central axon that enters CNS
both detected by sensory endings
structure of sensory ending receptor for pain and temp axon
free nerve endings (but not pacinian, merkel, etc.)
afferent fibers have cell body in DRG and central axon enters cord
pathway of pain and temp
1) sense in primary neuron
2) dorsal horn synapse
3) 2nd order neuron decussates at anterior commissure and ascend in spinothalamic tract
4) synapse on 3rd orde rneuron in VPL thalamus
5) project to somatosensory cortex or 2nd order neuron can also go to hypothal
know receptors that detect temp info
2 types of temp receptors on sensory endings
which are there more of
1) warm receptor (30-48 degr C)
= C fibers
2) cold receptors (10-37 degrC) = Adelta fibers
MORE COOL RECEPOTRS
know how temp receptors encode info
more sensitive to absolute temp or rate of change?
warm and cold receptors alter firing freq of AP in response to change in temp
more sensitive to rate of change than absolute temp
ex = cold receptor fire at steady rate then burst of rapid firing as temp dropping then slow again
in response to painful stim what are two types of pain? what are they separated by?
separated by time
1st pain = pricking pain (local and well tolerated, carry by Adelta fibers (slight myelin)
2nd pain = aching, burning pain; smaller, unmyelinated C fibers; poor localize and poor tolerate
which is better localized pricking or burning sensation
pinprick because Adelta fibers have smaller recepitve fields so better spatial discrim
2 major blocking manipulations
pressure
what does this cause?
what happens with incr pressure
1) pressure induces anoxia (first fibers affected are metab active = Aalpha and Abeta fibers
causes loss of touch, vibration, propioception, joint movement WITHOUT PAIN
but as pressure incr, pain fibers also affected (Adelta before C) and only sense burning
as even more pressure, C fiber block and no sensory
2 major blocking manipulations
local anesthetics
effect of 3 diff doses (low, med, high)
block small diameter fibers at concentration –> suppress burning pain first
higher doses block pricking pain
highest dose block touch and motor
example of activating manipulations?
what happens if incr intensity
electrical stim
single, low intesnity stim can activ Aalpha and Abeta fibers –> sensation of touch and join movement without pain
higher intensity = pricking pain
higher and repetitive = burning pain
what are afferent fibers for polymodal pain receptors
C fibers as afferents
have different receptors on different segments of the ending
also have diff receptors on single ending and respond to variety of stim
VR1 receptor activated by?
where is it located?
activ by capsaicin but also weakly responds to acid and moderate heat (43 degrC)
found in vanilloid moiety containing compounds and on polymodal nociceptors
ASICs respond to?
P2X responds to?
ASICs = acid
P2X = purines (ATP)
chemicals that act as pain activators
define
examples
activators = depol nerve ending to threshold
ex = bradykinin, K+, acid, serotonin
chemicals that act as pain sensitizers
define
examples
depolarizes but not to threshold and easier for activators
ex = prostaglandins, substance P, ATP, acetylcholine, serotonin
what type of pain info is carried by C fiber affernts
2nd pain = burning/aching poorly localized pain that is not well tolerated
location of first synapse in pain pathway
what NT operate here?
in dorsal horn of spinal column in the substantia gelatinosa = Rexed’s lamina II
major excitatory NT = glutamate
2nd order neurons in dorsal horn of pain pathway have what receptors
2 receptors = AMPA and NMDA
both ionotropic
AMPA = rapid synaptic response NMDA = simultaneous depol + glutamate
so fast and slow response
Difference btwn AMPA and NMDA at dorsal horn synapse
AMPA = rapid synaptic response
NMDA = slow excitatory potential
AMPA = require only glutamate
NMDA = require glutamate + depol to kick out Mg2+ +
what does NMDA recepotr gate?
produces __ changes in excitatability
gates Ca2+ channel so incr Ca2+ influx
produces long lasting changes in excitability
phosphorylation of NMDA by ___ does what?
phosphorylation by PKC and tyrosine kinase removes requirement of depol and NMDA can’t bind Mg2+
prolonged release of glutamate at dorsal horn enables NMDA to what?
more easily propagate AP –> central sensitization
NT at dorsal horn synapse
Glutamate released by?
acts on?
released by primary nociceptive sensory neurons at first synapse
acts on postsyn NMDA and AMPA
NT at dorsal horn synapse
Substance P
how is it released?
what does it bind on? and effect?
intense stim of C fibers releases at presynap terminal
binds on NK1 receptor and causes closing of K+ channels and depol
overall effect of substance P
enhancement and prolong actions of glutamate
may diffuse to many dorsal horn neurons for broad central sensitization at dorsal horn for long time
basis for peripheral sensitization
what is sensitization of nocicpetors also known as?
aka primary hyperalgesia because incr sensitivity to pain occurs at first site in path
agents that sensitize nociceptors
1) prostaglandins
2) substance P
3) ATP
4) ACh
5) serotonin
these decr threshold for activation of nociceptors
why do sensitizing agents decr threshold for activation of nociceptors
when you injure yourself, you stim C pain fibers
–> causes release of substance P
–> sensitize nociceptors in area bigger than original wound
therefold, a smaller stim needed to activate them promoting changes for better repair
basis for central sensitization
wind-up phase
1) as C fibers stim, postsyn AMPA receptors stim first since only glutamate around
2) if stim persistent, both glutamate + postsyn depol activ NMDA (larger response)
3) causes wind-up = stim dependent enhancement of postsyn response of dorsal horn neuron
basis for central sensitization
NMDA receptor phosphorylation
1) incr in intracellular Ca2+
2) causes phosphorylation of NMDA by PKC and tyrosine kinase inhibiting Mg2+ binding to NMDA
3) NMDA no longer requires depol so easier open
4) P-NMDA and AMPA now both open by glutamate alone
basis for central sensitization
effect of substance P
not removed by reuptake so persists
and can diffuse to many dorsal horn neurons –> broad sensitization
basis for analgesic action of aspirin
ASA inhib cyclooxygenase that converts arachidonic acid to prostaglandin
by block synth of prostaglandin, aspirin prevents nociceptors sensitization (primary hyperalgesia)
basis for triple response
triple response = central red + wheal + flare
central red and wheal
how does it occur?
1) tissue damage causes local bradykinin production
2) vasodilates and produce heat and redness (central reddening)
3) incr permeability of capillary membraens –> fluid accum and swelling (edema/wheal)
flare
how does it occur?
1) bradykinin activ C fiber nociceptors
2) AP propagate toward cell body of DRG and along collaterals to periphery
3) release of substance P surrounding wound site
4) mild vasodilator so pink flare
CALLED “AXON REFLEX”
location of action and effects of substance P
where is substance P released?
released at synapse and in periphery from C fibers
effect of substance P on peripheral collateral
how does it cause flare
how does it sensitize?
1) mild vasodilator producing flare in triple response in response to local tissue damage
2) also sensitizes to decr threshold of nocicpetors in tissue damage sites
3) therefore, responses to noxious stim are enhanced –> behavioral changes for better healing
effect of substance P in synapse (dorsal horn)
effect of intense stim on C fibers
acts as sensitizer
1) intense stim of C fibers terminating in subst gelatinosa causes release of subst P
2) binds NK1 receptors and closes K+ channels –> depol
3) enhances and prolongs glutamate action on AMPA and NMDA –> incr pain sensitization
4) also diffuse to nearby neurons so broad sensitization
PAG neurons located where? project where?
the project where?
what NT do they ahve?
found in midbrain
project to medulla
then project to dorsal lateral funiculus
medullary neurons are 5-HT
effect of 5-HT in spinal cord
use what NT? effect on pain sensation?
inhib second order neurons of dorsal horn by exciting inhib interneurons
they use enkephalin and blocks VG ca2+ channels presynap and open K+ channels postsynap
inhib of 2nd order neuron –> decr pain sensation
PAG neurons sensitive to?
sensitive to opiates
exposing endogenous or exogenous opioids –> greater excitatory output –> greater inhib of 2nd order neurons in dorsal horn
stroking or rubbing area of body experinencing pain causes ___
why?
decr sensation of pain
because activates non-nociceptive afferent pathways (touch and A-beta fibers)
activates dorsal horn interneurons that inhib synapses activated by nociceptive fibers
selective stim of A-beta fibers causes
causes reduction of pain (basis of transcutaneous electrical nerve stim)
elimination of inputs from A-beta fibers causes
incr pain sensation (hyperalgesia)
define gate control theory
nociceptive inputs open and non-nocicpetive afferents shut gate that leads to central transmission of noxious info
basis for placebo effect
PAG receive input from?
ultimate effect?
1) PAG receive input from limbic system and cortex
2) but expect to receive pain-releiving drug
3) incr activity in neocortex/limbic
4) PAG activated via secretion of endorphins that stim PAG excitatory output
–> incr stim of inhib interneurons in dorsal horn and inhib of 2nd order neurons in dorsal horn
placebo effect blocked by?
blocked by naloxone so PAG responsible
stress induced analgesia
what does it incr? result?
increases limbic system activity
activates PAG and stim of inhib interneurons in dorsal horn
results in inhib of 2nd order neurons in dorsal horn of pain pathway
effect of naloxone on stress induced analgesia
naloxone blocks some but not all analgesia so stress = opioid + nonopioid mechanism
rewiring in neuropathic pain
effect on signals from primary to secondary neurons
1) injury causes change in concentrations of neutrophrins
2) promotes inappropriate growth of neurons
3) neurons contact inappropriate targets
4) organization awry
5) primary neurons can’t be organized by stim around appropriate secondary neuron –> wrong signals from primary neurons may stim 2nd neuron
role of GABA in neuropathic pain
decr GABA + decr GABA and opiate receptors
causes decr inhib signals
decr second order neuron excitation
role of microglia in neuropathic pain
causes release of ___
after injury, microglia activated (incr ATP attract microglia via purine recepotrs)
release of BDNF
decr expression of KCC2 (extruder of Na)
alters Cl reversal potential
GABA activation causes ecitation
therefore, decr inhib in dorsal horn –> hyperalgesia
3 tracts after axons ascend in anterolateral tract
1) VPL thalamus
2) reticular formation
3) mesencephalon
VPL thalamus = spinothalamic tract contains what info
localizes the input (pain and temp)
spinoreticular tract cotains what info
sends info to hypothalamus, amygdala (behavioral/emotional responses to input) (pain and temp)
spinomesencephalic tract contains what info
important for descending modulatory influences of pain
3 types of pain
- Nociceptive = acute painful stimulus (flame, overinflated BP cuff, chemicals)
- Inflammatory = injury and inflamm signals released
- Neuropathic
for extreme temperature
extreme temp = Cold = what fibers
extreme temp = warm = what fibers
mechanical are primarily what fiber type
polymodal fibers are all what?
cold = C
hot = Adelta
opposite of well being
mechanical = adelta
polymodal = C
release of substance P requires
repetitive stim of c fibers
Distinguish btwn hyperalgesia and allodynia
hyperalgesia = incr sensitivity to pain (flare)
allodynia = non-noxious stim like touch becomes painful (sunburn then water in shower hurts rather than feel good)
why do you have referred pain
a. Due to convergance of inputs from cutaneous and visceral sites but cutaneous ones dominate so therefore have referred pain
Tabes dorsalis causes degeneration of ___
what effect
Abeta fibers = intolerable pain (losing Abeta because now losing endogenous way to produce analgesia)
Electrical stim of back relieves pain how?
although fibers ascend and feel pain but also fibers descend and activate enkephalinergic interneuron in many segments
Descending modulatory pathway of PAG
1) stim PAG
2) project to nucleus raphe magnus = medulla
3) project to dorsal horn of spinal cord (target enkephalinergic inhib interneurons)
Types of TTX Receptors
both sensitive to __
TTX-sensitive
TTX-resistant = in sensory neurons of heart, CNS
both sensitive to lidocaine
