Nociception (Exam 2) Flashcards
T/F
Transduction always refers to a painful stimulus.
False
Transdxn doesn’t necessarily mean painful; refers to converting into electrical impulse
Transduction
noxious stimuli (e.g., heat, cold, mechanical distortion)
⬇️
electrical impulse in sensory nerve endings
Whorls
spiral shape seen at end of sensory dendrite; deform/compress triggers signal to travel down dendrite to body (senses pressure)
Whorls sense what type of stimulus?
pressure
How does increasing T affect receptors?
can open and allow NA in»_space; allows stimulation
process of sensing heat
Sensing heat causes an influx of ___
Na
Tissue damage results in release of ___ ions, which can open certain receptors.
H+
Transmission
conduction of these electrical impulses to the CNS
major connections:
-dorsal horn (SC)
-thalamus with projections to the cingulate, insular, and somatosensory cortices.
Process of transmission
-Nerves enter dorsal horn (SC)
⬇️
projection pathways (somatosensory pathways)
⬇️
up SC
⬇️
brain
⬇️
branch off in certain places, esp the thalamus
Transmission
major connections:
-dorsal horn (SC)
-thalamus with projections to the cingulate, insular, and somatosensory cortices.
(T ➡️ CIS
Thalamus to Cingulate, Insular, Somatosensory)
Relay center for incoming pain signals
Thalamus
receive input; synapse to others ie neocortex
Levels of consciousness are found in
the cerebral cortex
Which cortices are a/w:
lower brain levels & emotional responses
cingulate, insular
Which cortices are a/w:
bringing things into consciousness
somatosensory
Modulation
Alters which stage of nociception?
altering pain transmission
inhibitory & excitatory mechanisms modulate pain/nociceptive impulse transmission in the PNS and CNS
T/F
mechanisms modulate pain/nociceptive impulse transmission in the PNS and CNS are inhibitory
False
inhibitory & excitatory
sensation of pain
nociception
Perception
mediated thru…
thalamus: central relay station for incoming pain signals
primary somatosensory cortex: discrimination of specific sensory experiences
T/F
Modulation can relieve pain
True
Severe sudden pain will shift focus almost 100% to it
Not sustainable
So we modulate pain immediately
Pain relieving in a sense
Perception
bringing pain into consciousness to process and make decision
primary somatosensory cortex
discrimination of specific sensory experiences
What pain is it? Biggie or no biggie? Where from?
all or nothing response
axon only has one choice: fire or dont
signal traveling down axon
axon can only signal down or not
Temporal signaling
(down an axon)
firing rate
T/F
There is no required time frame between an axon firing.
False
takes time for axon to reset and send another signal
minimum period of time between firing
Cells adjacent to an axon are sensing…
a time/signal pattern
a cell may only respond to a certain firing rate/pattern
the only way nerves can signal each other
temporal signaling
Very painful stimuli firing rate
very rapid
(type 1 neurons)
Firing rates/patterns:
Type I neuron vs. Type II neuron
Type I: more linear; can alter firing rate
Type II: have different patterns
discrimination of sensory experience is based on:
-which nerves fire
-rate/pattern of firing
Stepping on a lego vs marshmallow
The response is dependent on…
temporal signaling
(firing pattern)
The 4 components of Nociception
Transduction
Transmission
Modulation
Perception
T/F
Pain can only occur when all 4 components of nociception occur.
False
pain can occur without one or more of these steps
(ex: phantom limb pain)
phantom limb “pain”
Not always pain; sometimes just sensation
d/t higher processing neurons still responding/firing w/o stimuli
(not getting the stimuli they used to get but still firing)
T/F
phantom limb “pain” is d/t the hypersensitivity of the remaining sensory neurons.
False
d/t higher processing neurons still responding/firing w/o the original stimuli
C-fiber afferents
(unmyelinated & slowest conduction)
burning
sustained pressure
Type I fibers
(some Aβ and some Aδ)
myelinated
“polymodal fibers”
thermal, chemical & mechanical stimuli
T/F
Thermal pain is not the same as burning pain
True
Consistent firing in-between transmissions; only “pattern” is speeding up/slowing down (linear)
Type I fibers (some Aβ and some Aδ) “polymodal fibers”
T/F
Type I fibers respond to a single stimulus.
False
called “polymodal” bc they respond to multiple things
Thermal vs burning pain
burning = instantaneous pain
thermal = consistent, longer-term response
Non-linear/ “saddle transmission”
Type II fibers (some Aδ fibers; slower)
bizarre patterns
can also speed up and slow down
can signal pain from chemical and cold stimuli
Both myelinated and unmyelinated
Type II fibers
(some Aδ fibers; slower)
initial pain responses to heat
non-linear
bizarre patterns
Myelination is more critical to (motor/sensory) fxn.
motor
Myelinated Motor
“Capsation” receptor is a/w what sensation
burning
Capsation/Vanilloid Receptor/ Transient V receptor-1 (TVR1)
structure
Voltage gated
4 subunit
similar to NMDA
Capsation/Vanilloid (VR1) Receptor/ Transient V receptor-1 (TVR1)
MoA
Na & Ca in; K out
depending on state of neuron
scalding heat and pain
activated/augmented by:
PKC, PKA, Ca
PIP is located in ___ and can be broken down into ….
cell membrane
DAG & IP3
T/F
Prostaglandins and bradykinins are known to cause pain
False
do not cause
but
worsen/augment pain
substances that transmit pain when released from neurons
CGRP (Calcitonin gene-related peptide)
SP (substance P)
glutamate
T/F
Ca release aids in pain transmission
True
Ca stimulates NT release into synapse and communicates pain
What stimulates Ca release?
-Depolarization (Na influx)
-IP3
-PK3
-PKC
T/F
PKA stimulates Ca release and pain transmission
False
stimulates Ca release:
-Depolarization (Na influx)
-IP3
-PK3
-PKC
Role of bradykinin in pain
increases IP3»_space; Ca release»_space; NT release
increases DAG»_space; PKC»_space; Ca»_space; NT release
Augments pain, doesn’t cause it
Role of PGE2 in pain
(Prostaglandin E2)
increased cAMP > activates PKA > Na influx > depolarization > Ca release > NT release
Activates Na (depolarization)
PKC
PKA
Which substances act here to inhibit pain?
Endorphins
ACh
cannabinoids
Which act via G protein complexes?
Endorphins
ACh
cannabinoids
All
stimulate K channels
K out
hyperpolarize
cAMP role in nociceptive signal transduction
Increase cAMP = alter PKA = stimulate Na ion entry = depolarization & passage of signal
increase of cAMP will directly…
increase/alter PKA
end result: Na influx & depolarization
released from some sensory nerves as a means of pain transmission
Calcitonin gene-related peptide (CGRP)
Substance P (SP)
Substance P (SP)
undecapeptide
acts at Neurokinin-1 receptors (NK-1) (amygdala, hypothalamus, & periaqueductal gray)
brings pain into emotional consciousness
amygdala
“P” in SP stands for
powder
SP is found with ___ in __ __ that respond to painful stimuli
glutamate
primary afferents
Neurokinin-1 receptors (NK-1)
widely distributed in the brain
in areas a/with pain processing:
amygdala, hypothalamus, & periaqueductal gray
SP acts on this site
specific areas associated with pain processing
amygdala, hypothalamus, and periaqueductal gray
An NK-1 receptor antagonist would block…
Substance P
SP: undecapeptide that acts at Neurokinin-1 receptors (NK-1)
Aside from nociceptive pain transduction, CGRP causes ___
vasodilation
decreases BP
CGRP antagonist
MoA
attenuates the increase in BP (that causes migraine) and block pain
Gi/o receptor
“G inhibitory”
Inhibitory opioid receptor
inhibitory actions at pain receptors
Causes receptor hyperpolarization by increasing potassium conductance (K out)
T/F
Endorphin, cannabinoid, and acetylcholine receptors are examples of Transient V receptor-1 (TVR1)
False
Gi/o receptor system
hyperpolarization by increasing potassium conductance
Provides sensations of scalding heat and pain
Transient V receptor-1 (TVR1)
“Capsaicin/Vanilloid receptor”
Transient V receptor-1 (TVR1)/ Vanilloid/ Capcasin
when it is open….
K out
Na, Ca in
similar to NMDA
Increasing K conductance means…
more K flows OUT
Bradykinin is considered a..
inflammatory mediator
increasing Bradykinin results in
increased DAG & IP3
increases overall response of system
T/F
CNS neurons can be sensitized for pain transmission by many inflammatory mediators
False
peripheral
released in response to tissue damage
bradykinin
Chronic pain occurs when
inflammatory effects do not resolve
leading to hyperalgesia due to sensitization
T/F
Hyperalgesia is a result from nerve understimulation.
False
hyperalgesia is due to sensitization/overstimulation
Allodynia
perception of pain from normally non-painful stimuli
body’s response to sensitization
T/F
Allodynia can occur without a stimuli
False
It is specifically pain from a nonpainful stimuli
Where is adenosine released from?
damaged tissue
Pain inhibitory receptors
Mu (endorphins)
GABA A
M2 (ACh)
GIRK
SSTR2a
Endorphins act on ____ receptors
Mu
Which propagate pain? Which are inhibitory?
NMDA
GABA
AMPA
propagate: NMDA & AMPA
inhibit: GABA
Substance P
MoA
act on NK1 > G Prtn > cAMP & PKA >VR1/NMDA (increases + [ ]/depolarization)
Glutamate MoA
act on AMPA
Na in
depolarization/pain nociception
GABA MoA (pain)
increases Cl- conductance
hyper polarizes
signal harder to propagate
Dorsal Horn Synapse
Afferent substances
SP
glutamate
White and grey matter
SC vs brain
SC: grey inside; white outside
brain: grey outside; white inside
White matter vs grey matter
whats in it?
White matter: myelinated axons; pathways/tracts
Grey matter: cell bodies/cellular region
Stimulation of ___ ___ causes the anger a/w pain
insular cortex
Amygdala transmit signals to
insular cortex
Lower level pain structures
Rostral ventral medulla
Periaqueductal Gray (PAG)
-respiration
-BP
-emotion
-lizards
insular cortex
brings into consciousness
specifically conscious emotion
ie: anger
T/F
nociceptors synapse once at the spinal cord
False
can have 1 or more
The thalamus relays info to
somatosensory cortex
T/F
In the brain, most pathways are outside and transmit to cells in the inner region.
False
most brain pathways are INSIDE
&
transmit to cells the outer regions
Where do nociceptors enter the spinal cord?
Dorsal spinal column
functions as a relay center for nociceptive and other sensory activity
spinal dorsal horn
periaqueductal gray (PAG)-RVM (rostral ventromedial medulla) system may either depress or facilitate the integration of painful information in the ______
spinal dorsal horn
Primary afferent nociceptors convey noxious information to
projection neurons within the dorsal horn (SC)
make up the great majority of the neuronal population throughout the dorsal horn
interneurons
Ascending pathway
Ascending information also accesses neurons of the ___ and ___ to engage descending feedback systems that regulate the output from the spinal cord.
rostral ventromedial medulla (RVM)
midbrain periaqueductal gray (PAG)
T/F
Cell bodies are usually found in the dorsal horn.
false
dorsal root
Which fibers enter thru the dorsal root?
AB, Ad, C
Dorsal root fibers & their laminae
Processing neurons
augment or inhibit depending on…
the level the information comes in on
Gate Theory of Pain
Pain information is transmitted to the brain if the gate is open but not if the gate is closed by inhibitory stimulation
Explains how fibers can augment/modulate pain
Gate Theory of Pain
T/F
A neuron must synapse on another neuron’s terminal to inhibit the passage of pain signals.
False
does not have to synapse only here
The mechanism of rubbing skin when in pain
activates large myelinated afferents (Aβ) (“faster” than Aδ & C fibers that convey pain)
Aβ fibers deliver pressure & touch info to dorsal horn
↓
overrides some pain messages (Aδ & C fibers) by activating the inhibitory interneurons in the dorsal horn.
T/F
Rubbing skin stimulates additional mechanical inputs which inhibit the gate through A-delta fibers and diminishes pain transmission to the brain
False
inhibit the gate through Aβ fibers
rubbing activates large myelinated afferents (Aβ) (“faster” than Aδ & C fibers that convey pain)
Aβ fibers deliver pressure & touch info to dorsal horn
↓
overrides some pain messages (Aδ & C fibers) by activating the inhibitory interneurons in the dorsal horn.
Which fibers tend to be stimulating? Which are inhibitory?
Adelta
C
AB
Stimulating: Ad & C (small)
inhibiting: AB (large)
The gate is seen as an (excitatory/inhibitory) mechanism
inhibitory
How does a very strong pain stimulus affect Ad & C fiber modulation?
High degrees of pain can enhance the stimulating effect of Ad & C fibers
-block Ab fibers
-enhance pain by inhibiting the closing of the gate
esp if many fibers are affected
The neurologic “gate” is in….
the spinal dorsal horn
GCT
painful information is projected to the ____ brain regions if the gate is open, although painful stimulus is not felt if the gate is closed by….
supraspinal
simultaneous inhibitory impulses (ie: rubbing skin)
large-diameter myelinated afferent fibers
AB
How we harvest Opium
-Slice poppies open
-Collect dried resin (morphine & other natural opioids)
-Modify via chemical treatment to make diff compounds (semi-synthetics; heroin)
Opium first known use
100 AD rome
alkaloids
naturally occurring compound in plants
Codeine and Papaverine and examples of
alkaloids (naturally occurring compounds in plants)
Morphine chemically isolated in
1806
Papaverine
no pain relief activity
activity on GIT
TB: papverine & noscapine lack analgesic activity
Does codeine relieve pain?
Yes, but not as potent as morphine.
Meperidine is an example of…
Synthetic congeners
(fully synthetic)
T/F
Heroin is a synthetic product of morphine.
False
semi-synthetic
How we make semi-synthetic opioids
-Collect dried resin (morphine & natural opioids)
-chemical treatment to make diff compounds = semi-synthetic
ie: heroin
T/F
Opiates refers to all agents acting on morphine receptors, including antagonists.
False
Opiates = derived from opium
Opioids: all agents acting on morphine receptors, including antagonists
T/F
All opioids have pain-relieving properties.
False
Opioids = all agents acting on morphine receptors, including antagonists.
T/F
Stupor specifically refers to opioids.
False
anything that produces stupor in theory could be considered a narcotic
Opioid Receptors
major families
m, d, k, Nociceptin
“Four”
Four major families (m, d, k, Nociceptin) all belong to ….
the G protein-coupled class of receptors.
Endogenous ligands for opioid receptors are ___ with ___ for each receptor type
peptides
varying affinities
T/F
All opioid receptor activity is inhibitory
False
very low doses are actually excitatory (increases intracellular cAMP)
Opioids exhibit inhibitory activity by…
decreasing adenylate cyclase
↓
decreases intracellular cAMP
T/F
Excitatory responses to opioids can be seen with clinical doses.
False
this is seen in a testing/lab environment; usually not seen in pts
converts ATP to cAMP
adenylate cyclase
(Adenylyl cyclase = adenylate cyclase)
Which are excitatory?
Which are inhibitory?
Go
Gi
Gs
excite: Gs
inhibit: Gi Go
“stimulate”
Gi = inhibit
Ca and K conductance that will increase action potential
Decrease K cndxn
Increase Ca cndxn
“Keep my K. Ca, come in!”
T/F
Opioid Receptors are found all over the body.
true
Opioid Receptor Locations:
mu, kappa, delta
Mu: brainstem & thalamus; some SC; GIT
K: dorsal H; some Bstem medullary retic.
d: limbic
Which opioid receptors are mainly a/w lower level fxns?
Kappa
Delta (lower lvl consciousness & emotion)
“My K:D is a lower level”
Opioid Receptor Functions
Mu
analgesia
resp depression
euphoria
miosis
physical dependence
decreased GI motility
Mu = euphoria “Muphoria”
physical dependence
overstimulation = tolerance
body craves more to stimulate same pathway
Mu receptor [ ] is highest in…
the GIT
T/F
physical dependence is the reason for opioid abuse
False
euphoria leads to abuse
Opioid Receptor Functions
Kappa
supraspinal analgesia
sedation
dysphoria (psychoses)
Opioid Receptor Functions
Delta
analgesia (spinal?)
D Does 1 thing = analgesia
a/w recovery effects in long term addicts (craving/dependence)
Kappa receptor dysphoria (psychoses)
Endogenous Opioids are derived from
precursor polypeptides
Endogenous Opioids
agents
endorphins
dynorphins
enkephalins
Endogenous Opioids
All differ in ____, but share the same …
chain length
first few AA’s (61-65)
smallest unit that produces response at opioid receptors
Met-Enkephalin
(AA 61-65)
How we cleave to obtain the different endogenous opioids
B-endorphin (61-91)
y-endorphin (61-77)
A-endorphin (61-76)
Met-Enkephalin (61-65)
ACTH & B-LPH
both: neurohumoral control
ACTH: control adrenaline release
not pain relieving!
Met-Enkephalin (61-65) is a ___ unit structure
5
smallest unit that produces response at opioid receptors
Endomorphines
newly discovered mu-receptor selective tetrapeptides
T/F
Endomorphines come from the same peptide structure as the endorphins, dynorphins, and enkephalins.
False
Endomorphines role in pain
Act as NTs, neuromodulators, or neurohormones
decrease signal strength or block completely)
Body’s pain modulators
Opioid Receptor Homology
~65% homology exists among m, d, k
Open circles are AA’s that differ among each receptor type.
T/F
The opioid G receptor proteins are more similar in terms of their ligands rather than how they work.
False
more homologous in terms of intracellular side, which controls how it works
external portion (binding site) is less homologous
Analgesia mediated via receptors located in…
-dorsal horn (SC)
-periaqueductal gray matter
-thalamus
PAG process information & brings it to ___ levels of the brain.
The thalamus, brings info to ___ levels.
PAG → lower levels
thalamus → higher levels
Ventral brainstem receptors mediate effects on…
coughing
vomiting
respiration
pupillary diameter
Can create substances to augment pain
hypothalamus
Neuroendocrine functions controlled via the ___.
hypothalamus
amygdala is a/w
Mood and behavioral effects
associated mainly with the GI tract
Peripheral mu receptors
Opioid ligands can interact with opioid receptors in 4 primary ways:
-agonist (can be inhibitory!)
-antagonist
-partial agonist
-Mixed agonist/antagonist
T/F
An opioid agonist can inhibit the opioid receptor.
True
Agonist: binds & activates receptor.
Agonists CAN be INHIBITORY
“can be inhibitory in its agonist activity”
binds to the receptor but does not activate it
antagonist
Partial Agonist
-binds but produces a submaximal response
-Lacks intrinsic activity
Mixed Agonist/Antagonist
binds to more than 1 type of opioid receptor
acting as an agonist at one, and an antagonist at others
Stimulating a G protein receptor typically leads to a ___ action
inhibitory
T/F
If we give higher doses of a partial agonist/antagonist, it is possible to achieve maximal effect.
False
partial agonist/antagonist lacks intrinsic activity
Opioids are (bases/acids) and bind to receptors in (ionized/nonionized) form.
opioids = bases & bind in ionized form
ionized form = + charge
(bases accept protons)
Opioid MoA
CNS activity primarily in…
brainstem/spinal cord
Opioid MoA
Non-CNS activity
peripheral afferent neurons
Opioids
Primary action
decreased neurotransmission by presynaptic inhibition of neurotransmitter release (NE, ACh, DA, SubP)
↓
increased potassium conductance and/or calcium channel inactivation
Opioid action is (mostly/all/rarely) pre-synaptic.
mostly pre-synaptic
some post-synaptic inhibition
Central Opioid Effects
↓ Neuronal activity
Analgesia – ↑ perception threshold & tolerance
Resp dprsn – ↓ CO2 sensitivity (Cheyne-Stokes)
Mood – clouded state (agonists); euphoria
Sedation – agonist dependent
Miosis
N/V
antitussive
endocrine
Opioids
Endocrine effects MoA
inhibits LHRH secretion
Cheyne-Stokes resp
rapid RR, apnea, repeat
not sensing CO2 during apnea
CO2 builds up to a higher extent triggers rapid RR
CO2 drops
apnea restarts
Peripheral Opioid Effects
Histamine release – peripheral arteriole & venous dilatation
Venous dilatation – direct opioid receptor action.
Smooth muscle contraction – biliary and bladder sphincter muscles. (↓ bile & urine)
Inhibit ACh release – mesentery: constipation.
Codeine has (high/low) Mu activity.
low
Histamine release w/ opioids
innate response
can occur on the first dose
Don’t give large doses without resp support
Opioids constipation MoA
Inhibition of ACh release in mesentery
↓
decreases peristalsis
↓
constipation
T/F
constipation can cause infection
True
bacteria can multiply & move up intestines
30-50% fecal matter = bacteria
opioids + ___ ___ = worsened constipation
bowel manipulation/surgery
Therapeutic Opioid Uses
Analgesia – acute & chronic
Pre-op sedation, anesthesia, epidural analgesia.
Diarrhea (Lomotil)
Cough suppression(codeine)
Opioid withdrawal
Opioid overdose (antagonist)
Remember opioids can be antagonists too
Why do we give opioid w/drawl pts more opioids?
Trying to block internal response (N/V)
give opioid w/ more targeted action
“MOR”
Mu opioid receptor complex
MORs can be found (2)
PAG
Dorsal horn (SC)
Opiate analgesia pathway
Start → finish
Medulla
dorsal raphe
PAG
Locus coeruleus
spinal cord
MOR PAG Opiate action
MOR activation = Inhibits GABA release
↓
PAG outflow & signal passage
↓
activates forebrain, spinal & monoamine rcptrs
↓
input to higher centers & mood
MOR Spinal Opiate Action
second order dorsal horn:
Pre & Post synaptic MOR
Pre: block Ca
Post: ↑K cndxn (hyperpolarize)
Result: hyperpolarize POST synaptic membrane
_____ MOR are a/w K+ & Ca++ channels
Spinal/2nd order DH
Opiate receptor binding is highly expressed in the
superficial spinal dorsal horn (substantia gelatinosa)
presynaptic C fibers (small aff)
Opiate agonist acting @ spinal sites serves to…
Lessen afferent excitation of the second order neuron
small primary afferent fibers
C fibers
“C small af”
