Part 1 Flashcards
the final experience of pain results from concerted actions of what three orders of brain processing?
nociceptive matrix (ascending to thalamus, amygdala, reticular formation, SS regions)
perceptual/attentive matrix (ant insula and cingulate cortices)
reappraisal/emotional matrix (PFC)
nociceptors enter the dorsal or ventral horn?
dorsal spinothalamic tracts
Adelta neurons go to which types of lamina?
I and V
C neurons go to which types of lamina?
1 and II
What do Lamina I neurons respond to?
nociceptive, but also respond to warm, cold, itch and other innocuous stimuli
Which laminar neurons are wide dynamic range neurons?
Lamina V
What type of information do Lamina V neurons transmit? What neurons converge into Lamina V?
signals pain intensity and mechanical stimuli. Abeta (mechanical, chemical and thermal stimuli) and Adelta and C (pain)
Axons of lamina I and V decussate and form the _____________ pathway that projects to the______
ascending anterolateral pain pathway projects to the posterior thalamus
Which neuron type detects fast pain, sharp pricking sensations and has a high threshold?
Adelta fibers (mechano- and thermoreceptors)
Which neuron type detects slow pain, dull achy burning pain and can have a high or low threshold?
C fibers (mechano-, chemo- and thermoreceptors)
What three areas of cortex does that thalamus project to? What does this accomplish?
SS cortex, posterior insula and the cingulate cortex. this generates somato-specific conscious perception and vegetative responses to the pain sensation
The A5-7 spinothalamic tract into the reticular formation generates:
a NE pathway to the cortex/spinal cord for attention/arousal
The parabrachial tract into the reticular formation generates:
a pathway to the amygdala
The spinothalamic tract to the periaqueductal gray in the reticular formation generates:
a descending pathway that controls the sensitivity to pain
What areas of cortex does the perceptual matrix project to? What does this activity generate?
anterior insula, anterior, cingulate, PFC and posterior parietal cortex. this transforms vegetative reactions into internal feelings
How does the cingulate cortex react to pain? (What does it do?)
emotional aspects of pain- decides on behavioral patterns based on the experience
What does the insula do in response to pain?
integrates apppetitive and aversive valence of pain with the impact it will have on the body state
What 4 areas does the parabrachial nucleus in the RF project to? What is this circuit called?
amygdala, periaqueductal grey, hypothalamus, ventrolateral medulla. (results in sympathetic activation of physiologic systems).
spino-parabrachial-amygdala circuit
What does the amygdala do in response to pain sensation from the parabrachial nucleus?
generates anxiety, fear conditioning, antinociception, autonomic adjustments
What are some physiological effects of sympathetic activation generated by the spino-parabrachial-amygdala circuit?
diversion of blood to vital organs, increased HR and BP, increased RR, glyconeogenesis and glycogenolysis
the periaqueductal grey recieves input from what three sources? What is it involved in?
input from: ascending spinothalamic tracts, indirectly via the parabrachial nucleus, from the amygdala
involved in: defense responses (fight/flight) and supraspinal pain regulation
The defense responses generated by the periaqueductal grey are regulated by what 5 areas?
cingulate, insula, amygdala, hypothalamus, PFC
What two zones of defense responses does the PAG generate?
the ventrolateral (passive coping) and the lateral zone (active coping)
What are some aspects of the ventrolateral zone?
passive emotional coping, inhibition of sympathetic activity, wihtdrawl, disengagement, immobility, hyporeactivity, long-lasting opiod mediated analgesia
What are some aspects of the lateral zone?
active emotional coping, Rostral (FIGHT), caudal (FLIGHT), excitation of sympathetic activity, short-lasting opiod mediated analgesia
What is the descending pain pathway for supraspinal pain regulation? what is the central figure of this pathway and what is it responsible for?
cingulate cortex–> hypothalamus –>PAG –>reticular nuclei –>dorsal horn
PAG is central figure that is responsible for stress-induced hypoalgesia
What two things does the PAG project down to?
A5-7 reticular nuclei and the raphe
cells in the raphe nucleus that are stress mediated and induce tonic inhibition of pain transmission use what NT?
serotonin
What do non-serotonergic cells in the raphe nucleus mediate? What kind of mechanisms do the OFF cells use?
regulates immediate pain, alerting and arousal. ON cells facilitate pain transmission. OFF cells inhibit pain transmission via opiod mechanisms
What kind of NT do the A5-7 nuclei use? What does this do?
Norepineprhine (to inhibit pain transmission from alpha2 receptors)
What activates opiods?
painful stimuli
What do opiods and cannabinoids do?
upregulate the activity of medullary raphe OFF cells (to inhibit pain transmission)
how do tricyclic antidepressants and NE reuptake inhibitors enhance antinociceptive effects of opiods?
by increasing the availability of spinal NE (remember that A5-7 use NE to inhibit pain transmission)
Where are opiod interneurons? what are two things that they do?
in the dorsal horn. they decrease Substance P release and down regulate substance P neurokinin-1 receptors, thus inhibiting synaptic transmission between pain afferent and spinothalamic neurons
how do opiate drugs work?
stimulate opiate receptors in the hypothalamus, PAG and dorsal horn. (agonist of opiod NTs)
What are two ways in which C fibers excite pain projection?
either directly or by inhibiting enkephalin inhibitory transmission
How do Aalpha and Abeta mechanoreceptors inhibit C pain axons?
by stimulating enkephalin interneurons
What happens in TENS (transcutaneous electrical nerve stimulation)?
Aalpha and Abeta axons are selectively stiulated to suppress C fiber pain signals
interaction between the prefrontal cortex and the amygdala provides:
modulation of cognition in pain assessment of reward vs pain. (reappraisal-emotional)
The reappraisal emotional matrix is provided mainly by:
the cingulate and insular cortex (anticipation)
What is the anticipation of pain?
cingulate/insular coordination of SS features. and aspect of “secondary pain affect”
What is the opposite of placebo?
nocebo
The anticipated reduction of pain in the placebo effect is mediated by what structures and which corticostriate loops?
cingulate, insula, dlPFC (motivational and executive cs loops)
What is one theory on the cause of PTSD?
excess stress causes excess NE which can override/dampen cingulate activity, leading to excessive responses
Types of pain are differentiated by what three characteristics?
degree of injury, persistence of pain and the adaptive/maladaptive responses to the pain
What is nociceptive pain?
acute pain, in response to tissue injury, active asceding pathways, elicits pain inhibition to promote resolution (homeostasis). produces temporary peripheral and central sensitization
What is inflammatory pain?
chronic pain, generates descending excitement of pain pathways, induces peripheral and central neuronal excitability. pain stops when inflammation clears
What is neuropathic pain?
intense non-damaging pain due to dysfunction or damage of neurons in the peripheral or central NS. –>restructuring of sensory axons and dorsal horn neurons, descending pathways facilitate pain transmission (ON cells)
What are two effects of chronic pain and central sensitization?
hyperalgesia (primary-peripheral and secondary- central)
allodynia: pain in response to non-nociceptive stimulus (central sensitization, conveyed by low-threshold C fibers)
What is happening in hyperalgesia?
central increases in synaptic efficacy and reductions in inhibition –> increased amplitude, duration and spatial extent of pain response
What is happening in allodynia?
convergence of nociceptive and mechanoreceptive pathways such that low-threshold innocuous stimuli can activate pain pathways. C fibers disintergrate, leaving Abeta axons to project into the dorsal horn.
What are some ways in which inflammation increases pain pathways?
inflammatory substances activate nociceptors directly
histamine activate nociceptors, –>itching
PGE2 activate kinases that phosphorylate sodium channels, increasing sensitivity to pain
TRPV1 ion channel is upregulated
Where does central sensitization to pain occur?
at the synapse between sensory and second order neurons in the dorsal horn.
What are two effects that prolonged pain can have?
NMDA Ca Channels produce long term increases in dorsal horn neuron excitability by upregulating AMPA glutamate receptors
Microglia sensitize spinothalamic neurons by releasing cytokines
(also enhance excitability of the amygdalato pain)
What occurs during peripheral sensitization of neuropathic pain?
axon reflex (sensitizes axon ending similar to inflammatory pain) sprouting of axons and ephaptic communication causes spontaneous activity and pain
What are some syndromes in which neuropathic pain is sympathetically mediated?
complex regional pain syndrome Type 1 (reflex sympathetic dystrophy) and Type 2 (causalgia) and Raynauds syndrome
What happens in sympathetically mediated neuropathic pain?
neural trauma increases sensitivity to NE/EPI.
cytokines upregulate adrenergic receptors
increazed sympathetic activity sensitizes dorsal horn neurons
after recovery, excess NE/EPI triggers spontaneous pain
What compounds mediate primary and secondary hyperalgesia?
NMDA and PGE2
What is happening during referred hyperalgesia? what type of pain is this related to?
related to neuropathic pain
Type C afferents from viscera –>central sensitization of Abeta neurons
after prolonged pain, Abeta neurons sprout and respond to cutaneous and muscle input rather than proprioceptive input
What happens to medullary ON/OFF cells during prolonged pain?
shift from mostly OFF cell activation to mostly ON cell activation
ON cell activity is mediated by what compounds?
CCK, glutamate, NOREPI, neurotensin
how does prolonged exposure to opioids affect CCKs ability to excite ON cells?
prolonged opioid exposure enhances CCKs ability to excite ON cells
What do nocebos do?
enhance CKKs effect on ON cells
How does opioid withdrawl enhance hyperalgesia?
stimulate ON cells in the RVMedulla.
increases Glutamate and NOREPI activity in RVM, thus activating descending pathways, enhancing sensitization
how does the lateral orbitofrontal cortex increase activity in negative emotional states?
by enhancing descending pathways (ON cells)
The amygdala recieves bottom-up input from the _____ and top-down input from the________.
bottom-up info from the parabrachial nucleus/thalamus
top-down infro from the anterior cingulate gyrus
The amygdala projects to the ______ to regulate pain sensitivity.
the periaqueductal grey
What does the dlPFC pain pathway do? When is it most active?
emotion decision making (how to cope), localization of acute sitmuli. active more during acute pain. (pain inhibition!)
[PATH: thalamus, SS, posterior insula]
What does the mPFC pain pathway do? When is it most active?
emotional, hedonistic, hedonic quality of pain perception. more active during chronic pain (enhances pain perception). suffering
[PATH: amygdala, anterior insula, basal ganglia]
The dlPFC generally activates descending ______cells, whereas the mPFC generally activates descending ____ cells (ON/OFF?)
dlPFC–> OFF cells
mPFC–> ON cells
What do we think happens during chronic low back pain?
degeneration of the dlPFC enhances mPFC activation of ON cells. also decreased ability in emotion decision making
Degeneration of what grey matter is seen in chronic back pain?
bilateral dlPFC and unilateral thalamus
degeneration of what grey matter is seen in irritable bowel syndrome?
insula and cingulate gyrus
migraine involves both ______ and _______ sensitization
peripheral and central
What is required before migraines occur? and where does this happen (3 areas)
prior development of heightened sensitivity is required in the raphe nuclei, locus ceruleus and reticular formation
What happens during a migraine?
cortical spreading depression, oligemia, aura, visual scintillations
What causes pain during a migraine?
perivascular afferent neurons generate conscious pain from the trigeminal pathways, also stimulate parasympathetic reflex to vasodilate meningeal blood vessles
cortical spreading dpression causes the release of what five substances from the pia mater? what do these things do?
K+, H+, NO, arachadonic acid, PGE
these sensitive perivascular nerve afferents, causing pain
antidromic conduction of APs causes the release of peptides from neurons. what does this do?
generates local inflammation, enhancing pain
What are triptans and what effect do they have on migraines?
serotonin (5HT) agonists. these compounds alleviate migraine pain by binding to serotonin receptors and inhibiting peptide release (work best before sensitization occurs)
The dura is innervated by what nerves? What does this cause during a migraine headache?
innervated by the trigeminal nerve and C2 and C3
causes a counterintuitive referred pain during a migraine
photophobia is a type of:
allodynia
what can cause photophobia?
overcontraction of ciliary muscles (if unrelated to migraine)
OR melanopsin gangion cell-thalamo-cortical pathways which allow photic signals to converge into the thalamic region that is activated during a migraine
What are four changes in the brain tissue that occur with chronic pain?
decreased grey matter
decreased opioid receptor binding
decreased white matter integrity
increased inflammation in the ACC/PFC
