Itch/Scratch Cycle Flashcards
Where do the nerve cell bodies live?
Dorsal root ganglia (trigeminal nerve in the face only)
Where do the itch nerve fibers reach within the epidermis?
Stratum granulosum
Slow, amyelinated nerve fibers; “wide net”
C- fibers
Fast, myelinated nerve fibers
A-delta fibers
Which nonpeptidergic neurons respond to histamine (HR1)?
NP2, NP3
Which nonpeptidergic neurons respond to IL-4, IL-13
NP1, NP2, NP3 (all!)
Which nonpeptidergic neurons respond to IL-31
NP3, C-fibers
Which cytokines promote IL-31 production?
IL-4, IL-13 (poor pruritogens on their own)
What cutaneous sensation do type 1 and type 17 responses cause?
Pain
What type of cutaneous sensation does type 2 responses causes?
Itch
True or False: TSLP is pruritogenic
True
How is acute itch activated?
Leukotriene C4 via basophils (NOT mast cells!)
Which cytokine induces elongation and branching of nerves in the epidermis?
IL-31
How does IL-31 affect skin barrier?
-Suppresses filaggrin production by keratinocytes -> more TEWL
-Increases basal cell proliferation and thick skin
How does TSLP induce itch?
Activates NP1 via TRPA1 receptor
Name 3 neuropeptides that act on PEP neurons
Substance P (made by MCs)
CGRP (made by DRG)
Nerve growth factor (made by MCs)
True or false: some neurons directly innervate mast cells
True: A-delta or C-fibers can lie next to mast cells and stimulate them
On what does capsacin act?
TRPV1: transient receptor potential protein 1
-Induces histaminergic itch
Scratching upregulates which receptor, to reduce itch sensation?
IL-13-alpha R2 (nonfunctional receptor)
Which receptor dimer is functional, inducing itch when bound?
IL-4R-alpha and IL-13R-alpha 1
Which type of nerve fiber is responsible for touch, pressure, vibrations
Aß fibers
*Merkel cells
*Root hair plexus
*Meissner corpuscle
*Pacinian corpuscle
*Ruffini corpuscle
Which type of nerve fiber is responsible for pain
Aδ fibers
In dermis
Which type of nerve fiber is responsible for itch
C- fibers
-Unmyelinated
In epidermis
-Peptidergic vs Nonpeptidgergic
Where do nerve cell bodies live for the face and head
Trigeminal ganglion
What type of itch is NP1 responsible for
Neuropathic itch
What type of itch is NP2 responsible for
Chemical itch
Neuromediators: Substance P, NMB, Glutamate
What type of itch is NP3 responsible for
Inflammatory itch
Most important for cAD
Neuromediators: IL-31, IL-4/IL-13, Serotonin, Histamine, LTC4
Which nonpeptidergic c-fiber is most important for cAD itch
NP3
Inflammatory itch
Neuromediators: IL-31, IL-4/IL-13, Serotonin, Histamine, LTC4
BNP, glutamate activity (?)
Are histaminergic neurons important for ACUTE or CHRONIC itch
Acute
NOT important for chronic itch
What can activate nonhistaminergic neurons to perpetuate chronic itch
Proteases
like PAR2
What route up the spinal cord to the brain is important for transmission of itch
Spinothalamic tract
Does IL-31 induce acute or delayed itch
Both
Treatment of IL-31 reduces both acute and chronic atopic itch
What are the 2 parts of the IL-31 receptor
IL-31RA
OSMRb
What neuromediator inhibits the inhibitory interneurons
Somatostatin, dynorphin, GABA, Glycine
2 spinal nerves between DRG and brain (2nd pruriceptor). Inhibitory interneurons between each pruriceptor.
“Gate Control Theory”
To stimulate scratching are the below neuromediators increased or decreased: 5-HT, DA, NE, SP
Increased
To stimulate scratching are the below neuromediators increased or decreased: GABA, glycine
Decreased
(Decrease the inhibitory pathways)
Does cAD skin have increased or decreased intraepidermal nerve fibers
Increased
Imbalance of “nerve elongation factors” and “nerve repulsion factors”
What are the nerve elongation factors
TNFa, IL-31, NGF
These are all increased in cAD skin
What are the 4 receptors that are sensitized by G protein coupled receptors to transmit itch up the nerve
Ca2+ channels:
TRPV1 (vanilloid)
TRPA1 (Ankyrin)
Na+ voltage gated channels:
Na v1.7
Na v1.9
What causes peripheral sensitization of itch
- Inflammation induced itch causes PAR2 activation
- Upregulate itch receptors and molecules
- Dysfunction of inhibitor interneurons
What causes central sensitization
- Functional and structural changes due to chronic itch
- Attenuation of descending inhibitory pathways
Example of an H1 R inverse agonist
Benadryl
Keeps H1R in an INACTIVE state
Must be given BEFORE histamine is released
What type of itch is histamine effective for
Actue itch
Not for chronic itch (like cAD)
Which type of histamine receptor is responsible for plasma extravasation
H1R
Which histamine receptor is on endothelial cells and smooth muscle
H1R
Which histamine receptor is on gastric parietal cells and vascular smooth muscle
H2R
Which histamine receptor is on endothelial cells and the nervous system
H3R
Which histamine receptor is on leukocytes, mast cells, and dermal dendritic cells
H4R
What histamine receptors are present on sensory neurons
H1, H4 = ACTIVATIN
H3 = INHIBITING
T or F: Mast cells are increased in cAD skin
True
T or F: There is more histamine in mast cells of cAD skin, and more histamine is released in cAD skin than healthy skin
True
Function and location of Merkel cells
Light touch, spatial detail
Finger tips, lips, whiskers
Slow A-beta
Function and location of Meissners corpuscle
Vibration
Fingertips, palms, soles, lips, genitalia
Fast A-beta
Function of ruffini corpuscle
Stretch, warmth
Slow A-beta
Function of Pacinian corpuscle
Fast vibrations
Fast A-beta
Onion-like structure, in SC
Nerve fiber for non-noxious mechanical stimuli
A-beta fiber, fastest
Nerve fiber for noxious mechanical stimuli
A-delta fiber, fast pain
Nerve fiber for noxious heat, chemical stimuli (polymodal)
C fiber, slow pain
What is the gate control theory
Stimulation of nonpainful A-beta fibers can inhibit the sensation from painful fibers (A-delta, C-fibers)
A-beta can activate inhibitory interneurons
What 3 tissues can induce “itch”
*Skin
*Mucosa
*Cornea
T or F: Histaminergic and nonhistaminergic itch utilize the same neuronal pathways once they meet in the DRG
FALSE. Independent the whole way from the periphery to the brain
What are the receptors for Substance P
1) Neurokinin 1
2) mas-related G protein-coupled receptors (Mrgprs)
*Only Mrgprs are responsible for itch
Who is the main producer of Nerve Growth Factor (NGF)
Keratinocytes
NGF upregulates SP, to continue promoting itch
Which type of opioid can induce itch
μ-opioid agonists (morphine)
What activates PAR2
Proteases!
Especially Kallikrein (SC desquamation enzyme; upregulated in cAD skin)
Also proteases from HDM, Staph, etc
What receptor is activated by TSLP
TRPA1
Which receptor is shared by both IL-4 and IL-13
IL-4Ralpha subunit
What is neurogenic inflammation
Nerve fibers release Substance P, Calcitonin gene-related peptide (CGRP) –> causes vasodilation, leukocyte inflammation
What is neuronal sensitization
Increased density of IENFs (intraepidermal nerve fibers), which results in decreased itch threshold
Keratinocyte derived pruritogens
KLKs, TSLP, IL-33
Syringomyelia: how does this cause neuropathic itch
Alloknesis (itch evoked by light touching) OR Parasthesia (spontaneous itch)
Fluid filled cavities in the spinal cord
Scratch to one shoulder without contact = “phantom scratching”
Which breeds develop Acral Mutilation Syndrome
- German Shorthaired pointers
- English pointers
- English Springer spaniels
- French spaniels
Gene of Acral Mutilation Syndrome
GDNF (glial cell-derived neurotrophic factor)
Low GDNF protein in EXTREMITIES of acral mutilation dogs, so poor axon development. Decreases sensation of pain, temperature
Function of GDNF (glial cell-derived neurotrophic factor)
Decreases sensation of pain, temperature in EXTREMITIES.
–> Acral Mutilation Syndrome
What causes Tail Dock Neuroma
Nerves attempt to regrow after docking –> neuroma development
Stimulates pain –> lick/chew tail
Types of Radiculopathy (neuropathic itch) in people
1) CN V -> Herpes
2) C5-C6 -> brachioradial pruritus
3) T2-T6 -> notalgia paresthetica
Cause of neuropathic itch from feline herpes virus
Herpes virus kills neurons that mediate itch/pain
Clinical signs of Hyperaesthetic leucotrichia
Acute, severe pain on withers, dorsum in horses
Crusts –> alopecia
Lacey leucotricia withOUT leukoderma
True or False: Leukoderma is common in Hyperaesthetic leucotrichia horses
FALSE.
Lacey leucotricia withOUT leukoderma
What induces complete remission in 100% of cats with idiopathic ulcerative dermatitis on their necks
Environmental enrichment
“Behavioral ulcerative dermatitis”
Brain, Spinal Cord or Skin:
Lidocaine, Prilocaine, Pramoxine
Skin
Sodium channels, interfere with nerve conduction
Brain, Spinal Cord or Skin: capsaicin
Skin
Binds to TRPV1 on C nerve fibers. Causes release of Substance P –> burning sensation. Diminishes itch sensation
Brain, Spinal Cord or Skin: Gabapentin
Brain AND Spinal Cord
Brain, Spinal Cord or Skin: Kappa-opioid agonists
Brain AND Spinal Cord
Brain, Spinal Cord or Skin: TCAs, SSRIs, SNRIs
Brain
Brain, Spinal Cord or Skin: Mirtazapine
Brain
Brain, Spinal Cord or Skin: NK-1R inhibitors
ALL. Brain, Spinal Cord, AND Skin
Brain, Spinal Cord or Skin: Lokivetmab
Skin
Do topical TRPM8 antagonists decrease pruritus in cAD dogs? (cryosim-1)
No.
But they do in humans. Menthol binds TRPM8, releases GABA from inhibitory B5-I neuron
Receptor for topical palmitoyethanolamide
CB1, CB2
Topical cannabinoid
MOA of hydroxyzine
H1 R antagonist
Competitively block the formation of histamine-receptor complex –> inhibit histaminergic itch
MOA of maropitant
Neurokinin-1 receptor inhibitor
NK-1R throughout CNS, PNS.
Binds Substance P (mediator of pruritus).
Works for Feline atopic skin syndrome. Unknown efficacy in dogs
Other than cAD, what other diseases can Cytopoint help treat itch for?
*Mastocytosis
*CETL
MOA of Ranevetmab (dog), Frunevetmab (cat)
Anti-NGF mAb
Works for osteoarthritis pain, does NOT help itch.
MOA Gabapentin, pregabalin
Analogs of GABA (inhibitory neurotransmitter)
Inhibits voltage-gated Ca2+ in spinal cord, reducing CNS hypersensitization
MOA Topiramate
Increases GABA, inhibits glutamate
Blocks neuronal excitability, blocks Na channels –> prevents seizures, migranes.
**used in 1 case for Feline Idiopathic Ulcerative Dermatitis
MOA Butorphanol, Naloxone, Naltrexone
K-opioid agonists are antipruritic. Antagonists of u-opioid R are antipruritic.
Butorphanol is a mixed K-opioid agonist, u-opioid antagonist
Naloxone = u-opioid antagonist
Naltrexone = u-opioid antagonist
Amitryptyline MOA
TCA that inhibits serotonin –> more serotonin in neural synapses.
NONSPECIFIC. Can antagonize muscarininc, adrenergic, histaminergic receptors
MOA clomipramine
TCA
STRONGEST inhibitor of serotonin reuptake
BUT nonspecific (bc TCA)
MOA fluoxetine
Bicyclic SSRI
Selective on serotonin only.
MOA Doxepin
Serotonin norepinephrine reuptake inhibitor SNRI
Inhibits both serotonin and norepinephrine reuptake at presynaptic terminal
ALSO: anti-H1R !!!!
Which behavioral medication is also an antihistamine
Doxepin
SNRI + anti-H1R
Mirtazapine MOA
Atypical SNRI
Decrease serotonin and norepinephrine receptors – increase in central neurotransmission
Anti-nociception
Mild sedation –> good for noctural pruritus
Which behavioral drug may be best for noctural pruritus
Mirtazapine
Atypical SNRI with mild sedation
Buspirone MOA
Serotonin agonist
Diazepam MOA
Potentiation of GABA-r in CNS (inhibitory)
Benzodiazepine: Sedative, anticonvulsant
Depresses CNS
