Ch. 5 - Cutaneous Neurophysiology/Itch treatment JAAD CME Flashcards
What 3 fibres transmit the sensation of itch?
Small, unmyelinated C fibres- histaminergic
Small, unmyelinated C fibres- cohwagenic
Small, thinly myelinated A-delta fibres
What sensation is transmitted with itch via histaminergic fibres? Is mechanical stimuli?
Heat
Mechanically insensitive
Are C-fibres slow or fast velocity?
Slow, <0.2 sec
What sensation is transmitted with cowhagenic C-fibres? Is mechanical stimuli?
Burning
Mechanically sensitive
What 2 receptors are activated in Cowhagenic-sensitive C-fibres
PAR-2 and PAR-4
What % of C-fibres carry itch fibres
5%
What receptor transmits histamine induced itch via mechanically insensitive, capsaicin-sensitive C-fibers
TRPV-1
List 4 primary pruritogens that act peripherally
Histamine-
Proteases- elastase, kallikrein, tryptase, trypsin, and cathepsin S
IL-31
List 4 secondary mediators of peripheral itch (dont act directly)
Prostaglandin E1/E2
Substance P
Mu-Opioid receptor agonists
NGF-Nerve growth factor
IL-2
Name 3 substances, other than IgE or KIT-receptor mediated substances, that can cause mast cell degranulation
Substance P
NGF
Complement C5a
Opioids
What receptors mediate histamine related itch
H1
H4
What receptors do proteases activated?
Protease-activated receptors like PAR-2 and PAR-4 (GPCR)
-proteases cleave PARs, exposing a tethered ligand and thereby resulting in “self-activation
Name 3 central-acting itch mediators
Opioids
Gastrin-releasing peptide
B-type natriuretic peptide
Generally, how is itch sensation mediated
Itch is initiated when exogenous and endogenous pruritogens bind to their receptors on these sensory nerve endings
What are the two classes of itch receptors
1.G-protein coupled receptors (bind to pruritogen)
- Transient receptor potential (TRP) channels–> E.g. TRPV1 and TRP ankyrin 1, which activate Nav1.7 and Nav1.8 sodium channels, propagating the action potential of the itch signal.2
What are the two pathways of itch in general
Histaminergic
Non-histaminergic
How is histaminergic itch transmitted
Histamine release from mast cells, basophils, keratinocytes active H1 and H4 receptors on histaminergic nerve, activate TRPV1 channel that propagates itch signal
Name 4 cytokines that mediate itch
Il-31, IL-4, IL-13, Thymic stromal protein
IL-17, 22–> induce gastrin releasing peptide (GRP) pathway
What 2 cytokines have been implicated in ureic itch
Il-2 and 31
Name 2 neuropeptides (substances release by sensory neurons) that mediate itch
Substance P
Calcitonin gene regulating protein
How does SP and CGRP mediate itch
- Mast cell degranulation at high levels
- Neurogenic inflammation : Low levels activate neurokinin-1 (NK-1) receptors on mast cells, leading to sensitization of these cells and increased production of tumor necrosis factor, which further sensitizes nerves to substance P
- Spinal itch transmission.
How does NGF (nerve growth factor) propagate itch
Nerve growth factor, a neuropeptide secreted by eosinophils, binds to tropomyosin receptor kinase A on sensory nerves, sensitizing TRPV1 to SP and calcitonin gene-regulating protein
Which opioid receptor increases itch? Which surpresses itch?
Mu-opioid receptor increases itch
K-opioid activity decreases itch
Name a mediator of itch in the spinal cord
Gastrin releasing peptide
E.g. Activated sensory neurons release GRP which binds to GRP receptor (GRPR)-positive neurons in the spinal cord
How does k-opioid activity suppress itch?
BHLBH5 interneurons (helix-loop-helix family member B5 (bhlhb5), which are mediated by K-opioid activity, attenuate the itch signal by inhibiting GRPR-positive neurons with dynorphin, glycine, and gamma-aminobutyric acid
What is one way to active BHLBH5 neurons
Pain-pain neurons synapse with these interneurons
What are two mechanisms of opioid induced itch
1- degranulation of cutaneous mast cells and (2) activation of µ-opioid receptors with direct central and peripheral pruritogenic effects
How does capsaicin work at molecule level? What’s its indication?
Neuropathic itch localized
MOA:
Activates and subsequently desensitizes TRPV1,
Causes release from C neurons and (eventually) depleted stores of neuropeptides (e.g. substance P, CGRP, somatostatin)
Prolonged use leads to neuronal degeneration at sites of application, which can result in a reversible decrease in epidermal nerve fiber density
Name 3 topical anesthetics for itch
Lidocaine
Pramoxine
TKAL- topical ketamine amitryptiline lidocaine (10-5-5)
How do camphor and menthol work
Activate TRPM8 receptors on C-fibres= cooling sensation
How does strontium work
Calcimimetic thought to inhibit ion channels in nerve fibres
e.g. Strontium 4% Hydrogel (TriCalm)
Name 10 categories of topical treatment for itch and an example for each.
- TCS
- TCI
- PDE-4 inhibitors-Crisabarole
- Topical anesthetic- lidocaine, pramoxine
- Coolants-menthol, camphor
- Capsaicin
- Topical TCA- Doxepin
- Topical gabapentinoids- Topical gabapentin
- Cannabinoids: N-palmitoylethanolamine
- Botox injections
- Strontium
Name 10 categories of systemic therapies for itch and name 1 example of each
- Anti-histamines (hydroxyzine 1st gen, cetirizine 2nd)
- TCA- amitryptiline, doxepin
- Immunosuppressants
- Biologics-Dupixent
- Small molecule inhibitors-JAK inhibitors
- Opioid modulators- naltrexone, naloxone
- UV
- SSRIs-sertraline for cholestatic pruritus, mirtazapine
- Bile acid sequestrants-Cholestyramine
- Antibiotics-Rifampin
- Thalidomide
- Anti-convulsants: Gabapentin, pregabalin
- Neurokinin-1 inhibitors
Name 3 opioid modulator treatments for itch
Naltrexone ( u opioid antagonist)
Naloxone: intravenous infusion of 1 ug/ mL naloxone (u opioid antagonist) for 8 hours a day can also reduce itch from various etiologies
Difelikefalin (k agonist)
Intranasal butorphanol (u antagonist and k agonist)
What is the treatment of choice for uremic pruritus: mild, moderate, severe?
Mild: Topical anesthetics
Moderate: gabapentinoids +- UV
Severe: Opioid modulators (e.g. naltrexone)
What is the treatment of choice for cholestatic pruritus: mild, moderate, severe?
Mild: Cholestyramine
Moderate: Rifapmin
Severe: Opioid modulators
What is the treatment of choice for cholestatic pruritus: mild, moderate, severe?
Mild: Cholestyramine
Moderate: Rifapmin
Severe: Opioid modulators +- uv +- sertraline
Treatment of choice for neuropathic itch?
Mild: Capsaicin, topical anesthetics, TLAK
Moderate: Gabapentionoids, TCAs
Severe: Opioid neuromodulators
Name 5 treatments for aquagenic pruritus
Capsaicin
Betablockers
Phototherapy
Opioid modulators
