21: Neurobiology of the Skin Flashcards
What are the multiple functions of the nervous system in the skin?
- Collecting and transmitting environmental information on touch, pain, pruritus, and temperature to the brain.
- Reacting to ligands that induce nerve activation by the antidromic release of neuropeptides and initiation of vascular and inflammatory reactions.
- Communication with immune and endocrine systems.
- Maintaining skin homeostasis, thermoregulation, cell growth, inflammation, host defense mechanisms, apoptosis, and wound healing.
- Involvement in maintenance of pruritus, pain, and inflammatory skin diseases (e.g., psoriasis, atopic dermatitis).
What is the role of sensory nerve fibers in the skin?
- Arranged into well-defined segments called dermatomes, but may overlap.
- Free nerve endings are found in the epidermis and papillary dermis.
- Located in close proximity to keratinocytes, melanocytes, Langerhans cells, and Merkel cells.
- Essential for vasodilation.
How are the functional subgroups of sensory nerves classified?
Sensory nerves are classified based on:
Type of Fiber | Characteristics | Function |
|————–|—————-|———-|
| Aβ fibers | Myelinated to moderate degree (6-12 µm) | Stimulate touch receptors |
| Aδ fibers | Thin myelinated (1-5 µm), conduction velocity 4-30 m/s | Mediate cold and quick pain sensations, pressure, pruritus; express TRPV1 (warmth) vs TRPA1 (cold) |
| C fibers | Nonmyelinated (0.2 to 1.5 µm), slow conduction velocity 0.5 to 2.0 m/s | Mediate burning, pain, pruritus, warmth, and touch; express TRPV1 (warmth) |
What is the significance of cutaneous C and A fibers in pruritus?
Cutaneous C and A fibers play a crucial role in mediating pruritus by:
- C fibers mediate burning, pain, pruritus, warmth, and touch.
- Aδ fibers mediate cold and quick pain sensations, pressure, and pruritus.
- Both types of fibers express specific TRP ion channels that are involved in the sensation of warmth and cold, contributing to the overall experience of pruritus.
How does the nervous system contribute to thermoregulation in the skin?
The nervous system maintains skin homeostasis, including thermoregulation, through its dense cutaneous sensory and autonomic network.
What is the significance of TRPV1 and TRPA1 ion channels in sensory nerve fibers?
TRPV1 mediates warmth, while TRPA1 mediates cold sensations. Both are expressed in Aδ and C fibers.
How do autonomic nerve fibers contribute to skin conditions like hyperhidrosis?
Autonomic nerve fibers, composed mostly of sympathetic neurons, innervate sweat glands and are implicated in hyperhidrosis.
How does the nervous system interact with the immune system in the skin?
The nervous system communicates with the immune system to maintain skin homeostasis and host defense mechanisms.
A patient with diabetic neuropathy has skin symptoms. Which nerve fibers are likely affected?
Autonomic nerve fibers, which are implicated in diabetic neuropathy, may be affected.
How do sensory nerve fibers contribute to vasodilation in the skin?
Sensory nerve fibers release neuropeptides like CGRP and SP, which induce vasodilation.
What is the significance of dermatomes in sensory nerve fiber anatomy?
Dermatomes are well-defined segments of sensory nerve fibers that may overlap, aiding in touch and pain sensation.
How do autonomic nerve fibers differ from sensory nerve fibers in the skin?
Autonomic fibers are mostly sympathetic, innervating glands and vessels, while sensory fibers mediate touch and pain.
What is the role of Ach and VIP in autonomic nerve function?
Ach and VIP are released by parasympathetic neurons, influencing glandular and vascular functions.
What are the primary functions of the nervous system in the skin?
The nervous system of the skin has multiple functions including:
1. Collecting and transmitting environmental information on touch, pain, pruritus, and temperature to the brain.
2. Reacting to ligands that induce nerve activation by the antidromic release of neuropeptides and initiation of vascular and inflammatory reactions.
3. Communicating with immune and endocrine systems.
4. Maintaining skin homeostasis, thermoregulation, cell growth, inflammation, host defense mechanisms, apoptosis, and wound healing.
5. Involvement in the maintenance of pruritus, pain, and inflammatory skin diseases such as psoriasis and atopic dermatitis.
How do sensory nerve fibers contribute to skin function and what are their characteristics?
Sensory nerve fibers are essential for skin function and have the following characteristics:
- Arranged into well-defined segments called dermatomes, but may overlap.
- Free nerve endings are found in the epidermis and papillary dermis.
- Located in close proximity to keratinocytes, melanocytes, Langerhans cells, and Merkel cells.
- Essential for vasodilation.
- Subgroups include:
- Aβ fibers: Myelinated, stimulate touch receptors.
- Aδ fibers: Thin myelinated, mediate cold and quick pain sensations, pressure, and pruritus.
- C fibers: Nonmyelinated, mediate burning, pain, pruritus, warmth, and touch.
What is the role of autonomic nerve fibers in the skin and their implications in certain conditions?
Autonomic nerve fibers play a crucial role in the skin and have the following implications:
- Comprise a smaller fraction of cutaneous nerve fibers.
- Innervate skin through a sequential two-neuron pathway.
- Do not innervate the mammalian epidermis.
- Composed mainly of sympathetic neurons that innervate blood vessels, apocrine glands, lymphatic vessels, erector pili muscles, eccrine glands, and hair follicles.
- Implicated in conditions such as hyper/hypo-hidrosis, diabetic neuropathy, complex regional pain syndrome, and syringomyelia.
- Release noradrenaline or neuropeptide Y (NPY) by the sympathetic nervous system (SNS) and acetylcholine (ACh) or vasoactive intestinal peptide (VIP) by the parasympathetic nervous system (PNS).
How do C and A fibers contribute to the sensation of pruritus?
C and A fibers contribute to the sensation of pruritus in the following ways:
- C fibers: Nonmyelinated, slow conduction velocity (0.5 to 2.0 m/s), mediate sensations of burning, pain, pruritus, warmth, and touch. They express the TRPV1 ion channel, which mediates warmth.
- Aδ fibers: Thin myelinated, faster conduction velocity (4-30 m/s), mediate cold and quick pain sensations, pressure, and pruritus. They express the TRPV1 ion channel for warmth and TRPA1 for cold.
Both fiber types are essential for the perception of pruritus and play distinct roles in the sensory experience of the skin.
What are the two subgroups of C fibers that act as pruriceptors and their characteristics?
-
C MIA (C mechanoinsensitive afferences)
- Responds to histamine signaling through phospholipase B3 and ion channel TRPV1
- TLR3 boosts histamine-induced pruritus by intensifying TRPV1 activity
- Insensitive to mechanical stimuli
- Activation can release vasoactive neuropeptides (SP, CGRP)
-
CMH (C mechano-heat sensitive)
- Responds to cowhage via PAR2 and PAR4
- Cowhage is homologous to cathepsin S, associated with atopic dermatitis
- Responsive to heat and mechanical stimuli
- Responds to Mrgprs and induces pruritus via TRPA1
What is the role of neuropeptides in the efferent function of cutaneous sensory nerves?
Neuropeptides and their high affinity receptors are essential for:
- Retaining tissue integrity
- Restoring tissue integrity
How does the spinal cord contribute to the transmission of pruritus and pain?
The spinal cord, through the spinothalamic tract, transmits both pruritus and pain. It is speculated that scratching may trigger interneurons that modulate pain, potentially inhibiting systems that conduct pruritus transmission.
What are the roles of TLR 3, 4, and 7 in pruritus transmission?
TLR 3, 4, and 7 serve as innate sensors in the immune system and play a role in pruritus transmission, including conditions such as:
- Chloroquine-induced pruritus
- Endothelin-1
- Imiquimod pruritus
- Mrgprs agonists
What is the significance of IL-31 released by TH2 cells in skin diseases?
IL-31 released by TH2 cells is significant because it:
- Induces dermal nerve elongation and branching
- Contributes to cutaneous hyperinnervation, particularly in atopic dermatitis
A patient with atopic dermatitis has pruritus. Which cytokine is likely involved, and what is its effect on nerves?
IL-31, released by TH2 cells, induces dermal nerve elongation and branching, leading to cutaneous hyperinnervation.
What is the role of C fibers in pruritus, and how do they differ in their subgroups?
C fibers mediate burning, pain, pruritus, warmth, and touch. CMIA fibers respond to histamine signaling and are insensitive to mechanical stimuli, while CMH fibers respond to cowhage and mechanical stimuli.
A patient with cholestatic pruritus is unresponsive to antihistamines. What alternative treatment could you consider?
Use naltrexone, a u-opioid antagonist, for cholestatic pruritus.
A patient with atopic dermatitis shows signs of pruritus. Which neuropeptide and receptor interaction might be involved?
Cathepsin S, produced by gamma interferon, is associated with atopic dermatitis and interacts with PAR2 and PAR4 receptors.
What is the role of the spinothalamic tract in pruritus?
The spinothalamic tract transmits both pruritus and pain, and scratching may trigger interneurons that inhibit pruritus transmission.
A patient with psoriasis has increased levels of a specific interleukin. Which one, and what is its source?
IL-23, produced by dermal dendritic cells, is associated with psoriasis.
What is the role of TLR3 in histamine-induced pruritus?
TLR3 boosts histamine-induced pruritus by intensifying TRPV1 activity.
How does scratching influence pruritus transmission in the nervous system?
Scratching may activate interneurons that inhibit pruritus transmission in the spinothalamic tract.
What is the role of u-opioids in pruritus, and how can their effects be mitigated?
U-opioids are analgesic but induce pruritus. Antagonists like naltrexone can mitigate their effects.
A patient with chronic spontaneous urticaria has increased SP levels. What reaction does this cause?
Increased SP levels induce ‘wheal and flare’ reactions in chronic spontaneous urticaria.
How do CMH fibers respond to cowhage-induced pruritus?
CMH fibers respond to cowhage via PAR2 and PAR4 receptors, inducing pruritus through TRPA1 activation.
What is the role of TLR4 in pruritus transmission?
TLR4 acts as an innate sensor in the immune system, contributing to pruritus transmission.
How does IL-31 contribute to cutaneous hyperinnervation?
IL-31 induces dermal nerve elongation and branching, leading to increased nerve density.
What is the role of CGRP in chronic spontaneous urticaria?
CGRP contributes to ‘wheal and flare’ reactions in chronic spontaneous urticaria.
How do K-opioids differ from u-opioids in their effects on pruritus?
K-opioids are both analgesic and antipruritic, while u-opioids are analgesic but induce pruritus.
How does the nervous system influence inflammatory skin diseases like psoriasis?
The nervous system releases neuropeptides like SP and CGRP, which contribute to inflammation in psoriasis.
What is the role of PAR2 and PAR4 in pruritus?
PAR2 and PAR4 mediate pruritus induced by cowhage and cathepsin S.
What are the two subgroups of C fibers that act as pruriceptors and their primary functions?
- C MIA (C mechanoinsensitive afferences): Responds to histamine signaling through phospholipase B3 and ion channel TRPV1. TLR3 boosts histamine-induced pruritus by intensifying TRPV1 activity. Insensitive to mechanical stimuli. Activation can release vasoactive neuropeptides (SP, CGRP).
- CMH (C mechano-heat sensitive): Responds to cowhage via PAR2 and PAR4. Cowhage is homologous to cathepsin S, associated with atopic dermatitis. Responsive to heat and mechanical stimuli. Induces pruritus via TRPA1.
How do neuropeptides and their receptors contribute to the function of cutaneous sensory nerves?
Neuropeptides and their high affinity receptors are essential for retaining and restoring tissue integrity. They play a crucial role in the communication between sensory nerves and the immune system, influencing pruritus and pain transmission.
What role do TLRs play in the neurobiology of pruritus?
TLRs (Toll-like receptors) 3, 4, and 7 serve as innate sensors in the immune system and are involved in pruritus transmission by detecting various stimuli that can induce pruritus, such as chlorquine, endothelin-1, and imiquimod, and interacting with Mas-related GPCRs (Mrgprs) to mediate pruritus responses.
What is the significance of IL-31 in the context of atopic dermatitis?
IL-31, released by TH2 cells, is significant because it induces dermal nerve elongation and branching, contributing to cutaneous hyperinnervation, which is associated with the pathophysiology of atopic dermatitis.
How do U-opioids and K-opioids differ in their effects on pruritus?
Type of Opioid | Effect on Pruritus | Additional Notes |
|—————-|——————-|——————|
| U-opioids | Analgesic, but induces pruritus | Isoforms include GRPR and MOR1D; Antagonists like Naltrexone for cholestatic pruritus |
| K-opioids | Analgesic, antipruritic | Agonists like Nalfurafine for cholestatic pruritus |
How does the spinal cord contribute to the transmission of pruritus and pain?
The spinal cord, specifically the spinothalamic tract, transmits both pruritus and pain. It is speculated that scratching may trigger interneurons that modulate pain, potentially inhibiting systems that conduct pruritus transmission, thus affecting the perception of itch and pain.
What are the classifications of chronic pruritus according to the International Forum for the Study of Itch (IFSI)?
Chronic pruritus is classified into three groups by the IFSI:
- IFSI Group 1: Pruritus on inflamed skin - requires skin biopsy.
- IFSI Group 2: Pruritus on seemingly normal skin - requires lab workups.
- IFSI Group 3: Pruritus accompanied by chronic scratch lesions - requires skin biopsy and lab workups.
What are some elementary measures for the therapeutic approach to pruritus?
Elementary measures include:
- Emollients to prevent xerosis.
- Avoiding allergens and irritating substances.
- Antihistamines to alleviate symptoms.
- Ointments with antipruritic compounds, such as urea, menthol, and polidocanol.
What are the potential treatments for pruritus of known etiology?
For pruritus of known etiology, targeted therapy may include:
- Immunosuppressive drugs (e.g., cyclosporine) for atopic dermatitis.
- Gabapentinoids for neuropathic pruritus.
- Antidepressants (e.g., paroxetine) for paraneoplastic pruritus.
What is the significance of the ‘itch-scratch cycle’ in pruritus?
The ‘itch-scratch cycle’ refers to the phenomenon where patients feel an urge to scratch, leading to automatic scratching behavior, even when the pruritus is no longer present. This cycle can perpetuate the sensation of itch and complicate treatment.
What are some new drugs currently in clinical trials for pruritus?
New drugs in Phase II clinical trials for pruritus include:
- NK1R antagonists for inflammatory dermatoses, prurigo nodularis, cutaneous T cell lymphoma, and epidermolysis bullosa.
- IL 31R antagonist for atopic dermatitis.
A patient presents with chronic pruritus lasting over 6 weeks. What diagnostic steps would you take if the skin appears inflamed?
Perform a skin biopsy as per the International Forum for the Study of Itch (IFSI) Group 1 classification.
How would you manage a patient with neuropathic pruritus?
Use gabapentinoids for targeted therapy, and consider capsaicin for symptomatic relief.
What neuropeptides are involved in wound healing, and what are their specific roles?
BDNF aids in wound contraction, NGF promotes nerve regeneration and fibroblast differentiation, and SP supports collagen maturation and remodeling.
What therapeutic approach would you use for pruritus of unknown origin?
Symptomatic therapy, such as topical calcineurin inhibitors, capsaicin, or local anesthetics, can be used.
What is the role of neuropeptides like CGRP in skin physiology?
CGRP is involved in angiogenesis and vasodilation, contributing to vascular reactions in the skin.
What is the mechanism of action of NK1R antagonists in pruritus treatment?
NK1R antagonists block substance P signaling, which is involved in inflammatory dermatoses and pruritus.
What is the role of IL-31R antagonists in treating atopic dermatitis?
IL-31R antagonists block the effects of IL-31, reducing nerve elongation and pruritus in atopic dermatitis.
What is the role of neurotrophin-3 in skin physiology?
Neurotrophin-3 is involved in nerve regeneration, aiding in tissue repair.
How does the nervous system contribute to wound healing?
The nervous system releases neuropeptides like BDNF and NGF, which aid in wound contraction and fibroblast differentiation.
How does the ‘itch-scratch cycle’ perpetuate pruritus?
The cycle involves automatic scratching behavior, which persists even after the original cause of pruritus is eliminated.
What is the role of SP in collagen remodeling?
SP supports collagen maturation and remodeling, aiding in tissue repair.
How do antihistamines help in managing pruritus?
Antihistamines block histamine signaling, reducing pruritus symptoms.
What are the types of sensory nerve fibers involved in itch transmission and their characteristics?
Nerve Fiber Type | Diameter (μm) | Conduction Velocity (m/s) | Characteristics |
|——————|—————-|————————–|—————–|
| Aδ fibers | 1-5 | 5-30 | Express TRPV1, Puritus + pain |
| C fibers | 0.2-1.5 | 0.5-2 | Activated by histamine, express H1R, TRPV1, Puritus |
| CMH fibers | 6-12 | 1-5 | Polymodal nociceptors, activated by cowhage, express TRPV1, TRPA1, PAR2, 4MGR |
| C fibers (itch) | 0.2-1.5 | 0.5-2 | Respond to cowhage, express TRPV1, TRPA1, PAR2, 4MGR |
What is the role of TRPV1-targeting topical agents in pruritus treatment?
TRPV1-targeting agents reduce pruritus by modulating ion channel activity involved in warmth sensation.
What are the roles of C-fiber subgroups in itch transmission and how do they relate to the development of topical agents?
C-fiber subgroups play crucial roles in itch transmission:
-
C-fiber Types:
- C_h (C-hair): Activated by histamine. Expresses H1R, TRPV1. Involved in itch sensation.
- CMH fibers: Respond to coughing and express TRPV1, TRPA1, PAR2, Mrgpr. Associated with puritus and pain.
- Topical Agents: Targeting TRPV1, tyrosine receptor kinase A, and nerve growth factor receptor is being developed to modulate these pathways and alleviate itch.
What are the roles of C-fiber subgroups in itch transmission?
C-fiber subgroups play crucial roles in itch transmission, including:
- C_h (C-hair): Activated by histamine, expresses H1R, TRPV1, involved in itch sensation.
- C_MH (C-mechano-sensitive): Activated by cowhage, expresses TRPV1, TRPA1, PAR2, MrgprD, associated with puritus and pain.
What is the role of Histamine in pruritus?
Histamine is associated with the Histamine H1 receptor and is involved in urticaria. It generates action potential via TRPV1.
How does Serotonin contribute to pruritus?
Serotonin acts on the 5-HT2 receptor and is linked to atopic dermatitis, prurigo nodularis, and conditions with increased serum levels. It generates action potential via TRPA1.
What mediators are associated with cholestatic pruritus?
The mediators associated with cholestatic pruritus include Bile acids acting on the IgD receptor and Autotaxin/lysophosphatidic acid (LPA) acting on the LPA receptor. Both generate action potential via TRPV1 and TRPA1 respectively.
What are the classifications of chronic pruritus?
Chronic pruritus can be classified into:
- Pruritus on normal skin
- Pruritus on inflamed skin
- Pruritus with chronic scratch lesions
These further divide into Dermatologic, Systemic, Neurologic, Somatoform, and Unknown categories.
What is the role of Substance P in pruritus?
Substance P is involved in the generation of action potentials on sensory nerves and is associated with the Neurokinin-1 receptor (NK1R). It plays a role in conditions such as atopic dermatitis and prurigo nodularis.
What is the assumed clinical role of Thymic stromal lymphopoietin (TSLP) in pruritus?
Thymic stromal lymphopoietin (TSLP) is associated with the TSLP receptor and is implicated in conditions such as atopic dermatitis, allergic asthma, and seborrheic dermatitis.
What are the steps involved in the therapeutic approach to chronic pruritus?
The therapeutic approach to chronic pruritus involves the following steps:
- Elementary measures: Use of emollients, antihistamines, avoidance of allergens.
- Targeted therapy (if cause is known).
- Symptomatic therapy (if cause is unknown or refractory pruritus).
- Treatment of accompanying disorders: Addressing sleep disorders, managing reactive depression.
How does the approach to treating chronic pruritus differ when the cause is known versus unknown?
When the cause of chronic pruritus is known, the approach includes Targeted therapy aimed at the specific cause. If the cause is unknown, the approach involves Symptomatic therapy to alleviate symptoms without addressing the underlying cause, along with elementary measures and treatment of accompanying disorders.
