21: Neurobiology of the Skin

Question 1

What are the multiple functions of the nervous system in the skin?

Answer 1

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. Communication with immune and endocrine systems.
4. Maintaining skin homeostasis, thermoregulation, cell growth, inflammation, host defense mechanisms, apoptosis, and wound healing.
5. Involvement in maintenance of pruritus, pain, and inflammatory skin diseases (e.g., psoriasis, atopic dermatitis).

Question 2

What is the role of sensory nerve fibers in the skin?

Answer 2

• 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.

Question 3

How are the functional subgroups of sensory nerves classified?

Answer 3

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) |

Question 4

What is the significance of cutaneous C and A fibers in pruritus?

Answer 4

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.

Question 5

How does the nervous system contribute to thermoregulation in the skin?

Answer 5

The nervous system maintains skin homeostasis, including thermoregulation, through its dense cutaneous sensory and autonomic network.

Question 6

What is the significance of TRPV1 and TRPA1 ion channels in sensory nerve fibers?

Answer 6

TRPV1 mediates warmth, while TRPA1 mediates cold sensations. Both are expressed in Aδ and C fibers.

Question 7

How do autonomic nerve fibers contribute to skin conditions like hyperhidrosis?

Answer 7

Autonomic nerve fibers, composed mostly of sympathetic neurons, innervate sweat glands and are implicated in hyperhidrosis.

Question 8

How does the nervous system interact with the immune system in the skin?

Answer 8

The nervous system communicates with the immune system to maintain skin homeostasis and host defense mechanisms.

Question 9

A patient with diabetic neuropathy has skin symptoms. Which nerve fibers are likely affected?

Answer 9

Autonomic nerve fibers, which are implicated in diabetic neuropathy, may be affected.

Question 10

How do sensory nerve fibers contribute to vasodilation in the skin?

Answer 10

Sensory nerve fibers release neuropeptides like CGRP and SP, which induce vasodilation.

Question 11

What is the significance of dermatomes in sensory nerve fiber anatomy?

Answer 11

Dermatomes are well-defined segments of sensory nerve fibers that may overlap, aiding in touch and pain sensation.

Question 12

How do autonomic nerve fibers differ from sensory nerve fibers in the skin?

Answer 12

Autonomic fibers are mostly sympathetic, innervating glands and vessels, while sensory fibers mediate touch and pain.

Question 13

What is the role of Ach and VIP in autonomic nerve function?

Answer 13

Ach and VIP are released by parasympathetic neurons, influencing glandular and vascular functions.

Question 14

What are the primary functions of the nervous system in the skin?

Answer 14

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.

Question 15

How do sensory nerve fibers contribute to skin function and what are their characteristics?

Answer 15

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.

Question 16

What is the role of autonomic nerve fibers in the skin and their implications in certain conditions?

Answer 16

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).

Question 17

How do C and A fibers contribute to the sensation of pruritus?

Answer 17

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.

Question 18

What are the two subgroups of C fibers that act as pruriceptors and their characteristics?

Answer 18

1. 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)
2. 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

Question 19

What is the role of neuropeptides in the efferent function of cutaneous sensory nerves?

Answer 19

Neuropeptides and their high affinity receptors are essential for:
- Retaining tissue integrity
- Restoring tissue integrity

Question 20

How does the spinal cord contribute to the transmission of pruritus and pain?

Answer 20

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.

Question 21

What are the roles of TLR 3, 4, and 7 in pruritus transmission?

Answer 21

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

Question 22

What is the significance of IL-31 released by TH2 cells in skin diseases?

Answer 22

IL-31 released by TH2 cells is significant because it:
- Induces dermal nerve elongation and branching
- Contributes to cutaneous hyperinnervation, particularly in atopic dermatitis

Question 23

A patient with atopic dermatitis has pruritus. Which cytokine is likely involved, and what is its effect on nerves?

Answer 23

IL-31, released by TH2 cells, induces dermal nerve elongation and branching, leading to cutaneous hyperinnervation.

Question 24

What is the role of C fibers in pruritus, and how do they differ in their subgroups?

Answer 24

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.

Question 25

A patient with cholestatic pruritus is unresponsive to antihistamines. What alternative treatment could you consider?

Answer 25

Use naltrexone, a u-opioid antagonist, for cholestatic pruritus.

Question 26

A patient with atopic dermatitis shows signs of pruritus. Which neuropeptide and receptor interaction might be involved?

Answer 26

Cathepsin S, produced by gamma interferon, is associated with atopic dermatitis and interacts with PAR2 and PAR4 receptors.

Question 27

What is the role of the spinothalamic tract in pruritus?

Answer 27

The spinothalamic tract transmits both pruritus and pain, and scratching may trigger interneurons that inhibit pruritus transmission.

Question 28

A patient with psoriasis has increased levels of a specific interleukin. Which one, and what is its source?

Answer 28

IL-23, produced by dermal dendritic cells, is associated with psoriasis.

Question 29

What is the role of TLR3 in histamine-induced pruritus?

Answer 29

TLR3 boosts histamine-induced pruritus by intensifying TRPV1 activity.

Question 30

How does scratching influence pruritus transmission in the nervous system?

Answer 30

Scratching may activate interneurons that inhibit pruritus transmission in the spinothalamic tract.

Question 31

What is the role of u-opioids in pruritus, and how can their effects be mitigated?

Answer 31

U-opioids are analgesic but induce pruritus. Antagonists like naltrexone can mitigate their effects.

Question 32

A patient with chronic spontaneous urticaria has increased SP levels. What reaction does this cause?

Answer 32

Increased SP levels induce 'wheal and flare' reactions in chronic spontaneous urticaria.

Question 33

How do CMH fibers respond to cowhage-induced pruritus?

Answer 33

CMH fibers respond to cowhage via PAR2 and PAR4 receptors, inducing pruritus through TRPA1 activation.

Question 34

What is the role of TLR4 in pruritus transmission?

Answer 34

TLR4 acts as an innate sensor in the immune system, contributing to pruritus transmission.

Question 35

How does IL-31 contribute to cutaneous hyperinnervation?

Answer 35

IL-31 induces dermal nerve elongation and branching, leading to increased nerve density.

Question 36

What is the role of CGRP in chronic spontaneous urticaria?

Answer 36

CGRP contributes to 'wheal and flare' reactions in chronic spontaneous urticaria.

Question 37

How do K-opioids differ from u-opioids in their effects on pruritus?

Answer 37

K-opioids are both analgesic and antipruritic, while u-opioids are analgesic but induce pruritus.

Question 38

How does the nervous system influence inflammatory skin diseases like psoriasis?

Answer 38

The nervous system releases neuropeptides like SP and CGRP, which contribute to inflammation in psoriasis.

Question 39

What is the role of PAR2 and PAR4 in pruritus?

Answer 39

PAR2 and PAR4 mediate pruritus induced by cowhage and cathepsin S.

Question 40

What are the two subgroups of C fibers that act as pruriceptors and their primary functions?

Answer 40

1. **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). 2. **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.

Question 41

How do neuropeptides and their receptors contribute to the function of cutaneous sensory nerves?

Answer 41

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.

Question 42

What role do TLRs play in the neurobiology of pruritus?

Answer 42

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.

Question 43

What is the significance of IL-31 in the context of atopic dermatitis?

Answer 43

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.

Question 44

How do U-opioids and K-opioids differ in their effects on pruritus?

Answer 44

| 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 |

Question 45

How does the spinal cord contribute to the transmission of pruritus and pain?

Answer 45

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.

Question 46

What are the classifications of chronic pruritus according to the International Forum for the Study of Itch (IFSI)?

Answer 46

Chronic pruritus is classified into three groups by the IFSI: 1. **IFSI Group 1**: Pruritus on inflamed skin - requires skin biopsy. 2. **IFSI Group 2**: Pruritus on seemingly normal skin - requires lab workups. 3. **IFSI Group 3**: Pruritus accompanied by chronic scratch lesions - requires skin biopsy and lab workups.

Question 47

What are some elementary measures for the therapeutic approach to pruritus?

Answer 47

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.

Question 48

What are the potential treatments for pruritus of known etiology?

Answer 48

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.

Question 49

What is the significance of the 'itch-scratch cycle' in pruritus?

Answer 49

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.

Question 50

What are some new drugs currently in clinical trials for pruritus?

Answer 50

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.

Question 51

A patient presents with chronic pruritus lasting over 6 weeks. What diagnostic steps would you take if the skin appears inflamed?

Answer 51

Perform a skin biopsy as per the International Forum for the Study of Itch (IFSI) Group 1 classification.

Question 52

How would you manage a patient with neuropathic pruritus?

Answer 52

Use gabapentinoids for targeted therapy, and consider capsaicin for symptomatic relief.

Question 53

What neuropeptides are involved in wound healing, and what are their specific roles?

Answer 53

BDNF aids in wound contraction, NGF promotes nerve regeneration and fibroblast differentiation, and SP supports collagen maturation and remodeling.

Question 54

What therapeutic approach would you use for pruritus of unknown origin?

Answer 54

Symptomatic therapy, such as topical calcineurin inhibitors, capsaicin, or local anesthetics, can be used.

Question 55

What is the role of neuropeptides like CGRP in skin physiology?

Answer 55

CGRP is involved in angiogenesis and vasodilation, contributing to vascular reactions in the skin.

Question 56

What is the mechanism of action of NK1R antagonists in pruritus treatment?

Answer 56

NK1R antagonists block substance P signaling, which is involved in inflammatory dermatoses and pruritus.

Question 57

What is the role of IL-31R antagonists in treating atopic dermatitis?

Answer 57

IL-31R antagonists block the effects of IL-31, reducing nerve elongation and pruritus in atopic dermatitis.

Question 58

What is the role of neurotrophin-3 in skin physiology?

Answer 58

Neurotrophin-3 is involved in nerve regeneration, aiding in tissue repair.

Question 59

How does the nervous system contribute to wound healing?

Answer 59

The nervous system releases neuropeptides like BDNF and NGF, which aid in wound contraction and fibroblast differentiation.

Question 60

How does the 'itch-scratch cycle' perpetuate pruritus?

Answer 60

The cycle involves automatic scratching behavior, which persists even after the original cause of pruritus is eliminated.

Question 61

What is the role of SP in collagen remodeling?

Answer 61

SP supports collagen maturation and remodeling, aiding in tissue repair.

Question 62

How do antihistamines help in managing pruritus?

Answer 62

Antihistamines block histamine signaling, reducing pruritus symptoms.

Question 63

What are the types of sensory nerve fibers involved in itch transmission and their characteristics?

Answer 63

| 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 |

Question 64

What is the role of TRPV1-targeting topical agents in pruritus treatment?

Answer 64

TRPV1-targeting agents reduce pruritus by modulating ion channel activity involved in warmth sensation.

Question 65

What are the roles of C-fiber subgroups in itch transmission and how do they relate to the development of topical agents?

Answer 65

C-fiber subgroups play crucial roles in itch transmission: 1. **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**. 2. **Topical Agents**: Targeting **TRPV1**, **tyrosine receptor kinase A**, and **nerve growth factor receptor** is being developed to modulate these pathways and alleviate itch.

Question 66

What are the roles of C-fiber subgroups in itch transmission?

Answer 66

C-fiber subgroups play crucial roles in itch transmission, including: 1. **C_h (C-hair)**: Activated by **histamine**, expresses **H1R**, **TRPV1**, involved in **itch** sensation. 2. **C_MH (C-mechano-sensitive)**: Activated by **cowhage**, expresses **TRPV1**, **TRPA1**, **PAR2**, **MrgprD**, associated with **puritus** and **pain**.

Question 67

What is the role of Histamine in pruritus?

Answer 67

Histamine is associated with the **Histamine H1 receptor** and is involved in **urticaria**. It generates action potential via **TRPV1**.

Question 68

How does Serotonin contribute to pruritus?

Answer 68

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**.

Question 69

What mediators are associated with cholestatic pruritus?

Answer 69

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.

Question 70

What are the classifications of chronic pruritus?

Answer 70

Chronic pruritus can be classified into: 1. **Pruritus on normal skin** 2. **Pruritus on inflamed skin** 3. **Pruritus with chronic scratch lesions** These further divide into **Dermatologic**, **Systemic**, **Neurologic**, **Somatoform**, and **Unknown** categories.

Question 71

What is the role of Substance P in pruritus?

Answer 71

**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.

Question 72

What is the assumed clinical role of Thymic stromal lymphopoietin (TSLP) in pruritus?

Answer 72

**Thymic stromal lymphopoietin (TSLP)** is associated with the **TSLP receptor** and is implicated in conditions such as atopic dermatitis, allergic asthma, and seborrheic dermatitis.

Question 73

What are the steps involved in the therapeutic approach to chronic pruritus?

Answer 73

The therapeutic approach to chronic pruritus involves the following steps: 1. **Elementary measures**: Use of emollients, antihistamines, avoidance of allergens. 2. **Targeted therapy** (if cause is known). 3. **Symptomatic therapy** (if cause is unknown or refractory pruritus). 4. **Treatment of accompanying disorders**: Addressing sleep disorders, managing reactive depression.

Question 74

How does the approach to treating chronic pruritus differ when the cause is known versus unknown?

Answer 74

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.