Psyconeurodermatology Flashcards
Which growth factor is involved in supporting survival and outgrowth of sensory fibers?
Neurotrophin-4
There an increase in intraepidermal fibers in both atopic humans and dogs.
The skin is equipped with a dense network of highly specialized afferent ____ and efferent _____ nerve braches that can be found in all skin layers.
sensory
autonomic
What are the main functions of the cutaneous nervous system?
Sensory: touch, heat, cold, pressure, pain and itch
Motor: control vasomotor tonus, regulate the secretory activities of glands
What is the general anatomy of the cutaneous nervous system?
- Cutaneous nerve trunks carry myelinated postganglionic sympathetic fibers
- Stained by methylene blue staining, metallic impregnation
Dermatome
the area of skin supplied by the branches of one spinal nerve
Describe autonomic nervous innervation?
- Autonomic (sympathetic) nerves represent only a minority of cutaneous fibers innervating eccrine, apocrine, and sebaceous glands, hair follicles, hair erector muscles, and blood vessels.
- On activation, they release acethylocholine (Ach) and norepinephrine, which activate the target cells via muscarinic and catecholamine receptors.
Cutaneous sensation consists of?
Sensory nerves and receptors.
Sensory nerves surround hair follicles as well as encapsulated structures such as Pacini’s corpuscle, Meissners corpuscle, and Ruffinis corpuscle
Sensory nerves are derived from _____ and are present in all parts of the skin
dorsal root ganglion neurons
What are pencillate nerve endings?
Sensory nerves that end as free nerve endings
Arise from the terminal Schwann cell in the dermis as tuftlike structures and give rise to an arborizating network of fine nerves, and they terminate either subepidermnally or intraepidermally
• Unmyelinated
• Limited to the skin, mucous membranes, and cornea
On the basis of properties of afferent units, somatosensory activity can be subdivided into what three categories?
nociceptors, thermoreceptors, and mechanoreceptors:
Nociceptors:
involved in itch and pain; supplied by A, and C fibers
Mechanoreceptor units
4 types with A axons in most skin regions
Pacinian corpuscles
Rapidly adapting units
Within haired skin
Slowly adapting Type I endings
Neuropeptides
- Neuropeptides released by cutaneous nerves in response to a variety of noxious stimuli can activate a number of target cells such as keratinocytes, mast cells and endothelial cells (upregulating VCAM – 1, expression and causing secretion of IL-8).
- Synthesized and released predominantly by a subpopulation of small neurofilament-poor (unmyelinated) afferent neurons (C fibers) designated as C-polymodal nociceptors.
Mechanoreceptor units - within haired skin
many afferent units that are excited by hair movement and have both A and A axons.
• Units driven from large hairs: A β axons
• Units driven from down hairs have A δ units
• These axons provide the major tactile input from such regions
• Guard and down hairs receive many nerve terminations of the lanceolate types
Slowly adapting Type I endings
from Merkel’s cell complexes signal about steady pressure
Slowly adapting Type II units
Associated with Ruffini endings show directional sensitivity in response to skin stretch and may play a role in propioception
List 7 neuropeptides?
substance P*(more information in pruritus)
neurokinin A
calcitonin gene-related peptide
vasoactive intestinal peptide
neuropeptide Y
somatostatin
pituitary adenylate cyclase activity peptide
Neurohormones
such as alpha-melanocyte-stimulating hormone (α-MSH) are capable of modulating a range of cellular activities; can be detected in peripheral nerves and are produced by different cell types in the skin
What is the general function of neutropeptides and neurohormones?
Function of both neuropeptides and neurohormones include: the modulation of cell proliferation, cytokine production, and cellular adhesion molecule expression
What are the 3 main neuropeptide receptors and their functions?
different types of neuropeptide receptors have been identified on the neuronal and non-neuronal cells in the skin
- NK (3 principal neurokinin receptors): bind with high affinity to substance P, NK A, and NK B; seven-transmembrane G protein-coupled peptides; detected keratinocytes and dermal endothelial cells
- CGRP (2 subtypes): Dermal microvascular endothelial cells and Langerhans cells have been reported to respond specifically to CGRP
- Melanocortin (MC) receptors: a group of 5 G protein-coupled receptors with 7 transmembrane domains; epidermal and dermal cells as well as inflammatory and immunocompetent cells exhibit high affinity for αMSH.
NK (3 principal neurokinin receptors)
bind with high affinity to substance P, NK A, and NK B; seven-transmembrane G protein-coupled peptides; detected keratinocytes and dermal endothelial cells
CGRP (2 subtypes)
Dermal microvascular endothelial cells and Langerhans cells have been reported to respond specifically to CGRP
Melanocortin (MC) receptors
a group of 5 G protein-coupled receptors with 7 transmembrane domains; epidermal and dermal cells as well as inflammatory and immunocompetent cells exhibit high affinity for αMSH.
What are two neuropeptide-degrading enzymes
Neutral endopeptidase (NEP, CD10) Carboxypeptidase angiotensin-converting enzyme (ACE):
Neutral endopeptidase (NEP, CD10)
cell membrane associated protease capable of degrading neurokinins; an important regulator in terminating neurogenic inflammation
Carboxypeptidase angiotensin-converting enzyme (ACE):
biologic effects similar to those of NEP
Neurogenic inflammation
the inflammatory response in the skin by direct electrical stimulation of sensory nerves or by stimulation of these nerves by chemical irritants, such as capsaicin, mustard oil, formalin, xylene, or hypertonic solutions.
Major consequences of neuro-inflammatory responses include vasodilatation, increased vascular permeability, and plasma leakage.
What are the two hallmarks of neurogenic inflammation?
vasodilatation and plasma leakage
Neuroanatomy species differences
Cat haired skin: unmyelinated axon, the C mechanoreceptor Equine epitrichial (apocrine) sweat glands are controlled by a β adrenergic control Small animal epitrichial sweat glands do not appear to be innervated
What are the different classifications of itch? There are 9.
- Epicritic itch a spontaneous, sharp, well-demarcated pruritus.
- Protopathic itch pruritus that is poorly localized and possesses a burning quality.
- Spontaneous itch well-localized itch at the site of itch stimulation that persists briefly after the stimulus is removed.
- Itchy skin a poorly localized area adjacent to the site of the itch stimulation that doesn’t itch spontaneously, but is hyperresponsive when exposed to a minor stimulus such as light touch
- Physiologic itch a short-lived response in skin to the common environmental stimuli that may or may not provoke scratching.
- Pathologic itch an intense skin response occurring with pathologic changes that provoke severe scratching.
- Scattered itch multiple distant areas of pruritus present in the skin following the previous stimulation of itch at one primary site.
- Referred itch development of a focal area of pruritus during scratching of the primary pruritic site. Similar to scattered itch.
- Conversion itch the change of a normal cutaneous sensory experience (like touch) to pruritus.
Pruritoceptive
induced by stimulation of the free nerve endings of the specialized C-fibers by one or more of a range of pruritogens.
Pruriceptive primary afferents-
Pruritoceptive
induced by stimulation of the free nerve endings of the specialized C-fibers by one or more of a range of pruritogens.
Pruriceptive primary afferents
When stimulated by a pruritogen, a subset of specialized unmyelinated C-fibers (originating superficially in the skin) conveys impulses to the dorsal horn of the spinal cord and then via the spinothalamic tract to the thalamus, and on to the somatoseonsory cortex.
C-fibers
- Anatomically identical to those associated with pain BUT functionally distinct
- C-fibers that mediate itch comprise about 5% of the afferent C-fibers in human skin nerves
- Respond to histamine and other pruritogens but are insensitive to mechanical stimuli.
Aδ fibers
Myelinated
Carry sensations of pain, tactile temperature, and epicritic itch (spontaneous, well-localized itch)
List itch-producing mediators in the skin
Histamine Aceytlcholine Serotonin Endopeptidase Neuropeptides Eiconsanoids Cytokines
Histamine
- Directly stimulates histamine type 1 (H1) rececptors on itch-specific C-fibers
- Causes rapid tachyphylaxis with respect to vasodilation and increased vascular permeability – as a result of the secondary release of vasoactive substances from collateral axons (specifically calcitonin gene-related peptide (CGRP) and substance P)5
- Important mediator in short-lived wheal-and-flare reactions of the urticarial type
Aceytlcholine
• Stimulates histamine-sensitive and histamine-insensitive C-fibers
Endopeptidase
• Trypsin, papain (present in the spicules of Mucuna pruriens) – cause itch
• Tyrpsin: an important component of dermal mast cells; secreted upon mast cell activation
Recent studies (2000): suggest that mast cell-dervied tryptase, by its action on proteinase-actived receptor-2 (PAR-2) contained in adjacent C neuron terminals, evokes release of pruritogenic neuropeptides by the same terminals additional pathway of itch?
• Kallikrein: a kinin-forming enzyme, the best known product of which is bradykinin
Causes predominately pain rather than itch, by a peripheral action.
Eiconsanoids
Arachidonic acid transformation products (prostaglandins, leukotrienes, and other hydroxyl fatty acids) possess powerful pro-inflammatory properties, but are not directly pruritic.
Lipoxygenase pathway – results in the formation of leukotrienes
• LTD4 and LTE4 – may cause transient burning on injection, but not pruritus.
• LTB4 – one of the most potent neutrophil chemoattractants and may cause pruritus due to recruitment of leukocytes and potentiation of other mediators.
Acts in synergy with PGD2 as mediators of inflammation.
Cyclooxygenase pathway - results in the formation of prostaglandins
• PGE1 – unable to cause pruritus by itself, but significantly lowers the pruritus threshold in human skin.
• PGE2 and PGH2 – both capable of producing pruritus but PGE2 is more potent.
Eiconsanoids
Arachidonic acid transformation products (prostaglandins, leukotrienes, and other hydroxyl fatty acids) possess powerful pro-inflammatory properties, but are not directly pruritic.
Lipoxygenase pathway – results in the formation of leukotrienes
• LTD4 and LTE4 – may cause transient burning on injection, but not pruritus.
• LTB4 – one of the most potent neutrophil chemoattractants and may cause pruritus due to recruitment of leukocytes and potentiation of other mediators.
Acts in synergy with PGD2 as mediators of inflammation.
Cyclooxygenase pathway results in the formation of prostaglandins
• PGE1 – unable to cause pruritus by itself, but significantly lowers the pruritus threshold in human skin.
• PGE2 and PGH2 – both capable of producing pruritus but PGE2 is more potent.
PGE enhance itching due to other mediators. Pretreatment of human skin by low concentrations of PGE1 lowered the threshold the treated skin to itch produced by subsequent intradermal injection of histamine at the same sites.
Apart from a subset of HIV+ patients and polycythaemia vera, NSAIDS generally have no effect on itching; benefit may relate to blocking cytokine-induced PGE2 production
Cutaneous nerves of the somatic sensory generate _____ and thus influence development, sprouting and survival of nerve fibers.
neutrotrophins.
In general, cutaneous nerve fibers are associated with what structures?
- blood vessels
- tylotrich pads
- Pacini corpuscles
- Meissner corpuscles
- Ruffini corpuscles
- Sebaceous glands
- hair follicles
- arrestor pili muslces
The motor innervation of skin is attributed to ______ fibers for the _____ nervous system.
sympathetic fibers
autonomic nervous system
Small, hairless, knoblike innervated structures are present in the haired skin of cats and dogs these are called ____ and serve as slow-adapting mechanoreceptors.
tylotrich pads
Allodynia
touch evoked pain
Alloknesis
touch-evoked itch, itchy skin
End organ
The specialized terminals of peripheral afferent nerves that transducer sensory stimuli into action potentials.
Epicritic itch
Itch that is sharp and well localized; transmitted by aδ fibers (myelinated)
Nociceptor
A somatosensory neuron activated by noxious mechanical, thermal or chemical stimuli.
Protopathic itch
Itch that is poorly localized and may have a burning quality, transmitted by C fibers (non-myelinated)
Pruritoceptive
Itching resulting from activation of peripheral nerves
Pruriceptor
A somatosensory neuron activated by pruritus stimuli
Punctuate hyperkinesis
Skin prick inducing intense itch sensation
Rapid-adapting receptor
Light-touch receptor that responds robustly at the onset of a sustained mechanical stimulus.
Slow-adapting receptor
Light-touch receptor that fires at a low level throughout a sustained mechanical stimulus.
Meissner corpuscles
Rapid adapting mechanoreceptor
Located in superficial dermis, layers of cells enfold the large leaflike ending of two to six afferent nerves, responds to vibration
