pathophysiology of itch

Pathophysiology andPathophysiology andClinical Aspects of PruritusClinical Aspects of Pruritus

Dr Mesfin HunegnawDr Mesfin Hunegnaw

Consultant Dermatologist & VenerologistConsultant Dermatologist & Venerologist

AAU, Medical facultyAAU, Medical faculty

Dept. of DermtovenerologyDept. of Dermtovenerology

Defn: Defn: Itch: A sensation that brings a desire to scratch.Itch: A sensation that brings a desire to scratch. Prurigo:Prurigo:

Defn… Defn…

Spontaneous itch:Spontaneous itch: Itchy skin: Itchy skin: AlloknesisAlloknesis: : These two qualities of itch are served by rapidly These two qualities of itch are served by rapidly

conducting (A delta) and slowly conducting (C) fibers. conducting (A delta) and slowly conducting (C) fibers.

The main difficulties: lack of reproducible, standardized The main difficulties: lack of reproducible, standardized itch stimuli and itch stimuli and

Absence of satisfactory methods for statistically Absence of satisfactory methods for statistically analyzable quantification.analyzable quantification.

Medical, social effect.Medical, social effect.

The characteristic of itch is that the only peripheral The characteristic of itch is that the only peripheral tissue from which it can be evoked is skin. tissue from which it can be evoked is skin.

Itch Originating From Nerves in the Skin:Itch Originating From Nerves in the Skin: Injected itch-producing substances Injected itch-producing substances Maximal itch production at the basal cell layer. Maximal itch production at the basal cell layer. Denervation,Denervation, Capsiacin,Capsiacin, Cuff,Cuff, Stripping…Stripping…

Types of itch:Types of itch:

1-Pruriceptive,1-Pruriceptive,

3-Neuropatic, 3-Neuropatic,

3-Neurogenic, central3-Neurogenic, central

4-psychogenic4-psychogenic

Itch-Producing Chemicals in the SkinItch-Producing Chemicals in the Skin

1-Histamine 1-Histamine 2-Endopeptidases: Trypsin or papain.

3-Biogenic amines and kinins: Serotonin, bradykinin, 3-Biogenic amines and kinins: Serotonin, bradykinin, kallidin & kallikrein.kallidin & kallikrein.

4-U4-Unmyelinated fibers that contain peptides, which nmyelinated fibers that contain peptides, which are released on stimulation.are released on stimulation.

Some substances do not themselves produce itch but Some substances do not themselves produce itch but exaggerate ongoing itch; exaggerate ongoing itch; prostaglandins are examples.prostaglandins are examples.

5-Opiates5-Opiates have both a central and a peripheral itch-have both a central and a peripheral itch-producing action.producing action.

Externally applied factors that cause itch:Externally applied factors that cause itch:

PhysicalPhysical: Light touch, stroking, vibration, mild heat: Light touch, stroking, vibration, mild heat Electrical,Electrical, Chemical:Chemical: Histamin, Histamin liberators (Morphine, Histamin, Histamin liberators (Morphine,

codeine substance 48/80, serotonin, PAF, kalkerin, IL-2, codeine substance 48/80, serotonin, PAF, kalkerin, IL-2, Proteases, Substance P, PGs, CGRP, Opioid peptides…Proteases, Substance P, PGs, CGRP, Opioid peptides…

Emotional:Emotional:

Central Mechanisms of Itch:Central Mechanisms of Itch:o Why is itch specific to skin and not deep tissue? Why is itch specific to skin and not deep tissue? o Why have no specific itch fibers been detected? Why have no specific itch fibers been detected? o Why does itch require the presence of C fibers? Why does itch require the presence of C fibers? o Why does itch respond to scratching? Why does itch respond to scratching? o Why is itch socially infectious?Why is itch socially infectious?

Surround inhibition:Surround inhibition:LLocalization. ocalization.

Sensory pathways of highly effective surround inhibition. Sensory pathways of highly effective surround inhibition.

mild electrical , mild electrical ,

gentle stimuli moderate itch, gentle stimuli moderate itch, frankly painful stimuli…frankly painful stimuli…

NNeural mechanism that consists of an interplay eural mechanism that consists of an interplay between excitation at the maximum point of the stimuli between excitation at the maximum point of the stimuli and an inhibitory surround where the stimulus is and an inhibitory surround where the stimulus is smallersmaller permits precise localization of stimuli. permits precise localization of stimuli.

Surround inhibition…Surround inhibition… Small punctate stimuli are not large enough to activate Small punctate stimuli are not large enough to activate

this surround inhibition, this surround inhibition, Low-threshold mechanoreceptors, generate a tickle Low-threshold mechanoreceptors, generate a tickle that that

is abolished by enlarging the area of stimulus, i.e., by is abolished by enlarging the area of stimulus, i.e., by rubbing, which activates the surround inhibition. rubbing, which activates the surround inhibition.

If a limited group of C fibers are stimulated, a limited If a limited group of C fibers are stimulated, a limited group of dorsal horn cells fire in their exaggerated group of dorsal horn cells fire in their exaggerated fashion and produce itch. fashion and produce itch.

If a wide area, low-intensity A fiber input volley is If a wide area, low-intensity A fiber input volley is generated by rubbing or scratching, generated by rubbing or scratching, widespread widespread inhibitioninhibition results. results.

Hence:Hence: The arrival of volleys in large A fibers inhibits the The arrival of volleys in large A fibers inhibits the

response of spinal cord cells to both A and C fiber response of spinal cord cells to both A and C fiber inputs. inputs.

Scratching depolarizes by activation of suppressor Scratching depolarizes by activation of suppressor neurons of the substantiate gelatinosa and reduces the neurons of the substantiate gelatinosa and reduces the itch. itch.

Itch fibers:Itch fibers:

In humans, 5 to 10 % of the nociceptors are sensitive to In humans, 5 to 10 % of the nociceptors are sensitive to histamine.histamine.

Specific fibers to Histamin. Specific fibers to Histamin. These fibers are not specific itch fibers.These fibers are not specific itch fibers. The reason why no specific itch fibers have been The reason why no specific itch fibers have been

located is that they do not appear to exist. located is that they do not appear to exist.

Itch receptors:Itch receptors: Itch (and pain) are received by unspecialized free nerve Itch (and pain) are received by unspecialized free nerve

endings located close to DEJ. endings located close to DEJ. Itch receptors are unmyelinated, confined to the skin Itch receptors are unmyelinated, confined to the skin

and cornea, and cornea, Are members of the polymodal nociceptor class.Are members of the polymodal nociceptor class.

Neuropathophysiology: Neuropathophysiology:

Itch occurs as one of the transmission states of the Itch occurs as one of the transmission states of the somatosensory system. somatosensory system.

It’s initiated by the arrival of volleys in C fibers It’s initiated by the arrival of volleys in C fibers originating from skin. originating from skin.

PATHO…PATHO…

Direct Vs indirect nociceptor activation:Direct Vs indirect nociceptor activation: In primary (direct) activation of nociceptor C neurons, In primary (direct) activation of nociceptor C neurons,

cell damage by stimulus induces lower pH, potassium cell damage by stimulus induces lower pH, potassium release, and synthesis of prostaglandins.release, and synthesis of prostaglandins.

PATHO…PATHO…

In secondary activation, impulses generated in the In secondary activation, impulses generated in the stimulated terminal propagate not only to the spinal stimulated terminal propagate not only to the spinal cord but also to other terminal branches, where they cord but also to other terminal branches, where they induce release of substance P. induce release of substance P.

PATHO…PATHO…

Substance P activates mast cells via (NK-1) receptors. Substance P activates mast cells via (NK-1) receptors. Mast cells release histamine, which causes pruritus via Mast cells release histamine, which causes pruritus via

neuronal Hneuronal H11 receptors as well TNF-α, and tryptase. receptors as well TNF-α, and tryptase. TNF-α augments activated nociceptor C neurons, and TNF-α augments activated nociceptor C neurons, and

tryptase, by its action on C fiber terminal proteinase-tryptase, by its action on C fiber terminal proteinase-activated receptor-2 (PAR-2), causes release of activated receptor-2 (PAR-2), causes release of additional substance P.additional substance P.

Above fig.Above fig.

Typical cutaneous nerve and activation of nociceptor C Typical cutaneous nerve and activation of nociceptor C neurons.neurons.

There are two categories of axons: primary afferents Aβ, Aδ, and C There are two categories of axons: primary afferents Aβ, Aδ, and C (cell bodies in dorsal root ganglion), and sympathetic (cell bodies in dorsal root ganglion), and sympathetic postganglionic fibers (cell bodies in sympathetic ganglion). postganglionic fibers (cell bodies in sympathetic ganglion).

AA In primary (direct) activation of nociceptor C neurons, cell In primary (direct) activation of nociceptor C neurons, cell damage by stimulus induces lower pH, potassium release, and damage by stimulus induces lower pH, potassium release, and synthesis of prostaglandins (the latter increasing sensitivity of synthesis of prostaglandins (the latter increasing sensitivity of neuron terminals to a number of substances). neuron terminals to a number of substances).

BB In secondary activation, impulses generated in the stimulated In secondary activation, impulses generated in the stimulated terminal propagate not only to the spinal cord but also to other terminal propagate not only to the spinal cord but also to other terminal branches, where they induce release of substance P. terminal branches, where they induce release of substance P.

CC Substance P activates mast cells via neurokinin 1 (NK-1) Substance P activates mast cells via neurokinin 1 (NK-1) receptors. Mast cells release histamine, which causes pruritus via receptors. Mast cells release histamine, which causes pruritus via neuronal H1 receptors as well as tumor necrosis factor-α (TNF-α), neuronal H1 receptors as well as tumor necrosis factor-α (TNF-α), and tryptase. and tryptase.

DD TNF-α augments activated nociceptor C neurons, and tryptase, TNF-α augments activated nociceptor C neurons, and tryptase, by its action on C fiber terminal proteinase-activated receptor-2 by its action on C fiber terminal proteinase-activated receptor-2 (PAR-2), causes release of additional substance P. (PAR-2), causes release of additional substance P.

Perception:Perception: Unmyelinated C fibres enter the dorsal horn of the grey Unmyelinated C fibres enter the dorsal horn of the grey

matter of the spinal cord, matter of the spinal cord, Synapse there with secondary neurons which cross over Synapse there with secondary neurons which cross over

to the contralateral spinothalamic tract and ascend to to the contralateral spinothalamic tract and ascend to the thalamus. the thalamus.

There, tertiary neurons relay itch to the level of There, tertiary neurons relay itch to the level of conscious perception in the cerebral cortex. conscious perception in the cerebral cortex.

Perception…Perception…

The anterior cingulate cortex (Brodman 24) in the The anterior cingulate cortex (Brodman 24) in the recognition of itch sensation at conscious levels, recognition of itch sensation at conscious levels,

The premotor cortical areas participate in intention to The premotor cortical areas participate in intention to scratch.scratch.

Itching in Pathologic StatesItching in Pathologic States Environmental and local factors influence the sensitivity Environmental and local factors influence the sensitivity

of skin to itchy stimuli. of skin to itchy stimuli. Rise in skin temperature.Rise in skin temperature. Excessive drying of the skin.Excessive drying of the skin.

I-Pruritus of Chronic Renal DiseaseI-Pruritus of Chronic Renal Disease

The pathogenesis poorly known.The pathogenesis poorly known. Excessive dryness, Excessive dryness, Dialysis causes temporary relief,Dialysis causes temporary relief, Density of mast cells, Density of mast cells, Parathormone; Parathormone; Vitamin A concentrations in skinVitamin A concentrations in skin, , AAbnormal pattern of cutaneous nervesbnormal pattern of cutaneous nerves Release of a pruritogenic factor from GIT.Release of a pruritogenic factor from GIT.

II-Pruritus in CholestasisII-Pruritus in Cholestasis Bile salts themselvesBile salts themselves Closely associated substances, Closely associated substances, Possibly opioid peptides.Possibly opioid peptides.

III-Itching in Atopic EczemaIII-Itching in Atopic Eczema Pathogenesis: controversial,Pathogenesis: controversial, Increase Density of sensory nerve fibers in itchy Increase Density of sensory nerve fibers in itchy

lichenified skin. lichenified skin. There is increased density of mast cells .There is increased density of mast cells . Acute or chronic inflammatory changes,Acute or chronic inflammatory changes, Lichenification and excessive drying (xerosis). Lichenification and excessive drying (xerosis). Itching may be influenced by higher centers in t CNS. Itching may be influenced by higher centers in t CNS.

IV-Polycythemia Vera:IV-Polycythemia Vera: Bath itch.Bath itch. No visible changes are present in the skin,No visible changes are present in the skin, Elevated Serum and skin histamine levels, Elevated Serum and skin histamine levels, Increased tissue fibrinolytic activity. Increased tissue fibrinolytic activity.

V-Pruritus in Endocrine Disease:V-Pruritus in Endocrine Disease: ThyrotoxicosisThyrotoxicosis Generalized intractable itching.Generalized intractable itching. Skin blood flow.Skin blood flow. Itching at the genital area, Itching at the genital area,

Hypothyroidism:Hypothyroidism: Dryness: the characteristic itch of myxedema.Dryness: the characteristic itch of myxedema.

DM: DM: Generalized pruritus?; Generalized pruritus?; Localized pruritus:Localized pruritus:

VI-Aquagenic Pruritus:VI-Aquagenic Pruritus: Wetting the skin with water at any temperature causes Wetting the skin with water at any temperature causes

itching with a pricking quality; itching with a pricking quality; The molecular basis of the itching is unclear.The molecular basis of the itching is unclear.

Family history in about one-third of patients, Family history in about one-third of patients, Increased mast cell degranulation. Increased mast cell degranulation. ?Acetylcholine.?Acetylcholine. Increased acetyl cholinesterase activityIncreased acetyl cholinesterase activity Increased skin fibrinolytic activity Increased skin fibrinolytic activity

Aquagenic pruritus Vs water-induced itching of Aquagenic pruritus Vs water-induced itching of the elderly?the elderly?

Pruritus of Aged Skin:Pruritus of Aged Skin: At least 50 % of persons aged 70 or over suffer At least 50 % of persons aged 70 or over suffer

extensive pruritus.extensive pruritus. Postmenopausal syndrome, it also occurs in men. Postmenopausal syndrome, it also occurs in men. Desiccation of the skinDesiccation of the skin fine cracking. fine cracking. Water-induced itching of the elderlyWater-induced itching of the elderly is a well-is a well-

defined variant of this condition.defined variant of this condition.

HIV:HIV: HIV frequently asstd. with intense itching.HIV frequently asstd. with intense itching. This may be due to scabies, pediculosis, candidiasis, or This may be due to scabies, pediculosis, candidiasis, or

seborrheic dermatitis or to systemic disease, including seborrheic dermatitis or to systemic disease, including renal or hepatic dysfunction. renal or hepatic dysfunction.

Intensely Intensely pruritic papular eruptionpruritic papular eruption that that histologically histologically shows evidence of shows evidence of eosinophilic folliculitis.eosinophilic folliculitis.

Brachioradial pruritusBrachioradial pruritus

Notalgia paresthetica,Notalgia paresthetica,

DrugsDrugs

MX:MX:General Measures:General Measures: Itching is generally heightened if the skin is warm.Itching is generally heightened if the skin is warm. Cool the skin. cooling lotions or creams: calamine lotion Cool the skin. cooling lotions or creams: calamine lotion

or aqueous cream. or aqueous cream. A 1% menthol lotion A 1% menthol lotion If pruritus late evening a tepid shower or bath before If pruritus late evening a tepid shower or bath before

bed. bed. Topical steroids. Topical steroids. Localized itch: acupuncture and transcutaneous Localized itch: acupuncture and transcutaneous

electrical stimulationelectrical stimulation Topical capsaicin (8-methyl-Topical capsaicin (8-methyl-NN-vanillyl-6- nonenamide)-vanillyl-6- nonenamide)