Materiały źródłowe

• #1 Pruritus: Progress toward Pathogenesis and Treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5925168/

  Pruritus, the most common cutaneous symptom, is widely seen in many skin complaints. At present, the specific mechanism of pruritus still remains unclear. Recent evidence has suggested that, apart from histamine, many mediators and signaling pathways are involved in the pathogenesis of pruritus. […] Until now, the exact pathogenesis of pruritus remains unknown. Previously, it was thought that histamine mediator was primarily involved in the attack of pruritus. However, recent reports show that some mediators, such as 5-hydroxy tryptamine (5-HT), proteases, opioid peptide, and peptides, play crucial role in the mechanism of itching. […] Although the exact mechanism of itching has not been completely clarified, current studies indicate that some mediators are key contributors to the elicitation and aggravation of pruritus. These mediators play different roles in different itchy conditions. Moreover, it has been proved that signaling pathways and neurotransmitters are also responsible for itch sensation.

• #2 Pruritus and Systemic Disease: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1098029-overview

  Pruritus is defined as an unpleasant sensation that provokes the desire to scratch. Certain systemic diseases have long been known to cause pruritus that ranges in intensity from a mild annoyance to an intractable, disabling condition. Generalized pruritus may be classified into the following categories on the basis of the underlying causative disease: renal pruritus, cholestatic pruritus, hematologic pruritus, endocrine pruritus, pruritus related to malignancy, and idiopathic generalized pruritus. […] The sensation of pruritus is transmitted through slow-conducting unmyelinated C-polymodal and possibly type A delta nociceptive neurons with free nerve endings located near the dermoepidermal junction or in the epidermis. These neurons appear to be located more superficially and are more sensitive to pruritogenic substances than pain receptors. Activators of these nerves include histamine, neuropeptide substance P, serotonin, bradykinin, proteases (eg, mast cell tryptase), and endothelin (which stimulates the release of nitric oxide). Impulses are transmitted from the dorsal root ganglion to the spinothalamic tract and eventually to the thalamus.

• #3 Basic Mechanisms of Itch

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3170689/

  Chronic itch represents a burdensome clinical problem that can originate from a variety of etiologies. Pruriceptive itch originates following the activation of peripheral sensory nerve endings following damage or exposure to inflammatory mediators and ascends to the brain through the spinal thalamic tract. […] More than one sensory nerve subtype is thought to subserve pruriceptive itch which includes both unmyelinated C-fibers and thinly myelinated A nerve fibers. […] There are a myriad of mediators capable of stimulating these afferent nerves leading to itch, including biogenic amines, proteases, cytokines, and peptides. […] Studies have demonstrated that both peripheral and central sensitization to pruritogenic stimuli occur during chronic itch. […] Pruriceptive itch originates when specific sensory nerve terminals, generally located in the skin, are activated.

• #4 Pruritus and Systemic Disease: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1098029-overview

  Pruritus is defined as an unpleasant sensation that provokes the desire to scratch. Certain systemic diseases have long been known to cause pruritus that ranges in intensity from a mild annoyance to an intractable, disabling condition. Generalized pruritus may be classified into the following categories on the basis of the underlying causative disease: renal pruritus, cholestatic pruritus, hematologic pruritus, endocrine pruritus, pruritus related to malignancy, and idiopathic generalized pruritus. […] The sensation of pruritus is transmitted through slow-conducting unmyelinated C-polymodal and possibly type A delta nociceptive neurons with free nerve endings located near the dermoepidermal junction or in the epidermis. These neurons appear to be located more superficially and are more sensitive to pruritogenic substances than pain receptors. Activators of these nerves include histamine, neuropeptide substance P, serotonin, bradykinin, proteases (eg, mast cell tryptase), and endothelin (which stimulates the release of nitric oxide). Impulses are transmitted from the dorsal root ganglion to the spinothalamic tract and eventually to the thalamus.

• #5 Understanding itch: An update on mediators and mechanisms of pruritus – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/understanding-itch-an-update-on-mediators-and-mechanisms-of-pruritus/

  Microneurography experiments conducted in 1997 by Schmelz et al., identified afferent C-nerve fibers with slender axons and lot of terminal branching. These fibers were histamine sensitive but insensitive to mechanical stimuli. The detection of these low velocity fibers distinct from nociceptive fibers provided support for the labeled line theory which hypothesizes discrete and mutually exclusive afferent fibers for detecting either itch or pain. […] In summary, it is still not entirely clear if the neural pathways for itch and pain are completely independent or not. […] Oral antihistamines are ineffective in the treatment of many types of pruritus, suggesting a role for non-histaminic pathways in the sensation of pruritus. […] The C-nerve fibers synapse with lamina I neurons in the dorsal horn of spinal cord, then the secondary transmission neurons cross and enter into the opposite lateral STT to ascend to the thalamus.

• #6

  https://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/dermatology/pruritus-itch/

  Pruritus or itch is defined as an unpleasant sensation of the skin that provokes the urge to scratch. It is a characteristic feature of many skin diseases and an unusual sign of some systemic diseases. Pruritus may be localized or generalized and can occur as an acute or chronic condition. Itching lasting more than 6 weeks is termed chronic pruritus. Itching can be intractable and incapacitating, as well as a diagnostic and therapeutic challenge. […] Itch can be produced by mechanical (gentle touch, pressure, vibration, and wool), thermal and electrical stimuli such as transcutaneous or direct nerve stimulation. The sensation is received by free nerve endings in the skin and transmitted via unmyelinated C fibers and myelinated A fibers to the central spinothalamic tracts. Microneurography studies have demonstrated that itch and pain are transmitted by separate neural pathways.

• #7 The Complex Science Behind Itch in Atopic Dermatitis | National Eczema Association

  https://nationaleczema.org/blog/science-of-itch/

  Itch is often described as the hallmark of atopic dermatitis (AD) with nearly 100% of people with AD reporting itch as one of their major symptoms. […] In spite of the difficulties, several dedicated itch researchers have established that many different mechanisms underlie itch in AD, with keratinocytes (i.e., the main structural cells of the skin), as well as various immune cells, nerves and the brain all playing their part. […] The skin itself is an immune organ, a part of the innate immune system. […] The skin structure, immune system and neurons are integrated, not siloed. […] When the skin barrier is disrupted (as in AD), allergens and pathogens can get into the skin, increasing inflammation. […] Keratinocytes release signals that cause nerve endings in skin to activate. […] Brain imaging has shown that the areas of the brain involved in emotions, reward and memory of negative experiences, as well as processing of pain, are activated in AD itch significantly more than in healthy individuals.

• #8 Pruritus: Progress toward Pathogenesis and Treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5925168/

  Mediator-related pruritus implies that itching is associated with the mediation of mediators including histamine, 5-hydroxy tryptamine, proteases, opioid peptide, peptides, and eicosanoids. There are different mediators involved in the occurrence of pruritus at different stages. It has been found that a variety of mediators, apart from histamine, have much effects on the skin, mainly participating in the occurrence and development of itching. […] The itchy receptors exist in sensory nerve endings located in the epidermal-dermal connection. These receptors can be combined with the specific mediators mainly involving histamine, 5-HT, SP, and prostaglandins. […] Since a major of chronic refractory itch is resistant to antihistamine therapies, it seems that such a chronic pruritus relies on nonhistaminergic mediation. The nonhistaminergic signaling pathway is usually mediated by a class of mechanically sensitive C-type fibers (CMHs). […] Although the mechanism of Mrgprs mediating itching-related signaling pathways remains elusive, it has confirmed that Mrgprs- and Mrgpr-positive neurons, MrgprA3 in particular, play key roles in mediating chronic pruritus.

• #9 Mechanisms and Management of Itch in Dry Skin | HTML | Acta Dermato-Venereologica

  https://www.medicaljournals.se/acta/content/html/10.2340/00015555-3344

  A decline in skin barrier function is thought to be the primary cause of itch induced by dry skin. […] Many kinds of mediators, receptors, and channels are involved in itch signalling among the skin nervous system, skin cells, and central nervous system. […] The pathogenesis of pruritus in CLD is poorly understood and often refractory to treatment, with a prevalence of 40.3%. […] Several potential itch-causing substances may be involved, including bile salts, endogenous opioids, histamine, serotonin, and steroids. […] The sensation of itch is generated by the binding of itch-inducing substances to their cognate receptors on peripheral sensory afferents, e.g. unmyelinated C-fibre afferents and thinly myelinated A-fibre afferents. […] The evoked action potential is transmitted through the ascending sensory pathway to the somatosensory cortex, resulting in the perception of itch.

• #10 Itch – Wikipedia

  https://en.wikipedia.org/wiki/Itch

  Sensitivity to pruritic stimuli is evenly distributed across the skin and has a clear spot distribution with similar density to that of pain. […] Itch is often classified as that which is histamine mediated (histaminergic) and nonhistaminergic. […] Itch is readily abolished in skin areas treated with nociceptor excitotoxin capsaicin but remains unchanged in skin areas rendered touch insensitive by pretreatment with anti-inflammatory saponins. […] Using single-cell mRNA sequencing, clusters of genes expressed in itch-related tissues were identified, e.g. NP1-3, transmitting itch information; where NP3 expresses neuropeptides Nppb and Sst as well as genes involved in inflammatory itch (Il31ra, Osmr and Crystrl2). […] Staphylococcus aureus, a bacterial pathogen associated with itchy skin diseases, directly activates pruriceptor sensory neurons to drive itch.

• #11 Itch – Wikipedia

  https://en.wikipedia.org/wiki/Itch

  Sensitivity to pruritic stimuli is evenly distributed across the skin and has a clear spot distribution with similar density to that of pain. […] Itch is often classified as that which is histamine mediated (histaminergic) and nonhistaminergic. […] Itch is readily abolished in skin areas treated with nociceptor excitotoxin capsaicin but remains unchanged in skin areas rendered touch insensitive by pretreatment with anti-inflammatory saponins. […] Using single-cell mRNA sequencing, clusters of genes expressed in itch-related tissues were identified, e.g. NP1-3, transmitting itch information; where NP3 expresses neuropeptides Nppb and Sst as well as genes involved in inflammatory itch (Il31ra, Osmr and Crystrl2). […] Staphylococcus aureus, a bacterial pathogen associated with itchy skin diseases, directly activates pruriceptor sensory neurons to drive itch.

• #12 Itching – Dermatologic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/dermatologic-disorders/approach-to-the-dermatologic-patient/itching

  Itch can be prompted by diverse stimuli, including light touch, vibration, and wool fibers. There are a number of chemical mediators as well as different mechanisms by which the sensation of itch occurs. Specific peripheral sensory neurons mediate the itch sensation. These neurons are distinct from those that respond to light touch or pain; they contain a receptor, MrgA3, the stimulation of which causes the sensation of itching. […] Histamine is the well-known mediator. It is synthesized and stored in mast cells in the skin and is released in response to various stimuli. Other mediators (eg, neuropeptides) can either cause the release of histamine or act as pruritogens themselves, thus explaining why antihistamines ameliorate some cases of itching and not others. Opioids have a central pruritic action as well as stimulating the peripherally mediated histamine itch.

• #13 Pruritus and Systemic Disease: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1098029-overview

  Pruritus is defined as an unpleasant sensation that provokes the desire to scratch. Certain systemic diseases have long been known to cause pruritus that ranges in intensity from a mild annoyance to an intractable, disabling condition. Generalized pruritus may be classified into the following categories on the basis of the underlying causative disease: renal pruritus, cholestatic pruritus, hematologic pruritus, endocrine pruritus, pruritus related to malignancy, and idiopathic generalized pruritus. […] The sensation of pruritus is transmitted through slow-conducting unmyelinated C-polymodal and possibly type A delta nociceptive neurons with free nerve endings located near the dermoepidermal junction or in the epidermis. These neurons appear to be located more superficially and are more sensitive to pruritogenic substances than pain receptors. Activators of these nerves include histamine, neuropeptide substance P, serotonin, bradykinin, proteases (eg, mast cell tryptase), and endothelin (which stimulates the release of nitric oxide). Impulses are transmitted from the dorsal root ganglion to the spinothalamic tract and eventually to the thalamus.

• #14 Understanding itch: An update on mediators and mechanisms of pruritus – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/understanding-itch-an-update-on-mediators-and-mechanisms-of-pruritus/

  A bewildering myriad of mediators acting via a multitude of mechanisms are involved in pruritus. […] Histamine, despite being the most acknowledged mediator, plays a major part only in a few diseases like urticaria, insect bite reactions and mastocytosis. […] The role of histamine type 4 (H4) receptors expressed mainly on dendritic cells, mast cells and eosinophils is an exciting new field in our current understanding and management of pruritus. […] Acetylcholine (Ach) is a neurotransmitter which binds to both muscarinic and nicotinic receptors. In mice, activation of the muscarinic M3 receptors causes pruritus. […] The interest in the exact function of proteinases (like chymotrypsin, papain and trypsin) in itch has received renewed attention after studies revealed overexpression of chymotryptic enzyme within the stratum corneum in chronic itchy inflammatory skin diseases in mice.

• #15 Pruritus | AAFP

  https://www.aafp.org/pubs/afp/issues/2003/0915/p1135.html

  Serotonin appears to be a key component of the pruritus that occurs with several diseases, including polycythemia vera, uremia, cholestasis and lymphoma, and of morphine-associated pruritus. […] Opioids trigger pruritus in as many as 90 percent of patients receiving intraspinal injections of narcotics. […] The pruritus that occurs in herpes zoster prodrome may be a model for pruritus with a neuropathic cause. […] Atopic dermatitis appears to involve an immune-mediated release of cytokines and other pro-inflammatory agents, a mechanism analogous to airway hyperreactivity in patients with asthma. Superimposed on this hyperreactivity is a distorted touch sensation. Although patients without atopic dermatitis perceive mild mechanical stimulation as touch, patients with the condition perceive it as pruritus.

• #16 Understanding itch: An update on mediators and mechanisms of pruritus – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/understanding-itch-an-update-on-mediators-and-mechanisms-of-pruritus/

  A bewildering myriad of mediators acting via a multitude of mechanisms are involved in pruritus. […] Histamine, despite being the most acknowledged mediator, plays a major part only in a few diseases like urticaria, insect bite reactions and mastocytosis. […] The role of histamine type 4 (H4) receptors expressed mainly on dendritic cells, mast cells and eosinophils is an exciting new field in our current understanding and management of pruritus. […] Acetylcholine (Ach) is a neurotransmitter which binds to both muscarinic and nicotinic receptors. In mice, activation of the muscarinic M3 receptors causes pruritus. […] The interest in the exact function of proteinases (like chymotrypsin, papain and trypsin) in itch has received renewed attention after studies revealed overexpression of chymotryptic enzyme within the stratum corneum in chronic itchy inflammatory skin diseases in mice.

• #17

  https://www.jci.org/articles/view/28553

  Chronic skin inflammation causes peripheral sensitization to itch It has been known for decades that acute or chronic skin inflammation lowers the threshold for pruritic stimuli and thus causes peripheral itch sensitization (56, S2). The complex mechanisms underlying these phenomena (wheal, flare, edema) are becoming better understood. During inflammation, several cells release mediators that potentially bind to and activate high-affinity receptors on sensory neurons. […] Proteinase-activated receptors play a key role in pruritus during neurogenic inflammation In fact, we have learned that proteases are more than just scissors of destruction; rather, they are representative of a group of mediators that communicate with nerves, thereby modulating inflammation, pain, and pruritus (64, 65). Similar to histamine or prostaglandins, certain proteases act as signaling molecules by activating PARs (66, S11).

• #18 Pruritus and Systemic Disease: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1098029-overview

  Opioids are known to modulate the sensation of pruritus, both peripherally and centrally. Stimulation of opioid mu receptors accentuates pruritus, while stimulation of kappa receptors and blockage of mu receptors suppress pruritus. […] In the mouse model that mimics atopic dermatitis in humans, the histamine (H4) receptor mediates both TH-2 inflammation and pruritus. A variety of interleukins (ILs) and chemokines play a role in the pruritus of atopic dermatitis. IL-4 and IL-13, as well as TH2 chemokines CCL17, CCL22, and CCL26 play a pivotal role in the development of atopic dermatitis inflammation. IL-33 induces IL-31, thereby promoting pruritus and scratching behavior. IL-31 promotes growth, elongation, and branching of sensory nerves in atopic dermatitis. […] Renal pruritus can occur in patients with chronic renal failure (CRF) and is most often seen in patients receiving hemodialysis (HD). This term is synonymous with uremic pruritus; however, the condition is not due to elevated serum urea levels. The actual pruritogenic substance has yet to be identified.

• #19 Pruritus and Systemic Disease: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1098029-overview

  Opioids are known to modulate the sensation of pruritus, both peripherally and centrally. Stimulation of opioid mu receptors accentuates pruritus, while stimulation of kappa receptors and blockage of mu receptors suppress pruritus. […] In the mouse model that mimics atopic dermatitis in humans, the histamine (H4) receptor mediates both TH-2 inflammation and pruritus. A variety of interleukins (ILs) and chemokines play a role in the pruritus of atopic dermatitis. IL-4 and IL-13, as well as TH2 chemokines CCL17, CCL22, and CCL26 play a pivotal role in the development of atopic dermatitis inflammation. IL-33 induces IL-31, thereby promoting pruritus and scratching behavior. IL-31 promotes growth, elongation, and branching of sensory nerves in atopic dermatitis. […] Renal pruritus can occur in patients with chronic renal failure (CRF) and is most often seen in patients receiving hemodialysis (HD). This term is synonymous with uremic pruritus; however, the condition is not due to elevated serum urea levels. The actual pruritogenic substance has yet to be identified.

• #20 The Complex Science Behind Itch in Atopic Dermatitis | National Eczema Association

  https://nationaleczema.org/blog/science-of-itch/

  The sensation of itch is a switch to turn on the immune system, leading to protection against foreign materials and pathogens from entering the skin. […] Interactions between nerves and different types of immune cells have been shown to be involved in itch in AD. […] The interleukin IL-31, first discovered in 2004, is the cytokine most directly implicated in mediating itch. […] Blocking antibodies to IL-31 or its receptor rapidly decreased itch in mice, dogs and humans. […] Exciting recent work has shown some major differences in how the immune system reacts in an acute AD flare, which is often caused by exposure to an allergen, compared to the chronic itch associated with AD. […] Researchers now understand that, in general, acute flares are mediated by cross-talk between basophils and neurons, while chronic itch is mediated by cells that release TSLP, IL-4, IL-13 and IL-31 to activate neurons.

• #21 Mechanisms and Management of Itch in Dry Skin | HTML | Acta Dermato-Venereologica

  https://www.medicaljournals.se/acta/content/html/10.2340/00015555-3344

  In healthy skin, most cutaneous nerve fibres terminate under dermoepidermal junctions. […] An increased intraepidermal nerve density has been observed in the skin of patients with pruritic dermatological diseases, such as senile xerosis and AD, as well as in dry skin mice models. […] The controlling mechanism of cutaneous nerve density is regulated by the balance of NEFs, such as NGF, ARTN and AR, and NRFs, such as Sema3A, produced by keratinocytes. […] The process of cutaneous nerve growth in dry skin requires several MMPs for growth cones to penetrate the 3-dimensional extracellular matrix barriers. […] The levels of expression of MMP-2 and MMP-8 were upregulated by NGF and down-regulated by Sema3A. […] The neuropeptide gastrin-releasing peptide (GRP) is characterized as a neurotransmitter that specifically relays itch signals and specifically expressed in a small subset of peptidergic dorsal root ganglion (DRG) neurones.

• #22

  https://journals.lww.com/itch/fulltext/2018/12000/possible_role_of_neutrophils_in_itch.1.aspx

  Cathepsin S is an endogenous cysteine protease that activates PAR-2 and PAR-4 and elicits itch in humans. […] PGE2 is thought to potentiate histamine-induced itch. […] Human neutrophils are able to produce PGE2; however, the significance of neutrophil-derived PGE2 in itch has not yet been elucidated. […] LTB4 has been implicated in the pathogenesis of allergic pruritic diseases such as AD, psoriasis, and Sjgren-Larsson syndrome. […] Neutrophils may play a role in AD itch possibly through secreting S100A8/9. […] Neutrophils play a major role in the pathogenesis of psoriasis. […] Expression levels of neutrophil elastase and LTB4 are upregulated in the lesional skin of psoriasis, suggesting these mediators may be involved in psoriatic itch. […] Neutrophils are involved in the pathogenesis of PPP, and are present in the infiltrate of PPP lesions.

• #23 Understanding itch: An update on mediators and mechanisms of pruritus – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/understanding-itch-an-update-on-mediators-and-mechanisms-of-pruritus/

  Advances in dermatological and neurobiological research have lead to a significant unravelling of the pathophysiological basis of pruritus. Despite being the standard treatment for itch, antihistamines are not effective in lessening pruritus in various cutaneous and systemic diseases; therefore, a better understanding of itch assumes a crucial importance from a therapeutic point of view. […] Many theories have been proposed to elucidate the encoding of itch; the most important ones are as follows. […] For long itch has been considered as a sub-modality of pain. Intensity hypothesis postulates neurons that are activated by both painful and pruritogenic stimuli, but weaker activation of nociceptive receptors results in itch. However, recent evidence against this theory is accumulating and suggests that the neurophysiology of itch is much more complex than initially thought.

• #24

  https://journals.lww.com/itch/fulltext/2018/12000/possible_role_of_neutrophils_in_itch.1.aspx

  Interactions between keratinocytes, immune cells, and sensory nerve endings strongly influence the sensation of itch. […] However, neutrophils are capable of producing and releasing a variety of pruritogens such as histamine, proteases (neutrophil elastase and cathepsin S), prostaglandin E2, leukotriene B4, and platelet-activating factor. […] Neutrophils are involved in both innate and adaptive immunity and in inflammation. […] Neutrophils exert their functions via phagocytosis, the formation of neutrophil extracellular traps, the release of granules and secretion of a variety of cytokines and chemokines, and by acting as antigen presenting cells. […] Human neutrophils possess several types of proteases, including elastase, which can activate PAR-2. […] There are reports that indicate the involvement of neutrophil elastase in itch.

• #25 The Complex Science Behind Itch in Atopic Dermatitis | National Eczema Association

  https://nationaleczema.org/blog/science-of-itch/

  The sensation of itch is a switch to turn on the immune system, leading to protection against foreign materials and pathogens from entering the skin. […] Interactions between nerves and different types of immune cells have been shown to be involved in itch in AD. […] The interleukin IL-31, first discovered in 2004, is the cytokine most directly implicated in mediating itch. […] Blocking antibodies to IL-31 or its receptor rapidly decreased itch in mice, dogs and humans. […] Exciting recent work has shown some major differences in how the immune system reacts in an acute AD flare, which is often caused by exposure to an allergen, compared to the chronic itch associated with AD. […] Researchers now understand that, in general, acute flares are mediated by cross-talk between basophils and neurons, while chronic itch is mediated by cells that release TSLP, IL-4, IL-13 and IL-31 to activate neurons.

• #26

  https://journals.lww.com/itch/fulltext/2018/12000/possible_role_of_neutrophils_in_itch.1.aspx

  Interactions between keratinocytes, immune cells, and sensory nerve endings strongly influence the sensation of itch. […] However, neutrophils are capable of producing and releasing a variety of pruritogens such as histamine, proteases (neutrophil elastase and cathepsin S), prostaglandin E2, leukotriene B4, and platelet-activating factor. […] Neutrophils are involved in both innate and adaptive immunity and in inflammation. […] Neutrophils exert their functions via phagocytosis, the formation of neutrophil extracellular traps, the release of granules and secretion of a variety of cytokines and chemokines, and by acting as antigen presenting cells. […] Human neutrophils possess several types of proteases, including elastase, which can activate PAR-2. […] There are reports that indicate the involvement of neutrophil elastase in itch.

• #27 Basic Mechanisms of Itch

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3170689/

  Chronic itch represents a burdensome clinical problem that can originate from a variety of etiologies. Pruriceptive itch originates following the activation of peripheral sensory nerve endings following damage or exposure to inflammatory mediators and ascends to the brain through the spinal thalamic tract. […] More than one sensory nerve subtype is thought to subserve pruriceptive itch which includes both unmyelinated C-fibers and thinly myelinated A nerve fibers. […] There are a myriad of mediators capable of stimulating these afferent nerves leading to itch, including biogenic amines, proteases, cytokines, and peptides. […] Studies have demonstrated that both peripheral and central sensitization to pruritogenic stimuli occur during chronic itch. […] Pruriceptive itch originates when specific sensory nerve terminals, generally located in the skin, are activated.

• #28

  https://www.jci.org/articles/view/28553

  Chronic skin inflammation causes peripheral sensitization to itch It has been known for decades that acute or chronic skin inflammation lowers the threshold for pruritic stimuli and thus causes peripheral itch sensitization (56, S2). The complex mechanisms underlying these phenomena (wheal, flare, edema) are becoming better understood. During inflammation, several cells release mediators that potentially bind to and activate high-affinity receptors on sensory neurons. […] Proteinase-activated receptors play a key role in pruritus during neurogenic inflammation In fact, we have learned that proteases are more than just scissors of destruction; rather, they are representative of a group of mediators that communicate with nerves, thereby modulating inflammation, pain, and pruritus (64, 65). Similar to histamine or prostaglandins, certain proteases act as signaling molecules by activating PARs (66, S11).

• #29 Mechanisms and Management of Itch in Dry Skin | HTML | Acta Dermato-Venereologica

  https://www.medicaljournals.se/acta/content/html/10.2340/00015555-3344

  In healthy skin, most cutaneous nerve fibres terminate under dermoepidermal junctions. […] An increased intraepidermal nerve density has been observed in the skin of patients with pruritic dermatological diseases, such as senile xerosis and AD, as well as in dry skin mice models. […] The controlling mechanism of cutaneous nerve density is regulated by the balance of NEFs, such as NGF, ARTN and AR, and NRFs, such as Sema3A, produced by keratinocytes. […] The process of cutaneous nerve growth in dry skin requires several MMPs for growth cones to penetrate the 3-dimensional extracellular matrix barriers. […] The levels of expression of MMP-2 and MMP-8 were upregulated by NGF and down-regulated by Sema3A. […] The neuropeptide gastrin-releasing peptide (GRP) is characterized as a neurotransmitter that specifically relays itch signals and specifically expressed in a small subset of peptidergic dorsal root ganglion (DRG) neurones.

• #30 Mechanisms and Management of Itch in Dry Skin | HTML | Acta Dermato-Venereologica

  https://www.medicaljournals.se/acta/content/html/10.2340/00015555-3344

  In healthy skin, most cutaneous nerve fibres terminate under dermoepidermal junctions. […] An increased intraepidermal nerve density has been observed in the skin of patients with pruritic dermatological diseases, such as senile xerosis and AD, as well as in dry skin mice models. […] The controlling mechanism of cutaneous nerve density is regulated by the balance of NEFs, such as NGF, ARTN and AR, and NRFs, such as Sema3A, produced by keratinocytes. […] The process of cutaneous nerve growth in dry skin requires several MMPs for growth cones to penetrate the 3-dimensional extracellular matrix barriers. […] The levels of expression of MMP-2 and MMP-8 were upregulated by NGF and down-regulated by Sema3A. […] The neuropeptide gastrin-releasing peptide (GRP) is characterized as a neurotransmitter that specifically relays itch signals and specifically expressed in a small subset of peptidergic dorsal root ganglion (DRG) neurones.

• #31

  https://www.jci.org/articles/view/28553

  Chronic skin inflammation may cause central itch sensitization Recent findings shed new light on the role of chronic inflammatory stimuli in pruritus with special regard to central sensitization of itch fibers. Activity in pruriceptors not only provokes itch but additionally facilitates spinal itch processing, resulting in touch- or brush-evoked pruritus around an itching site (itchy skin) (S2, S12).

• #32 Aetiology, pathogenesis and management of neuropathic itch: A narrative review with recent updates – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/aetiology-pathogenesis-and-management-of-neuropathic-itch-a-narrative-review-with-recent-updates/

  Neuropathic itch is a relatively common yet under-reported cause of systemic pruritus. […] The pathogenesis of neuropathic itch is complex and can result from an insult at any point along the itch pathway, ranging from the peripheral receptors and nerves until the brain. […] The present article focuses on various pruritic conditions associated with damage or insult to the nervous system, that is, neuropathic pruritus. […] The insult to the nervous system can occur at any level, extending from the receptors and afferent pathway of an itch to the level of the brain. […] In neuropathic itch, there is a complex interplay between excitatory and inhibitory interneurons, and several inflammatory mediators are responsible, in addition to histamine, the canonical itch mediator. […] Thus, these patients often fail to improve with conventional therapies like systemic corticosteroids or antihistamines, and the underlying cause needs to be addressed to obtain relief.

• #33 Mechanisms and Management of Itch in Dry Skin | HTML | Acta Dermato-Venereologica

  https://www.medicaljournals.se/acta/content/html/10.2340/00015555-3344

  In healthy skin, most cutaneous nerve fibres terminate under dermoepidermal junctions. […] An increased intraepidermal nerve density has been observed in the skin of patients with pruritic dermatological diseases, such as senile xerosis and AD, as well as in dry skin mice models. […] The controlling mechanism of cutaneous nerve density is regulated by the balance of NEFs, such as NGF, ARTN and AR, and NRFs, such as Sema3A, produced by keratinocytes. […] The process of cutaneous nerve growth in dry skin requires several MMPs for growth cones to penetrate the 3-dimensional extracellular matrix barriers. […] The levels of expression of MMP-2 and MMP-8 were upregulated by NGF and down-regulated by Sema3A. […] The neuropeptide gastrin-releasing peptide (GRP) is characterized as a neurotransmitter that specifically relays itch signals and specifically expressed in a small subset of peptidergic dorsal root ganglion (DRG) neurones.

• #34 Central circuit mechanisms of itch | Nature Communications

  https://www.nature.com/articles/s41467-020-16859-5

  Itch, in particular chronic forms, has been widely recognized as an important clinical problem, but much less is known about the mechanisms of itch in comparison with other sensory modalities such as pain. […] Major components of the spinal neural circuit underlying both chemical and mechanical itch have now been identified, along with the circuits relaying ascending transmission and the descending modulation of itch. […] Recent studies have identified the molecular markers for excitatory neurons involved in the processing of chemical itch. […] This is evidenced by data showing that ablation of spinal GRPR+ neurons in mice almost completely abolishes the scratching behavior induced by both histamine-dependent and histamine-independent pruritogens. […] In addition, ablation of neuropeptide natriuretic polypeptide b (Nppb) receptor (Npra)-expressing neurons in the dorsal spinal cord also selectively eliminates the itch responses induced by pruritogens, suggesting an important role of Npra+ neurons in itch processing.

• #35 Mechanisms and Management of Itch in Dry Skin | HTML | Acta Dermato-Venereologica

  https://www.medicaljournals.se/acta/content/html/10.2340/00015555-3344

  The transcription factor Tlx3 in the spinal cord was demonstrated to be essential for the development of GRPR+ neurones. […] The GRP and its receptor (GRPR), a Gq-protein-coupled receptor (GPCR), were reported as itch-specific signalling molecules and expressed in the spinal cord. […] These data suggest that the spinal GRP/GRPR system is partly involved in the induction of itch in dry skin. […] The AEW mouse model exhibited persistent upregulation of TLR4 mRNA and increased TLR4 expression in GFAP-expressing astrocytes in the spinal dorsal horn. […] These findings suggest that spinal TLR4 signalling is important for spinal astrocyte activation and astrogliosis, which may underlie chronic itch and alloknesis. […] This review presented recent knowledge regarding the mechanisms of dry skin-induced itch and its management.

• #36 Pruritus | AAFP

  https://www.aafp.org/pubs/afp/issues/2003/0915/p1135.html

  Pruritus originates within the skin’s free nerve endings, which are most heavily concentrated in the wrists and ankles. The sensation of pruritus is transmitted through C fibers to the dorsal horn of the spinal cord and then to the cerebral cortex via the spinothalamic tract. Pruritus generates a spinal reflex response, the scratch, which is as innate as a deep tendon reflex. Regardless of the cause, pruritus often is exacerbated by skin inflammation, dry or hot ambient conditions, skin vasodilation, and psychologic stressors. […] A single mechanism cannot explain all causes of pruritus. Histamine, which is released by mast cells in persons with urticaria and other allergic reactions, classically is associated with pruritus. However, with the exception of allergic conditions, histamine must be considered only one of several chemical mediators of itch.

• #37 Pruritus and Systemic Disease: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1098029-overview

  Opioids are known to modulate the sensation of pruritus, both peripherally and centrally. Stimulation of opioid mu receptors accentuates pruritus, while stimulation of kappa receptors and blockage of mu receptors suppress pruritus. […] In the mouse model that mimics atopic dermatitis in humans, the histamine (H4) receptor mediates both TH-2 inflammation and pruritus. A variety of interleukins (ILs) and chemokines play a role in the pruritus of atopic dermatitis. IL-4 and IL-13, as well as TH2 chemokines CCL17, CCL22, and CCL26 play a pivotal role in the development of atopic dermatitis inflammation. IL-33 induces IL-31, thereby promoting pruritus and scratching behavior. IL-31 promotes growth, elongation, and branching of sensory nerves in atopic dermatitis. […] Renal pruritus can occur in patients with chronic renal failure (CRF) and is most often seen in patients receiving hemodialysis (HD). This term is synonymous with uremic pruritus; however, the condition is not due to elevated serum urea levels. The actual pruritogenic substance has yet to be identified.

• #38

  https://journals.lww.com/itch/fulltext/2018/12000/possible_role_of_neutrophils_in_itch.1.aspx

  Cathepsin S is an endogenous cysteine protease that activates PAR-2 and PAR-4 and elicits itch in humans. […] PGE2 is thought to potentiate histamine-induced itch. […] Human neutrophils are able to produce PGE2; however, the significance of neutrophil-derived PGE2 in itch has not yet been elucidated. […] LTB4 has been implicated in the pathogenesis of allergic pruritic diseases such as AD, psoriasis, and Sjgren-Larsson syndrome. […] Neutrophils may play a role in AD itch possibly through secreting S100A8/9. […] Neutrophils play a major role in the pathogenesis of psoriasis. […] Expression levels of neutrophil elastase and LTB4 are upregulated in the lesional skin of psoriasis, suggesting these mediators may be involved in psoriatic itch. […] Neutrophils are involved in the pathogenesis of PPP, and are present in the infiltrate of PPP lesions.

• #39 Pruritus and Systemic Disease: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1098029-overview

  Other theories include elevated levels of circulating histamine in patients receiving HD. Researchers have found increased numbers of mast cells in various organ systems. However, antihistamines are, at best, marginal in the treatment of renal pruritus, suggesting other causative factors. […] An immune hypothesis has also been suggested. In patients with CRF, a systemic inflammatory response involving overexpression of activated type 1 helper T lymphocytes (which secrete interleukin 2) may induce pruritus. […] Cholestasis, or a decrease or arrest in the flow of bile, is associated with pruritus. The deposition of bile salts in the skin was thought to directly cause a pruritogenic effect, but this theory has been proven incorrect. In addition, indirect hyperbilirubinemia does not induce pruritus. Pruritus is more common with intraheptic cholestasis than extrahepatic cholestasis.

• #40 Pruritus and Systemic Disease: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1098029-overview

  Other theories include elevated levels of circulating histamine in patients receiving HD. Researchers have found increased numbers of mast cells in various organ systems. However, antihistamines are, at best, marginal in the treatment of renal pruritus, suggesting other causative factors. […] An immune hypothesis has also been suggested. In patients with CRF, a systemic inflammatory response involving overexpression of activated type 1 helper T lymphocytes (which secrete interleukin 2) may induce pruritus. […] Cholestasis, or a decrease or arrest in the flow of bile, is associated with pruritus. The deposition of bile salts in the skin was thought to directly cause a pruritogenic effect, but this theory has been proven incorrect. In addition, indirect hyperbilirubinemia does not induce pruritus. Pruritus is more common with intraheptic cholestasis than extrahepatic cholestasis.

• #41 Scratching the Itch: Management of pruritus in cholestatic liver disease | AASLD

  https://www.aasld.org/liver-fellow-network/core-series/clinical-pearls/scratching-itch-management-pruritus-cholestatic

  The pathophysiologic mechanism of pruritus in cholestasis remains poorly understood. It is thought that cholestasis leads to the accumulation of unknown pruritogenic substances that bind to receptors on primary itch neurons (C-fibers) in the skin. This signal gets transmitted across neuronal pathways to the central nervous system, resulting in the sensation of itch. Several potential pruritogens have been proposed, including bile acids, endogenous opioids, and lysophosphatidic acid. However, a definitive culprit has not been identified. […] Pruritus associated with cholestasis is characteristically localized to the palms and soles, although generalized itching can also occur. Symptoms are often most intense at night, which interferes with sleep and exacerbates fatigue. […] Despite a significant impact on quality of life, pruritus is undertreated in cholestatic liver disease.

• #42 Itch, pruritus

  https://dermnetnz.org/topics/pruritus

  Cholestasis is thought to release toxic substances from the liver, which stimulates neural itch fibres in the skin. […] In Hodgkin lymphoma, pruritus is thought to be caused by histamine release, which may be related to eosinophilia. […] The management of chronic severe itch is difficult and often requires the use of combination therapy over a long period of time.

• #43 Pruritus and Systemic Disease: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1098029-overview

  Other theories implicate elevated venous histamine levels, retention of pruritogenic intermediates in bile salt synthesis, and high hepatic concentrations of bile salts resulting in hepatic injury and release of a pruritogenic substance. […] Iron is a critical factor in many enzymatic reactions. Although iron deficiency has not been proved to be a cause of pruritus, it may contribute to pruritus through a variety of metabolic paths. […] Hyperthyroidism has been associated with pruritus. Excess thyroid hormone may activate kinins from increased tissue metabolism or may reduce the itch threshold as a result of warmth and vasodilation. […] Numerous reports have linked pruritus to almost every type of malignancy. Release of toxins and the immune system have been suggested to play roles in malignancy-related pruritus.

• #44 Aetiology, pathogenesis and management of neuropathic itch: A narrative review with recent updates – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/aetiology-pathogenesis-and-management-of-neuropathic-itch-a-narrative-review-with-recent-updates/

  It occurs primarily due to insults to the peripheral and/or central nervous system. […] The sensory afferent unmyelinated C-nerve fibres transduce an itch signal from the skin to the spinal cord via the dorsal root ganglion. […] Axonal damage by any systemic disease like diabetes mellitus, vitamin deficiencies, plasma-cell dyscrasias and toxin exposure may interrupt the transmission of itch signals towards the spinal cord and result in small-fibre polyneuropathy. […] The causes of neuropathic itch may be broadly classified based on the location of pathology in the itch pathway- peripheral nervous system, spinal cord, or brain. […] Neuropathic itch is an emerging area of interest and often remains underdiagnosed and untreated. […] The treatment plan must be formulated based on underlying etiology, existing comorbidities, risk of possible drug interactions and patient preferences. […] The focus should be given to improving the quality of life of the patient. […] Several emerging therapies based on newer receptors and signalling pathways have also been discussed to highlight the current understanding of neuropathic itch.

• #45 Why do wounds itch? – Elena Conde

  https://elenaconde.com/en/why-wounds-itch/

  Proinflammatory cytokines released in any wound (acute or chronic) can activate sensory neurons and produce itching. This is termed the neuro-immunologic pathway of pruritus and multiple cells appear to be involved, including white blood cells, keratinocytes and endothelial cells. Pruritogenic molecules such as interleukin 31(IL-31) activate afferent sensory fibers in the skin and these neurons synapse with second-order neurons in the spinal cord. After communication with a complex of spinal interneurons, a signal is sent to the brain where the itch sensation is recognized. Instructions are then sent to the motor neurons responsible for scratching. […] The persistence of pruritus after a burn is striking. The precise trigger for this phenomenon is unknown, but it seems that the neuropathic mechanism is the main one involved. In fact, these patients may report paresthesias (needle pricks). Neuropathic pruritus is due to increased sensitivity and excitability of damaged peripheral afferent fibers, which form neuromas. It may therefore respond to neuroleptic agents such as gabapentin and pregabalin. […] In pathologic scars following wounds with an intense inflammatory phase, i.e. hypertrophic and keloid scars, chronic pruritus is not uncommon. In keloids, abnormalities of afferent nerve fibers have also been reported, which could explain this itching.

• #46 Psychogenic itch | Translational Psychiatry

  https://www.nature.com/articles/s41398-018-0097-7

  Psychogenic itch can be defined as an itch disorder where itch is at the center of the symptomatology and where psychological factors play an evident role in the triggering, intensity, aggravation, or persistence of the pruritus. […] Psychological factors are known to modulate itch in all patients, but there is a specific diagnosis of psychogenic itch that must be proposed cautiously. […] Neurophysiological and psychological theories are not mutually exclusive and can be used to better understand this disorder. Itch can be mentally induced. Opioids and other neurotransmitters, such as acetylcholine and dopamine, are probably involved in this phenomenon. […] In the brain, sensory, motor, and affective areas are activated at the same time when pruritus occurs and even when we think about pruritus or scratching.

• #47 Psychogenic itch | Translational Psychiatry

  https://www.nature.com/articles/s41398-018-0097-7

  Hence, a new definition of pruritus could be a sensation accompanied by the contralateral activation of the anterior cortex and the predominantly ipsilateral activation of the supplementary motor areas and the inferior parietal lobule; scratching may follow, reflecting the fact that it is the brain that itches, not the skin. […] This very important role of the brain in the pathogenesis of pruritus confirms that a psychological component could be present in every case of pruritus and that a specific psychogenic pruritus is possible. […] People with psychogenic pruritus (or other causes of itch) frequently scratch more and more, inducing nerve hyperplasia in the skin and further pruritus. […] The understanding of central sensitization for itch improves our understanding of psychogenic pruritus.

• #48 Psychogenic itch | Translational Psychiatry

  https://www.nature.com/articles/s41398-018-0097-7

  The contagious itch has been experienced by all readers of this paper. […] An overactive limbic system, particularly the anterior cingulated cortex, which is essential in modulating emotional and cognitive activities, may be clue to our underlying desire to itch. […] The co-activation of the prefrontal cortex in conjunction with the limbic system upon application of itch stimuli suggests interplay of this network on motivation and emotion. […] The involvement of midbrain strongly suggests that there is a role for the dopaminergic system in the addictive nature such a circle. […] While there have been no prospective studies on this subject, some experimental and cross-sectional studies indicate that stress factors can influence itch. […] Many mediators are implicated in enhancing itch after stress. Among them, 2-adrenoceptors mediate itch hypersensitivity following chronic stress by inducing proinflammatory factors, such as TNF-, in the skin.

• #49 Skin Barrier Damage and Itch: Review of Mechanisms, Topical Management and Future Directions | HTML | Acta Dermato-Venereologica

  https://www.medicaljournals.se/acta/content/html/10.2340/00015555-3296

  Barrier dysfunction results in an increase in transepidermal water loss (TEWL). […] Elevated TEWL is a marker of the disrupted skin barrier in inflammatory skin diseases. […] Another self-perpetuating cycle is the itchscratch cycle. Scratching mechanically disrupts the skin barrier, promotes inflammation and transiently activates inhibitory neurons at the spinal level to reduce itch sensation and prolong pruritus. […] In addition to the non-histaminergic PAR-2-stimulated pathway, itch can also be induced via a histamine-dependent pathway. […] Itch is a complex modality with multiple components and pathways, many of which have yet to be fully elucidated.

• #50 Ways to Relieve Itch from Eczema | National Eczema Association

  https://nationaleczema.org/blog/why-does-eczema-itch/

  When you have eczema, your skin barrier may be weakened, leading to more itchiness. Strengthening your skin barrier can help prevent or treat eczema and your itch. […] Eczema flares are frequently triggered by the itch-scratch cycle. This cycle is when itching leads to scratching, which results in the release of inflammatory mediators, which results in more dry skin and the need to itch. […] According to researchers, itch and pain have a yin-yang relationship. When pain is present, the feeling of itch subsides. That’s why scratching can relieve the feeling of itchy skin because it causes low-grade pain. But the relief from scratching is temporary and can cause more problems, such as scarring or a more severe itch. Too much scratching can lead to more eczema, thickened skin and infections if the surface of the skin is broken.

• #51 Itch, pruritus

  https://dermnetnz.org/topics/pruritus

  Pruritus is often a symptom of an underlying disease process such as a skin problem, a systemic disease, or abnormal nerve impulses. […] Mechanisms underlying pruritus are complex. […] The itch signal is transmitted mainly through small, itch-selective C-fibres in the skin in addition to histamine-triggered and non-histaminergic neurons. […] Patients with chronic pruritus usually have both peripheral and central hypersensitisation (a heightened reaction) which means they tend to overreact to noxious stimuli which normally inhibit itch (such as heat and scratching) and also misinterpret non-noxious stimuli as an itch (eg, light touch). […] The way scratching stops itching has been explained by an interaction with pain pathways within the dorsal horn of the spinal cord. […] Once chronic pruritus has occurred, there may be secondary changes in the nerves in the skin and central nervous system which heighten the sensation of itch.

• #52 The Complex Science Behind Itch in Atopic Dermatitis | National Eczema Association

  https://nationaleczema.org/blog/science-of-itch/

  Emotional states such as stress, anxiety and mood changes can affect the skin-inflammation-nerve-brain axis. […] Experiencing itch causes the desire to scratch, which can temporarily provide itch relief. […] Recent studies have shown that two different types of nerves become activated in the brain when a person itches and scratches their skin the gamma-aminobutyric acid (GABA) nerves and the dopaminergic (DA) nerves. […] Keratinocytes are also an active part of the immune system; they have the ability to release signaling molecules that talk to other immune cells and nerves. […] Keratinocytes secrete active proteins called enzymes, specifically kallikreins (KLK) that cut up other proteins. […] KLK7 itself was found to activate nerves implicated in itch without involvement of the immune system.

• #53 Psychogenic itch | Translational Psychiatry

  https://www.nature.com/articles/s41398-018-0097-7

  The contagious itch has been experienced by all readers of this paper. […] An overactive limbic system, particularly the anterior cingulated cortex, which is essential in modulating emotional and cognitive activities, may be clue to our underlying desire to itch. […] The co-activation of the prefrontal cortex in conjunction with the limbic system upon application of itch stimuli suggests interplay of this network on motivation and emotion. […] The involvement of midbrain strongly suggests that there is a role for the dopaminergic system in the addictive nature such a circle. […] While there have been no prospective studies on this subject, some experimental and cross-sectional studies indicate that stress factors can influence itch. […] Many mediators are implicated in enhancing itch after stress. Among them, 2-adrenoceptors mediate itch hypersensitivity following chronic stress by inducing proinflammatory factors, such as TNF-, in the skin.

• #54 Skin Barrier Damage and Itch: Review of Mechanisms, Topical Management and Future Directions | HTML | Acta Dermato-Venereologica

  https://www.medicaljournals.se/acta/content/html/10.2340/00015555-3296

  Barrier dysfunction results in an increase in transepidermal water loss (TEWL). […] Elevated TEWL is a marker of the disrupted skin barrier in inflammatory skin diseases. […] Another self-perpetuating cycle is the itchscratch cycle. Scratching mechanically disrupts the skin barrier, promotes inflammation and transiently activates inhibitory neurons at the spinal level to reduce itch sensation and prolong pruritus. […] In addition to the non-histaminergic PAR-2-stimulated pathway, itch can also be induced via a histamine-dependent pathway. […] Itch is a complex modality with multiple components and pathways, many of which have yet to be fully elucidated.

• #55

  https://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/dermatology/pruritus-itch/

  It is important to establish if pruritus preceded the appearance of a skin eruption. Severe itching leads to scratching that causes secondary skin changes of excoriation, lichenification, dryness, eczematization, and infection. Excessive bathing and contact allergy to topical therapies can lead to dermatitis. These findings should not be interpreted as the primary skin disorder. […] Select systemic conditions associated with itching are listed in Box 2. Several are potentially serious, and it can be dangerous to label a case of generalized pruritus nonspecific eczema until these conditions are excluded. Pruritus of systemic disease is usually generalized, it may be the only manifesting symptom, and a specific rash is not present. Neurologic and psychiatric conditions associated with chronic pruritus are included in Box 2. […] Identifying and treating the underlying cause is the most effective therapy for pruritus. Symptomatic treatment should be prescribed while the primary condition is being treated.

• #56 Scientists uncover mechanism behind the need to scratch an itch – ABC News

  https://www.abc.net.au/news/science/2025-01-31/itch-scratch-mechanism-science/104872090

  US researchers have discovered that scratching an itch releases immune cells and produces inflammation, but also reduces bacteria on the skin. […] Understanding more about the mechanism behind what causes itching could allow researchers to create better medicines and treatments for skin conditions like contact dermatitis. […] To understand more about the mechanism behind what causes itching, Professor Kaplan and his colleagues investigated how scratching affects the immune system. […] This suggested that scratching itself was a required part of producing inflammation. […] The reason for this reaction is a type of immune cell called mast cells. […] The study shows mast cells are activated in two ways. […] This then creates that itch-scratch cycle. […] It has long been understood that scratching removes parasites and toxins from the skin, but the new study shows that bacteria is also removed during a good scratching session. […] There was a benefit from a host defence standpoint. […] Professor Kaplan’s team is now looking at expanding the research focus to humans, and looking at potential treatments for inflammatory skin conditions like dermatitis.

• #57 Common Skin Bacterium Acts Directly on Nerve Cells to Trigger Itching

  https://www.genengnews.com/topics/translational-medicine/common-skin-bacterium-acts-directly-on-nerve-cells-to-trigger-itching/

  Scientists at Harvard Medical School have shown for the first time that the common skin bacterium, Staphylococcus aureus, can cause itching by acting directly on nerve cells. […] The team’s study showed that S. aureus releases a protease enzyme, known as V8, which activates a receptor on the nerve fibers that transmit signals from the skin to the brain. […] We’ve identified an entirely novel mechanism behind itch—the bacterium Staph aureus, which is found on almost every patient with the chronic condition atopic dermatitis. […] Up until now, it was thought that the itch associated with eczema and atopic dermatitis arose from the accompanying inflammation of the skin. But the new findings show that S. aureus single-handedly causes itch by instigating a molecular chain reaction that culminates in the urge to scratch.

• #58 Researchers identify what’s behind that urge to scratch — Harvard Gazette

  https://news.harvard.edu/gazette/story/2023/11/researchers-identify-whats-behind-that-urge-to-scratch/

  Scientists at Harvard Medical School have shown for the first time that a common skin bacterium Staphylococcus aureus can cause itch by acting directly on nerve cells. […] Up until now, the itch that occurs with eczema and atopic dermatitis was believed to arise from the accompanying inflammation of the skin. But the new findings show that S. aureus single-handedly causes itch by instigating a molecular chain reaction that culminates in the urge to scratch. […] Weve identified an entirely novel mechanism behind itch the bacterium Staph aureus, which is found on almost every patient with the chronic condition atopic dermatitis. […] The analyses showed that V8 triggers itch by activating a protein called PAR1, which is found on skin neurons that originate in the spinal cord and carry various signals touch, heat, pain, itch from the skin to the brain.

• #59 Researchers identify what’s behind that urge to scratch — Harvard Gazette

  https://news.harvard.edu/gazette/story/2023/11/researchers-identify-whats-behind-that-urge-to-scratch/

  Scientists at Harvard Medical School have shown for the first time that a common skin bacterium Staphylococcus aureus can cause itch by acting directly on nerve cells. […] Up until now, the itch that occurs with eczema and atopic dermatitis was believed to arise from the accompanying inflammation of the skin. But the new findings show that S. aureus single-handedly causes itch by instigating a molecular chain reaction that culminates in the urge to scratch. […] Weve identified an entirely novel mechanism behind itch the bacterium Staph aureus, which is found on almost every patient with the chronic condition atopic dermatitis. […] The analyses showed that V8 triggers itch by activating a protein called PAR1, which is found on skin neurons that originate in the spinal cord and carry various signals touch, heat, pain, itch from the skin to the brain.

• #60 Common Skin Bacterium Acts Directly on Nerve Cells to Trigger Itching

  https://www.genengnews.com/topics/translational-medicine/common-skin-bacterium-acts-directly-on-nerve-cells-to-trigger-itching/

  The investigators hypothesized that specific host receptors may mediate neuronal recognition of V8 protease to drive itch. […] Their analyses showed that V8 triggers itch by activating PAR1, which is found on skin neurons that originate in the spinal cord and carry various signals—touch, heat, pain, itch—from the skin to the brain. […] Experiments in mice also demonstrated that once activated, PAR1 initiates a signal that the brain eventually perceives as itch. […] Our study adds a bacterial protease as a pruritogen that acts through PAR1. […] Overall, we ruled out a role for MYD88, mast cells, basophils, IL31RA, IL4RA, and lymphocytes in itch. […] We show that these things can be decoupled, that you don’t necessarily have to have inflammation for the microbe to cause itch, but that the itch exacerbates inflammation on the skin.

• #61 Researchers identify what’s behind that urge to scratch — Harvard Gazette

  https://news.harvard.edu/gazette/story/2023/11/researchers-identify-whats-behind-that-urge-to-scratch/

  When we started the study, it was unclear whether the itch was a result of inflammation or not, Deng said. We show that these things can be decoupled, that you dont necessarily have to have inflammation for the microbe to cause itch, but that the itch exacerbates inflammation on the skin. […] The itchy mice whose skin was exposed to S. aureus experienced rapid improvement when treated with the drug. Their desire to scratch diminished dramatically, as did the skin damage caused by scratching. […] One possibility, the researchers said, is that pathogens may hijack itch and other neural reflexes to their advantage. […] Its a speculation at this point, but the itch-scratch cycle could benefit the microbes and enable their spread to distant body sites and to uninfected hosts, Deng said.

• #62 Researchers identify what’s behind that urge to scratch — Harvard Gazette

  https://news.harvard.edu/gazette/story/2023/11/researchers-identify-whats-behind-that-urge-to-scratch/

  When we started the study, it was unclear whether the itch was a result of inflammation or not, Deng said. We show that these things can be decoupled, that you dont necessarily have to have inflammation for the microbe to cause itch, but that the itch exacerbates inflammation on the skin. […] The itchy mice whose skin was exposed to S. aureus experienced rapid improvement when treated with the drug. Their desire to scratch diminished dramatically, as did the skin damage caused by scratching. […] One possibility, the researchers said, is that pathogens may hijack itch and other neural reflexes to their advantage. […] Its a speculation at this point, but the itch-scratch cycle could benefit the microbes and enable their spread to distant body sites and to uninfected hosts, Deng said.

• #63 Scientists uncover mechanism behind the need to scratch an itch – ABC News

  https://www.abc.net.au/news/science/2025-01-31/itch-scratch-mechanism-science/104872090

  US researchers have discovered that scratching an itch releases immune cells and produces inflammation, but also reduces bacteria on the skin. […] Understanding more about the mechanism behind what causes itching could allow researchers to create better medicines and treatments for skin conditions like contact dermatitis. […] To understand more about the mechanism behind what causes itching, Professor Kaplan and his colleagues investigated how scratching affects the immune system. […] This suggested that scratching itself was a required part of producing inflammation. […] The reason for this reaction is a type of immune cell called mast cells. […] The study shows mast cells are activated in two ways. […] This then creates that itch-scratch cycle. […] It has long been understood that scratching removes parasites and toxins from the skin, but the new study shows that bacteria is also removed during a good scratching session. […] There was a benefit from a host defence standpoint. […] Professor Kaplan’s team is now looking at expanding the research focus to humans, and looking at potential treatments for inflammatory skin conditions like dermatitis.

• #64 Pathomechanism of Pruritus in Psoriasis and Atopic Dermatitis: Novel Approaches, Similarities and Differences

  https://www.mdpi.com/1422-0067/24/19/14734

  Pruritus is defined as an unpleasant sensation that elicits a desire to scratch. Nearly a third of the world’s population may suffer from pruritus during their lifetime. This symptom is widely observed in numerous inflammatory skin diseases—e.g., approximately 70–90% of patients with psoriasis and almost every patient with atopic dermatitis suffer from pruritus. […] Despite the high prevalence of pruritus in the general population, the pathogenesis of this symptom in various conditions remains elusive. This review aims to summarize current knowledge about the pathogenesis of pruritus in psoriasis and atopic dermatitis. Each molecule involved in the pruritic pathway would merit a separate chapter or even an entire book, however, in the current review we have concentrated on some reports which we found crucial in the understanding of pruritus. However, the pathomechanism of pruritus is an extremely complex and intricate process. Moreover, many of these signaling pathways are currently undergoing detailed analysis or are still unexplained. As a result, it is currently difficult to take an objective view of how far we have come in elucidating the pathogenesis of pruritus in the described diseases. Nevertheless, considerable progress has been made in recent years.

• #65 Pathogenesis of pruritus | CoLab

  https://colab.ws/articles/10.1111%2Fj.1610-0387.2011.07585.x

  Specific receptors have been discovered on cutaneous and spinal neurons to be exclusively involved in the processing of pruritic signals. […] Just recently, the gastrin-releasing peptide receptor (GRPR) was identified on spinal neurons that are crucially involved in pruritus but not pain processing. […] Chronic pruritus is notoriously difficult to treat. […] Newer insights into the underlying pathogenesis of pruritus have enabled novel treatment approaches that target the pruritus-specific pathophysiological mechanism. […] For example, kappa-opioid receptor agonists and neurokinin-1 antagonists have been found to relieve chronic pruritus.

• #66 Itch, pruritus

  https://dermnetnz.org/topics/pruritus

  Cholestasis is thought to release toxic substances from the liver, which stimulates neural itch fibres in the skin. […] In Hodgkin lymphoma, pruritus is thought to be caused by histamine release, which may be related to eosinophilia. […] The management of chronic severe itch is difficult and often requires the use of combination therapy over a long period of time.

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