<unk>  can originate in the peripheral nervous system (dermal or neuropathic) or in the central nervous system (neuropathic, neurogenic, or psychogenic). Dermal/pruritoceptive A chipmunk scratching itself.<unk>  originating in the skin is known as pruritoceptive, and can be induced by a variety of stimuli, including mechanical, chemical, thermal, and electrical stimulation. The primary afferent neurons responsible for histamine-induced<unk>  are unmyelinated C-fibres. Two major classes of human C-fibre nociceptors exist: mechano-responsive nociceptors and mechano-insensitive nociceptors. Mechano-responsive nociceptors have been shown in studies to respond to mostly pain, and mechano-insensitive receptors respond mostly to<unk>  induced by histamine. However, it does not explain mechanically induced<unk>  or<unk>  produced without a flare reaction that involves no histamine. Therefore, it is possible that pruritoceptive nerve fibres have different classes of fibres, which is unclear in current research. Studies have been done to show that<unk>  receptors are found only on the top two skin layers, the epidermis and the epidermal/dermal transition layers. Shelley and Arthur verified the depth by injecting individual<unk>  powder (Mucuna pruriens) spicules and noting that maximal sensitivity occurred at the basal cell layer or the innermost layer of the epidermis. Surgical removal of those skin layers removed the ability for a patient to perceive<unk> .<unk>  is never felt in muscle or joints, which strongly suggests that deep tissue probably does not contain<unk>  signaling apparatuses.<unk>  is often classified as that which is histamine mediated (histaminergic) and nonhistaminergic. Sensitivity to pruritic stimuli is evenly distributed across the skin and has a clear spot distribution with similar density to that of pain. The different substances that elicit<unk>  upon intracutaneous injection (injection within the skin) elicit only pain when injected subcutaneously (beneath the skin).<unk>  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. Although experimentally induced<unk>  can still be perceived under a complete A-fiber conduction block, it is significantly diminished. Overall,<unk>  sensation is mediated by A-delta and C nociceptors located in the uppermost layer of the skin. Molecular diversity of<unk>  transmitting primary afferents Using single-cell mRNA sequencing, sensory-modality specific primary afferent have been molecularly defined into clusters based on gene expression patterns. Here, 11 sub clusters were detected; NF1-3, transmitting innocuous nociceptive information; NF4-5, which transmit proprioceptive information; NP1-3, transmitting<unk>  information; PEP1-2, nociceptive information and TH, which is involved in pleasant touch, The pruriceptive NP1-3 were shown to express genes related to histaminergic and non-histaminergic signaling, where NF1 expresses genes responding to lysophosphatidic acid (Lpar3 and Lpar5), NP2 chloroquine-responsive genes (Mrgpra3 and Mrgprx1), whereas NP3 expresses neuropeptides Nppb and Sst as well as genes involved in inflammatory<unk>  (Il31ra, Osmr and Crystrl2). The histamine receptor gene Hrh1 was found in NP2 and NP3, suggesting that histaminergic<unk>  is transmitted by both these pruriceptive sub clusters. The spinal<unk>  pathway After the pruriceptive primary afferent has been activated, the signal is transmitted from the skin into the spinal dorsal horn. In this area, a number of interneurons will either be inhibited or activated to promote activation of projection neurons, mediating the puriceptive signal to the brain. The GRP-GRPR interneuron system has been found to be important for mediating both histaminergic and non-histaminergic<unk> , where the GRP neurons activate GRPR neurons to promote<unk>  Neuropathic Neuropathic<unk>  can originate at any point along the afferent pathway as a result of damage of the nervous system. They could include diseases or disorders in the central nervous system or peripheral nervous system. Examples of neuropathic<unk>  in origin are notalgia paresthetica, brachioradial pruritus, brain tumors, multiple sclerosis, peripheral neuropathy, and nerve irritation. Neurogenic Neurogenic<unk> , which is<unk>  induced centrally but with no neural damage, is mostly associated with increased accumulation of exogenous opioids and possibly synthetic opioids. Psychogenic<unk>  is also associated with some symptoms of psychiatric disorders such as tactile hallucinations, delusions of parasitosis, or obsessive-compulsive disorders (as in OCD-related neurotic scratching). Peripheral sensitization Inflammatory mediators—such as bradykinin, serotonin (5-HT) and prostaglandins—released during a painful or pruritic inflammatory condition not only activate pruriceptors but also cause acute sensitization of the nociceptors. In addition, expression of neuro growth factors (NGF) can cause structural changes in nociceptors, such as sprouting. NGF is high in injured or inflamed tissue. Increased NGF is also found in atopic dermatitis, a hereditary and non-contagious skin disease with chronic inflammation. NGF is known to up-regulate neuropeptides, especially substance P. Substance P has been found to have an important role in inducing pain; however, there is no confirmation that substance P directly causes acute sensitization. Instead, substance P may contribute to<unk>  by increasing neuronal sensitization and may affect release of mast cells, which contain many granules rich in histamine, during long-term interaction. Central sensitization Noxious input to the spinal cord is known to produce central sensitization, which consists of allodynia, exaggeration of pain, and punctuate hyperalgesia, extreme sensitivity to pain. Two types of mechanical hyperalgesia can occur: 1) touch that is normally painless in the uninjured surroundings of a cut or tear can trigger painful sensations (touch-evoked hyperalgesia), and 2) a slightly painful pin prick stimulation is perceived as more painful around a focused area of inflammation (punctuate hyperalgesia). Touch-evoked hyperalgesia requires continuous firing of primary afferent nociceptors, and punctuate hyperalgesia does not require continuous firing which means it can persist for hours after a trauma and can be stronger than normally experienced. In addition, it was found that patients with neuropathic pain, histamine ionophoresis resulted in a sensation of burning pain rather than<unk> , which would be induced in normal healthy patients. This shows that there is spinal hypersensitivity to C-fiber input in chronic pain.
Itch
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Body odor
Sharsheret 
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