Chronic Pruritus in the Absence of Specific Skin Disease: An Update on Pathophysiology, Diagnosis, and Therapy

Nicoletta Cassano; Gianpaolo Tessari; Gino A. Vena; Giampiero Girolomoni

Disclosures

Am J Clin Dermatol. 2010;11(6):399-411. 

In This Article

Neurophysiology of Itch

Skin-nerve Interactions and Itch

The skin is highly innervated by primary sensory nerves, postganglionic cholinergic parasympathetic and postganglionic sympathetic nerves, resulting in a complex cutaneous afferent/efferent neuronal network. Itch-specific fibers are unmyelinated C fibers, mainly peptidergic, with slow conduction velocity and large innervation territories.[2] They account for about 5% of the afferent C fibers in human skin, respond to histamine and thermal stimuli but are insensitive to mechanical stimuli. Nerve fibers usually end at the dermal-epidermal junction, but some unmyelinated C fibers also project into the epidermis to the subcorneal layers.[3] Therefore, nerve fibers may reciprocally communicate with all skin cell types. The number of peripheral and central mediators thought to be involved in the generation of an itch sensation is rapidly increasing ( table I ). Opioid receptors, especially μ- and κ-receptors, modulate pruritus perception in the CNS and in the skin.[4] Activation of μ-opioid receptors stimulates itch perception, whereas activation of κ-opioid receptors suppresses itch perception. Keratinocytes can release mediators with both pruritic and antipruritic effects, including endovanilloids, endorphins, neuropeptides, proteases, and cytokines, and express on their cell surface the receptors for several itch mediators such as histamine, neuropeptides, neurotrophin, cannabinoids, nerve growth factor, proteinase-activated receptor-2, and the transient receptor potential vanilloid 1 ion channel (TRPV1). Physical (e.g. dry skin, skin barrier disruption) and chemical stimuli can induce keratinocytes to release pruritogenic or antipruritogenic substances.[3,5,6]

Spinal and Central Processing of Itch

Pruritoceptive primary afferent fibers activate spinal neurons in lamina I of the dorsal horn, which projects to the lateral part of the thalamus.[7] Substance P and calcitonin gene-related peptide are the most studied neurotransmitters, and present both peripheral and central activity.[8,9] In addition, a recent study in an animal model has proposed a relevant role for gastrinreleasing peptide in the spinal transmission of itch stimuli.[10] Direct excitatory connections from the thalamus project to the anterior cingulated cortex, insular cortex, and primary and secondary somatosensory cortices.[11] Histamine-induced itch produces the co-activation of some motor areas, suggesting the existence of an organic link between itch and scratching.[12] In contrast to pain sensation, which induces an 'avoiding' motor response, pruritus evokes an 'active' scratching motor activity. The inhibition of itch by painful stimuli can occur at both the central and peripheral levels. It is commonly observed in patients with severe pruritus who stop scratching when skin lesions start bleeding and become painful. Conversely, spinal administration of opioids suppresses pain and induces segmental severe itch. Some mediators of itch (e.g. substance P, neuropeptides) can also induce pain.[13] Itch and pain share the same cortical brain areas, but a different pattern of activation exists. Itch processing is characterized by a weaker activation of somatosensory cortices with a stronger activation of ipsilateral motor areas as compared with pain processing.[14,15]

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