Neural Mechanisms of Itch
A. Primary Afferent Nerves
• The most commonly used pruritogen, or itch producing stimulus, employed in experimental studies of itch is
histamine.
• histamine activated mainly C-fibers
• These histamine-sensitive C-fibers had conduction velocities slower than most C-fibers and were not
stimulated by heat or mechanical forces and were classified as a subset of heat- and mechano-insensitive
C-fibers
B. Biologic Mediators of the Itch
• Histamine
• Serotonin
• 5-HT stimulates action potential discharge in a subset of human cutaneous C-fibers
• Weaker
• Acetylcholine
• in normal healthy participants, injection of acetylcholine consistently evoked sensations of pain, while
acetylcholine injection into the skin of subjects with atopic dermatitis resulted in the sensation of itch
• patients with atopic dermatitis have a greater than 10-fold concentration of acetylcholine in their skin
compared to normal healthy controls
• Substance P
• SP is also found outside the nervous system and has been localized to human skin mast cells
• Cutaneous administration of SP in humans evoked itch in normal healthy individuals and in patients with
atopic dermatitis
• SP stimulates histamine release from human skin mast cells
• A large body of evidence demonstrates that TRPV1 is a key transduction channel that functions downstream of
histamine receptors to induce neuronal excitation and promote itch behaviors; first, TRPV1 antagonists inhibit
histamine-evoked signals in DRG neurons; second, patients with allergic rhinitis display increased itch sensations
following TRPV1 stimulation; and third, mice lacking TRPV1-expressing neurons or TRPV1 itself display
substantially less histamine-induced scratching than wild-type littermates
• Chloroquine- and BAM-evoked itch also requires the irritant receptor TRPA1, which acts as the primary
transduction channel downstream of MrgprA3 and MrgprC11.
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, [1] 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.
