Anatomy and neurophysiology of pruritus

Abstract

Itch has been described for many years as an unpleasant sensation that evokes the urgent desire to scratch. Studies of the neurobiology, neurophysiology, and cellular biology of itch have gradually been clarifying the mechanism of itch both peripherally and centrally. The discussion has been focused on which nerves and neuroreceptors play major roles in itch induction. The "intensity theory" hypothesizes that signal transduction on the same nerves leads to either pain (high intensity) or itch (low intensity), depending on the signal intensity. The "labeled-line coding theory" hypothesizes the complete separation of pain and itch pathways. Itch sensitization must also be considered in discussions of itch. This review highlights anatomical and functional properties of itch pathways and their relation to understanding itch perception and pruritic diseases.

Figure 1

The neural pathway for itch. Histamine activates H1R on the “labeled-line” that is specific to itch, which consists of CMi and spinothalamic tract nerves. Recent studies on itch induced by cowhage, whose protease exerts neural activation via PARs, such as PAR₂, indicate the presence of another itch pathway that is composed of polymodal C-nerves and different spinothalamic tract nerves. Both pathways ascend to the thalamus via the dorsal horn in the spinal cord. The activation of several brain areas, including the primary somatosensory cortex (S1), ACC, and insula, seems to be involved in itch perception.

Figure 2

The neurotransmission for itch in the spinal cord. GRP and SP released from presynaptic neurons may exert their pruritogenic roles via BB2 and NK1R, respectively, in the spinal cord. The antipruritic effect of aprepitant, an NK1R antagonist, has been reported. The administration of morphine induces itch via binding to MOR, whereas itch is suppressed by blocking MOR with MOR antagonists, such as naloxone and naltrexone, or activating KOR with KOR agonists, such as nalfurafine. NMDA receptors (NMDA-R) become sensitized by continuous inputs from presynaptic neurons. In such circumstances, glutamate release, which can be blocked by gabapentin- or pregabalin-induced decrease in Ca²⁺-inflow, leads to more intense activation of NMDA-R, and is supposed to cause more itch.