New insights into the mechanisms of itch: are pain and itch controlled by distinct mechanisms?

Abstract

Itch and pain are closely related but distinct sensations. They share largely overlapping mediators and receptors, and itch-responding neurons are also sensitive to pain stimuli. Itch-mediating primary sensory neurons are equipped with distinct receptors and ion channels for itch transduction, including Mas-related G protein-coupled receptors (Mrgprs), protease-activated receptors, histamine receptors, bile acid receptor, toll-like receptors, and transient receptor potential subfamily V1/A1 (TRPV1/A1). Recent progress has indicated the existence of an itch-specific neuronal circuitry. The MrgprA3-expressing primary sensory neurons exclusively innervate the epidermis of skin, and their central axons connect with gastrin-releasing peptide receptor (GRPR)-expressing neurons in the superficial spinal cord. Notably, ablation of MrgprA3-expressing primary sensory neurons or GRPR-expressing spinal cord neurons results in selective reduction in itch but not pain. Chronic itch results from dysfunction of the immune and nervous system and can manifest as neural plasticity despite the fact that chronic itch is often treated by dermatologists. While differences between acute pain and acute itch are striking, chronic itch and chronic pain share many similar mechanisms, including peripheral sensitization (increased responses of primary sensory neurons to itch and pain mediators), central sensitization (hyperactivity of spinal projection neurons and excitatory interneurons), loss of inhibitory control in the spinal cord, and neuro-immune and neuro-glial interactions. Notably, painful stimuli can elicit itch in some chronic conditions (e.g., atopic dermatitis), and some drugs for treating chronic pain are also effective in chronic itch. Thus, itch and pain have more similarities in pathological and chronic conditions.

Figure 1. Peripheral itch mediators and their respective receptors in skin nerve terminal

Upon tissue damage or inflammation, skin cells (keratinocytes, fibroblasts) and residential and infiltrating immune cells (macrophages, mast cells, neutrophils) release itch mediators that can activate pruriceptors in nerve terminal of C-fiber nociceptor. These itch mediators (pruritogens), such as ET-1, serotonin, histamine, tryptase, thromboxanes, leukotrienes, bile acids, LPA, nerve growth factor (NGF), tumor necrosis factor α (TNF-α) and RNAs can directly bind their cognate receptors such as GPCRs (ETA, 5HTR, H1R or H4R, PAR2/4, Mrgprs, LPAR, TGR5), TLRs (TLR3/7), and cytokines receptors (IL-31R/OSMR), expressed by pruriceptors. Activation of these itch receptors results in activation of PLCβ3 and increases in intracellular calcium through TRPV1 and/or TRPA1 to elicit itch transduction and sensation (pruriception). Activation of pruriceptors also releases additional itch mediators such as substance P to induce neurogenic inflammation and potentiate itch signaling.

Figure 2. Crosstalk of the itch and pain pathways in physiological conditions

Itch and pain are encoded by the unique labeled lines in the physiological conditions. In dorsal root ganglia or trigeminal ganglia, the large population of pain-responsive neurons (e.g., TRPV1-expressing neurons) consists of the small population of itch-responsive neurons (e.g. MrgprA3-expressing neurons) which are polymodal and also respond to painful stimuli. These pruriceptors may also express H1, PAR2, TLR3/7, TRPA1/V1, and neuropeptides (GRP, CGRP, SP). Activation of itch primary afferents stimulates neurotransmitter release from the central terminals of the pruriceptors in the spinal cord dorsa horn, leading to GRP and opioids release to activate GRPR and MOR1D-expressing neurons for itch transmission. Activation of nociceptors results in the activation of secondary nociceptive neurons (e.g., NK1R+ neurons) in the spinal cord for nociceptive transmission. Activation of nociceptors also causes subsequent activation of Bhlhb5+ inhibitory neurons to suppress itch transmission in GRPR+ neurons. In addition, spinal cord opioids can activate MOR1 to suppress pain and also activate MOR1D to elicit itch via its coupling to GRPR.

Figure 3. Crosstalk of the itch and pain pathways in pathological conditions

In pathological conditions, multiple mechanisms contribute to the development of chronic itch. (1) Activation of mast cells and T cells in injured skins causes the release of itch mediators such as histamine and IL-31, leading to the activation of pruriteptors and induction of peripheral sensitization. (2) Growth factors (e.g., NGF or artemin), released from skin cells may cause sprouting of C-fibers (including pruriceptive fibers), leading to itch hypersensitivity. Furthermore, tissue injury and damage or dysfunction of the nervous system causes central sensitization in spinal cord neurons which is associated with (3) up-regulation of GRP and GRPR, (4) decrease or loss of inhibitory control from Bhlhb5+ neurons, (5) decrease of VGLUT2-dependent glutamate release from nociceptors, and (6) activation of glial cells (astrocytes or microglia) in the spinal cord. Thus, the crosstalk of the pain and itch labeled lines are disrupted in pathological conditions. Central sensitization not only drives chronic pain but also potentiates and maintains chronic itch. In addition, descending facilitation from the brainstem may further potentiate chronic itch. These mechanisms of peripheral and central sensitization are also known to drive chronic pain.