The multiple pathways for itch and their interactions with pain

Abstract

Multiple neural pathways and molecular mechanisms responsible for producing the sensation of itch have recently been identified, including histamine-independent pathways. Physiological, molecular, behavioral and brain imaging studies are converging on a description of these pathways and their close association with pain processing. Some conflicting results have arisen and the precise relationship between itch and pain remains controversial. A better understanding of the generation of itch and of the intrinsic mechanisms that inhibit itch after scratching should facilitate the search for new methods to alleviate clinical pruritus (itch). In this review we describe the current understanding of the production and inhibition of itch. A model of itch processing within the CNS is proposed.

Figure 1

A schematic illustrating multiple anatomical pathways for itch, including transduction at the peripheral terminals in the skin, synaptic transmission in the spinal cord, and central projections to the thalamus. (A) Polymodal C-fibers are activated in the epidermis by the non-histaminergic pruritogen, cowhage. Box A: Cowhage releases mucunain, a protease that cleaves and activates the Protease Activated Receptor 2 (PAR-2) located in the peripheral terminal. Activation of PAR-2 activates Phospholipase-C (PLC) which, in turn, sensitizes Transient Receptor Potential Vanilloid-1 and Ankyrin-1 (TRPV1 and TRPA1). Additionally, PAR-2 leads to membrane depolarization by inhibiting a voltage-gated K⁺ channel. (B) Histamine, typically released by mast cells in the dermis, activates a population of mechanically-insensitive C-fibers (CMi). These fibers innervate a broad territory and, upon activation, release pro-inflammatory mediators such as Calcitonin-Gene-Related-Peptide (CGRP) into the skin leading to vasodilation and widespread flare. Box B: Histamine receptor-1 activates PLCβ3 and phospholipase A2 (PLA₂) leading to sensitization of TRPV1. The presence of TRPV1 is required for the histamine evoked response (i.e. TRPV1 and the histamine receptor-1 act together as an “AND-GATE” to produce a response to histamine). The chloroquine receptor, MgrprA3 is present on histamine responsive fibers, but may have independent, intracellular signaling mechanisms. The bradykinin receptors (B1 and B2) are also expressed on histamine responsive DRG. (C) Both non-histaminergic C-polymodal fibers and histamine-responsive CMi fibers terminate centrally in the dorsal horn of the spinal cord. Each excites distinct populations of spinothalamic tract neurons that maintain separate histaminergic and non-histaminergic channels in primates. Little is known of itch responsive thalamic neurons. Box C: Polymodal C-fibers and CMi fibers release excitatory neurotransmitters as well as peptide neuromodulators such as substance-P (SP), CGRP, and the gastrin-releasing-peptide (GRP). The central terminals of primary afferent neurons form synapses with spinal interneurons possessing the Gastrin-Related-Peptide-Receptor (GRPR).

Figure 2

A simple model of somatosensory encoding for itch, pain and touch by functionally distinct polymodal spinal neurons. Bottom: The skin is exposed to various stimuli: pruritogenic, noxious and tactile. These stimuli activate different subpopulations of spinothalamic tract (STT) neurons. Middle: STT neurons are either pruriceptive (pruri) or not-pruriceptive (non-pruri) and either of the wide dynamic range (WDR) or high threshold (HT) type. The smaller subpopulation of STT neurons that are pruriceptive are represented by smaller circles, and the larger population of STT neurons that are nociceptive (non-pruriceptive) are represented by larger circles. The output from selective activation of these four types of neurons could distinctively encode touch, pain and itch. Tactile stimuli activate WDR, but not HT neurons. Noxious stimuli activate all four types of neurons. Itch producing stimuli activate only the pruriceptive subpopulation of neurons. Top: When only the pruriceptive STT neurons are activated (i.e., in the absence of activation of the other nociceptive STT neurons), then itch is signaled. Pruriceptive neurons may also contribute to tactile and nociceptive processing, but without complementary activity in the nociceptive-type neurons, activation of pruriceptive STT neurons produces itch. Thus, the absence of activation of certain subpopulations of STT neurons is hypothesized to be important in transmitting specific sensory information to the brain.

Figure 3

A schematic of a current working model for the inhibition of pruriceptive spinothalamic tract neurons by scratching. (A) Itch and scratch stimuli activate dorsal root ganglion (DRG) neurons which synapse in the dorsal horn of the spinal cord. Pruritic information ascends in the spinothalamic tract (STT). Descending modulation of pruriceptive spinal neurons may arise from neurons in the periaquaductal grey (PAG). (B) From the boxed region in (A): Pruritogen-responsive primary afferent fibers are hypothesized to synapse (directly or indirectly) onto STT neurons and make another synapse onto an inhibitory interneuron (black). The synapse to the STT neuron drives action potential production, but the synapse onto the inhibitory interneuron is proposed to be too weak to drive action potential production alone. However, simultaneous activation of the pruritogen-responsive primary afferent fiber along with activation of a nociceptive fiber that also synapses onto the same inhibitory interneuron would provide an adequate stimulus. This “AND-gate” inhibitory interneuron is proposed to have strong inputs to the STT neuron and can block the response evoked by histamine. This is consistent with the idea that scratching produces central inhibition only during an itch. Also depicted is the possible involvement of a descending pathway hypothesized to originate from the PAG (green). Other possibilities such as inhibition of central terminals by retrograde signaling from dorsal horn neurons exist, but are not illustrated.