Sensory neurons and circuits mediating itch

Abstract

Chemicals that are used experimentally to evoke itch elicit activity in diverse subpopulations of cutaneous pruriceptive neurons, all of which also respond to painful stimuli. However, itch is distinct from pain: it evokes different behaviours, such as scratching, and originates from the skin or certain mucosae but not from muscle, joints or viscera. New insights regarding the neurons that mediate the sensation of itch have been gained from experiments in which gene expression has been manipulated in different types of pruriceptive neurons as well as from comparisons between psychophysical measurements of itch and the neuronal discharges and other properties of peripheral and central pruriceptive neurons.

Figure 1. Sensory responses to pruritic or painful stimuli

Humans, monkeys, and mice respond differently to chemical agents that are predominantly pruritic than they do to those that are painful. A. Graph shows mean ratings of perceived intensity of itch by humans in response to injection (inj.) of histamine and to various chemical agents that evoked a histamine-independent itch, including cowhage, β–alanine, BAM8-22 and capsaicin (the latter two each delivered by means of a heat-inactivated cowhage spicule). These are compared with the perceived intensity of burning elicited by a painful injection of capsaicin. Subjects moved a cursor along a labeled magnitude scale from “no sensation” to “strongest imaginable sensation of any kind”. Four of the descriptor labels are shown on the right vertical axis in correspondence with the numerical ratings of perceived intensity indicated on the left vertical axis. B. Graph shows the scratching response of monkeys to some of the same agents. They scratched in response to application of cowhage spicules or injection of histamine solution but not in response to application of inactive spicules, saline, or injection of capsaicin or its vehicle. C. Mice, like humans, respond differently to injections of histamine (gray) and capsaicin (black). In the left panel, for each of 15 humans, the area under the intensity-time rating curve (auc) for itch was plotted against the auc for nociceptive sensations (pricking/stinging or burning, which every was judged greater at the time of a given rating) in response to histamine or capsaicin at a given dose injected into the forearm (from experiments described in REF. 7). For histamine and capsaicin: squares = 0.1 μg in 10 μl, circles = 1.0, triangles = 10. In the right panel, for each of 8–10 mice the number of bouts of scratching/20 min was plotted against the number of wipes/20 min directed toward the site of injection in the cheek of a given dose of histamine or capsaicin. Histamine: squares = 10 μg in 10 μl, circles = 20, triangles = 50; capsaicin: squares = 1 μg in 10 μl, circles = 10, triangles = 40 (modified from fig. 5, REF 15). Panel a is modified, with permission from REFS , , and . Panel b is reproduced, with permission, from REF . Panel C is modified, with permission from REFs and .

Figure 2. Pruriceptive neurons are a subset of nociceptive neurons

The circles symbolize subtypes of nociceptors that express receptors for different types of stimuli in their axonal terminals in the skin. The hypothetical combinations of receptors are based on published recordings of the capacities of different types of stimuli to activate primary, cutaneous sensory neurons when delivered either to their peripheral receptive fields in vivo (in mouse, monkey or human) or to their dissociated, cultured, cell bodies, in vivo (mouse only). There are two main types of nociceptors: those that respond to pruritic chemicals and those that do not (pruriceptive and non-pruriceptive nociceptors, respectively). Both types of nociceptor also respond to one or more noxious stimuli (mechanical or heat stimuli or capsaicin injection) that elicit pain and not itch. The symbols illustrate some of the receptors expressed by each subtype. In mice, some pruriceptive nociceptors have been shown to express the receptor for chloroquine, Mas-related G-protein coupled receptor member A3 (MrgprA3), and the receptor for bovine adrenal medulla 8–22 peptide (BAM8-22), MrgprC11. Primates have been shown to express the receptor for either of these ligands (MrgprX1) in a subset of nociceptors. The transduction of protease contained in cowhage is poorly understood but is hypothesized to involve protease-activated receptor 2 (PAR2) and/or PAR4. Other receptors shown are for histamine (H1), β-alanine (MrgprD), capsaicin, noxious mechanical stimuli (mechanoreceptors), and heat that is trandsuced either by transient receptor potential vanilloid 1 (TRPV1)), or by a mechanism independent of TRPV1. For clarity, other combinations of the receptors shown or other markers associated with nociceptive/pruriceptive transduction (such as TRPA1,TRPM8 and P2X3) or intracellular signaling are omitted.

Figure 3. Hypothesized cutaneous input to pruriceptive and non-pruriceptive spinothalamic tract neurons in primate

On the left of the figure, different types of stimuli are presented to the same set of 9 nociceptors and the nociceptors that they activate in each case are shown. Shaded circles indicate activated nociceptors and empty circles indicate unresponsive nociceptors. The presence of particular transduction mechanisms in each neuron are as shown. Non-pruriceptive nociceptors include those that respond only to noxious mechanical stimuli (brown) and mechanically insensitive nociceptors expressing transient receptor potential vanilloid 1 (TRPV1) (red). The nociceptors depicted in green respond to one or more pruritic chemicals but also to one or more noxious stimuli. On the right, the schematic shows how these different types of peripheral sensory neurons might provide input to three types of nociceptive spinothalamic tract (STT) neurons, based in part on information obtained in the monkey. All three types of STT neurons respond to noxious heat, capsaicin and/or mechanical stimuli but one pathway (red) is non-pruriceptive whereas the other two are pruriceptive (green). The pruriceptive neurons consist of two populations: STTs that are more responsive to cowhage than to histamine (green dashed line) and thus presumably receive a dominant input from C- and A-mechanosensitive afferent (MSA) neurons and STTs that are more responsive to histamine than to cowhage (green solid line) and receive a dominant pruriceptive input from histamine responsive mechanically insensitive afferent (MIA) neurons. The unknown synaptic mechanisms by which each type of afferent fiber contacts the STT neurons are indicated with arrows: these including a direct monosynaptic input and, via one or multiple interneurons, polysynaptic input (not shown). Action potential activity in the STT neurons is also subject to modulation by excitatory and inhibitory interneurons (not shown) as described in Fig. 5. The image also shows the relatively greater spatial spread of a noxious stimulus or pruritogen when it is applied by injection than when it is applied by a spicule (as illustrated by the size of the shaded area on the left).

Figure 4. Pruriceptive neuronal activity matches the time course of itch sensation

The mean perceived intensity of itch in humans and the mean discharge rates of primary afferents and spinothalamic tract neurons recorded in the monkey are shown (n = number of human subjects or number of nerve fibers or STT neurons tested). The responses of pruriceptors – that is, mechanoheat sensitive C-fibers and mechanosensitive A-fiber nociceptors – to cowhage and histamine are compared with the responses of pruriceptive spinothalamic tract (STT) neurons to the same stimuli. The responses of each neuron and each subject were normalized to the peak value obtained for that subject or neuron for a given pruritic agent (baseline activity for each STT is subtracted from the responses). Assuming that similar sensations are present in monkeys and humans, the finding that itch begins with the onset of activity in these neurons, reaches a peak magnitude and declines in approximate correspondence with the activity suggests that the itch is mediated at least in part by the activity of these neurons. Data obtained from REFS , , , and .

Figure 5. Models of modulation of itch transmission in the dorsal horn

A: The activity of pruriceptive (green) spinothalamic tract (STT) neurons is influenced by opposing inputs from excitatory and inhibitory interneurons. Here, the excitatory interneuron remains active (filled circle), whereas the inhibitory interneuron is either silenced (open circle), for example, by activation of an opiate receptor (blue symbol) by intrathecal morphine or absent as a result of elimination of inhibitory interneurons such as those expressing the transcription factor Bhlhb1. This results in the generation of ‘spontaneous’ itch sensations. B: Pruriceptive afferents selectively sensitize (dashed line) interneurons that receive input from low-threshold mechanoreceptors. As a result a pruriceptive STT neuron now exhibits enhanced responses to innocuous tactile stimuli (to induce tactile alloknesis). C: Simultaneous activity in histamine responsive pruriceptive neurons and activity generated by scratching in non-pruriceptive (red) mechanosensitive nociceptors, activate an interneuron that inhibits a pruriceptive - STT neuron (modified from an “and-gate” model ). All STT neurons are also subject to modulation by suprasegmental descending pathways that are not shown. For simplicity, both the neuropeptides and their receptors that are thought to be involved in the itch circuit are not included.

Figure 6. Secondary dysesthesias in response to pruritic or algesic chemicals

A. The images show, for a human subject, the typical areas of skin reactions and hypersensitivities to mechanical stimulation surrounding the site of intradermal injection of either histamine or capsaicin. The chemical stimuli elicit a neurogenic flare and areas of increased pain and itch in response to punctuate mechanical stimuli. These responses include hyperalgesia, an enhanced pricking pain to a normally painful von-Frey filament (200 μm diameter, 200 mN bending force) and hyperknesis (enhanced pricking evoked itch to a von-Frey filament of 50 μm and 20mN). Histamine can evoke alloknesis but not allodynia (that is, it can evoke itch, but not pain or tenderness, in response to gently stroking the skin) whereas the reverse is true after capsaicin. In addition, the area of allodynia is “anti-pruritic” – that is, itch cannot be elicited by injection of histamine. B. The schematic shows that chemosensitive nociceptive primary afferents differ in their central projections and capacities to selectively enhance (sensitize, shown by dashed lines and + symbols) the responses of a projection neuron to certain types of input (here tactile receptors are used as an example). Pruriceptive primary afferents, such as those responsive to histamine enhance the responses of some but not all pruriceptive (P) STT neurons. Non-pruriceptive nociceptive primary afferents that respond to capsaicin are capable of sensitizing some, though not all, non-pruriceptive (N) STT neurons thereby contributing to tactile allodynia. The presence of allodynia blocks (indicated by the - symbol) the occurrence of itch and alloknesis.

Figure 7. Representing itch versus pain in the responses of nociceptive neurons

A: The matrix of circles represents a population of neurons exposed to noxious stimulation produced by heat (yellow), mechanical indentation (brown) or capsaicin injection (red). Responsive and non-responsive neurons are respectively shaded in or open. In this example, the pruriceptive neuron (green dashed circle) expresses MrgprA3 (in mouse). Both pruriceptive (green circles) and non-pruriceptive (orange circles) neurons respond to noxious stimuli B: Selective activation of the pruriceptive neuron by histamine, by a cowhage spicule, and by an injection of capsaicin (the latter in a mouse in which the capsaicin receptor has been knocked out. The schematic illustrates how the sensation of itch may be derived from both the specific types of neurons activated and the number and distribution of neurons activated as predicted by the ”specificity”, “population”, “intensity”, and “spatial contrast” models of itch.