For a long time, itch appeared to be a neglected symptom - not because of a lack of interest from researchers, but perhaps owing to a misguided concept that somehow itch was the 'little brother of pain' and, therefore, relatively less important. In fact, this particularly disturbing sensation was more like an orphan, equally neglected by funding agencies and medical authorities.

The initial lack of clues into the mechanisms of itch transmission made this oversight rather understandable. However, this situation is now changing, and itch is increasingly receiving attention from many research groups. Notable progress has been made in recent years to better understand itch generation, transmission, signaling and processing within the higher structures of the central nervous system (CNS). However, with a few exceptions, itch still cannot be easily or fully suppressed using any pharmacologic means currently available, owing to the simple fact that we are still missing an effective itch-specific approach. Itch therapy is complicated because its causes can be multiple, and can differ depending on the particularities of the specific etiology involved.

Table 1. List of abbreviations used throughout the article.

Novel Molecular Receptors for Itch

The first receptors implicated in itch were the H1 histamine receptors. However, most chronic itches of various etiologies, with the exception of urticaria, remained refractory to antihistamines directed at H1 receptors. Recent advances in the field have uncovered that the novel H4 receptor plays an important role in inflammatory and allergic responses, as well as in pruritus, which might explain, at least in part, the limited ability of H1 antihistamines to relieve chronic itch. Furthermore, it is now known that itch can be transmitted via several non-histaminergic pathways (Figure 1) and thus this is the most likely explanation as to why antihistamines fail to relieve itch.

Therefore, attention has turned in recent years to 'alternative' receptors for itch. Although it has been known for many decades, thanks to the pioneering work of Shelley and Arthur, that the spicules of the tropical plant cowhage (Mucuna pruriens, velvet bean) can induce an itch that is unquenchable by antihistamines, it was only revealed a few years ago that the mechanism involved a protease called mucunain, which acted on proteinase-activated receptor 2 (PAR2).¹ Corroborating evidence indicates that PAR2 is an important mediator of itch in atopic dermatitis, where it is also overexpressed.² PAR2 can be activated by a variety of proteases such as trypsin, tryptase and kallikreins, and its activation by a cysteine protease gave more traction to the idea that endogenous proteases such as cathepsin S could be important factors in itch induction.³

Since the identification of the transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor as the molecular target of the powerful irritant capsaicin,⁴ an avalanche of discoveries in the field of pain research has impacted itch transmission. Capsaicin - mainly used as an analgesic in arthritis and post-herpetic neuralgia, etc. - is an unconventional antipruritic agent, producing a powerful and lasting desensitization of nerve fibers.⁵ This molecule elicits itch sensation upon topical application, which suggests a role for TRPV1 in itch mediation. Subsequent findings about the larger family of TRPV3,⁶ TRPV4 and melastatin receptors (e.g. TRPM8 which, when stimulated by menthol, produces a cooling, itch-relieving effect) have cemented their clear role in itch modulation.^7,8 TRPV1 has been reported to be required for the transmission of histaminergic itch. Conversely, TRPV1 is co-expressed in the small population of neurons expressing PAR2, suggesting cross-talk and/or a dual-gating mechanism required for the transmission of itch via non-histaminergic routes (Figure 1).

One of the most significant developments in the field occurred when a specific itch G-protein-coupled receptor (GPCR) called gastrin-release peptide receptor (GRPR), from the bombesin receptor family, was reported in the superficial dorsal horn in mice.⁹ GRPR-positive neurons were also found in the dorsal root ganglion (DRG), and act as interneurons in the spinal cord. Ablation of GRPR-positive neurons with bombesin-saporin (which induces selective neuronal cell death) significantly diminished scratching behavior in response to non-histamine pruritogens in mice (e.g. chloroquine and the PAR2 agonist peptide SLIGHR-NH₂ ), but did not affect pain responses. Genetic knockout of the GRPR also led to a reduced response to itch stimuli but did not affect pain transmission.

In a related development, the discovery of Mas-related gene product receptors (Mrgprs) as the molecular relays of chloroquine itch is particularly interesting, as Mrgrps are reportedly co-expressed with GRPR in small- and medium-diameter neurons, which suggests a potential interaction between specific itch afferents and specialized itch neurons in the spinal cord.¹⁰ Both are G-protein-coupled receptors. The antimalarial drug chloroquine is a powerful itch inducer in rodents, and also induces severe itch in humans, selectively in the Black African population. Chloroquine acts specifically on a subset of Mrgprs - MrgprA3 and C11 - in mice, whereas the corresponding receptor that it acts upon in humans, MrgprX1, is present in DRG neurons. Recently, the topical application of a specific agonist peptide of MrgprX1, BAM8-22, has been tested in humans and has produced itch and nociceptive sensations that could not be inhibited by pre-administration of the potent antihistamine doxepin.¹¹ This is a significant finding, as it shows that some important itch discoveries in animal models are translatable to humans. In addition, the ankyrin TRPA1 receptor is required for the induction of itch evoked by chloroquine.¹²

Quite a stir in the field has been produced by findings suggesting that Toll7, the target of the immunomodulator drug imiquimod, may be directly involved in itch signaling.¹³ However, the exact mechanism of action currently remains controversial, as a newer report using transgenic models has concluded that, ultimately, TRPV1 is responsible for the itching induced by this drug, which only managed to re-emphasize the central role for TRPV1 in modulating or gating different itch modalities.¹⁴ It thus became obvious that a specific subset of TRPV1-positive neurons could be equipped with diverse intracellular mechanisms in order to respond to histamine, chloroquine and imiquimod. The translational potential of this finding has been disputed, however, as imiquimod rarely causes itch in humans.

Recent discoveries suggest that the SLIGRL peptide, formerly considered to be a typical PAR2 agonist for induction of itch in mice, works through the newly discovered MrgprC11 receptor.¹⁵ Among the four types of MrgrprX found in humans, the corresponding PAR2 peptide human agonist SLIGKV was found to activate MrgprX2 specifically. However, the role of these receptors, and their subsequent signaling pathways, may function differently across species, and thus PAR2 can still function as a primary itch transducer in humans - for example, by mediating the action of tryptase. In a comparative biology context, the confirmation of a specific itch pathway mediated via GRPR has yet to be produced in humans, which is needed in order for the current models developed in mice to gain more traction and to encourage the development of therapies targeting specific itch mechanisms.

Figure 1. Signaling pathways for itch involve transduction at the peripheral nerve fibers in the skin, synaptic transmission in the spinal cord, and central projections to the thalamus. Cowhage-induced itch is mediated by PAR2 receptors and conducted by polymodal C-fibers, whereas histamine itch is mediated by a population of mechanically insensitive C-fibers; both terminate in the dorsal horn of the spinal cord, where they synapse with distinct spinothalamic tract neurons. Therefore, histaminergic and non-histaminergic itch pathways are separated in primates. The antimalarial chloroquine can induce itch acting upon the MgrprA3 receptor. B1 or B2, bradykinin receptors; CGRP, calcitonin gene-related peptide; GRPR, gastrin-releasing peptide receptor; MgrprA3, MAS-related gene-related product A3; PLA2, phospholipase A2; PLC, phospholipase C; SP, substance P; TRPV1 and TRPA1, transient receptor potential vanilloid-1 and ankyrin-1. Reprinted with permission from Davidson and Giesler.²¹

Advances in our Understanding of Systemic Itch

Itch of systemic origin can embrace many clinical forms and could be produced by various mechanisms. Progress has been made in understanding the etiology of cholestatic pruritus, in which lysophosphatidic acid (LPA) produced by autotaxin from lysophosphatidylcholine has been proposed as a novel mediator.¹⁶ LPA is a signaling molecule that can activate neurons through LPA receptors and provokes itch in mice upon intradermal injection. Autotaxin serum levels were reported to be highly elevated in patients with chronic cholestatic pruritus. Another severe form of systemic itch with a complex etiology is uremic pruritus. The underlying processes were hard to identify owing to the multitude of metabolic, electrolytic and endocrine disturbances present in end-stage renal disease; however, recent findings converge to suggest that uremic pruritus can be understood as a systemic inflammatory disease that is characterized by an imbalance in T helper cell (Th1/Th2) differentiation favoring Th1, which is subsequently aggravated by an excess production of Th1-derived cytokines, such as interleukin-2, a well-known pruritogen.¹⁷

The Complex Dialectic Relationship Between Itch and Pain, and the Implications for Itch Signaling

It is currently established that neurons specialized in itch transmission can also convey pain. However, some nociceptive neurons are uniquely equipped with itch-sensing capabilities - through itch receptors or pruriceptors - whereas others (the majority of them) are strictly nociceptive. The molecular basis for this distinction is still a matter of intense investigation.¹⁸ Itch and pain appear to share the same neuronal afferent pathways, but with a twist: pain can suppress itch, whereas the relief of pain can induce, unmask or amplify pruritus. For example, the pharmacologic segmental analgesia acquired with μ-opioid receptor agonists, such as morphine, is accompanied by an induction of segmental itch, whereas conversely, κ-opioid agonists can relieve itch. This suggests that the interplay between pain and itch can be regulated by the balance in μ- versus κ-opioid receptor activation. Recently, spinal cord neurons expressing the Nav1.8 ion channel and which deliver glutamate via the vesicular transporter VGLUT2 were proposed as a molecular basis for the switch underlying pain transmission and itch inhibition, as transgenic mice lacking VGLUT2 were impervious to pain stimuli, but displayed an increased scratching behavior.^19,20

The current models for neuronal itch transmission recognize distinct pathways for histamine-mediated and non-histaminergic forms of itch, the latter involving several receptors. To date, no consensus has been reached on whether itch is conveyed via a dedicated (labeled) line, or whether it is encoded by the differential participation of subpopulations of neurons expressing specific pruriceptors. It is becoming increasingly likely that itch-specific information is primarily encoded or regulated at the spinal level by a delicate interplay of inputs from peripheral afferents, spinal cord interneurons, inhibitory inputs from strictly nociceptive afferents, and top-bottom regulatory/inhibitory inputs from higher CNS structures (possibly relayed via periaqueductal gray formation).^21,22 It is also possible that neurons in the thalamus can distinguish nociceptive versus pruriceptive information via a selection mechanism.

Neuroimaging of Itch

Because the exact projections of the third neuron conveying "itch information" from the thalamus to the cerebral cortex have not been identified, they instead can be inferred from brain imaging studies. Imaging the central processing of itch can help us better understand itch perception and its mechanisms, can provide a valuable insight into potentially altered CNS processing in pathologic chronic itch states, and can explain the phenomenon of "central sensitization" (a heightened sensitivity to itch stimuli arising within the CNS). There is still much to learn about how the itch sensation is formed, processed, centrally modulated or possibly inhibited. An increased understanding of the central nervous processes involved in itch will therefore be critical to develop specific itch treatments.

The current picture emerging from neuroimaging studies shows that the brain processing of itch is complex and involves somatosensory, multiple primary and secondary motor centers (confirming the important link between itch and scratching), as well as extensive areas in the posterior and lateral parietal cortex, which is not observed in pain. Itch activates deep-seated areas of the limbic system and the posterior and anterior cingulate cortices (related to affective, emotional and motivational functions), and it also involves areas controlling addictive behavior (insula). Recent studies using arterial spin-labeling fMRI (functional magnetic resonance imaging), which contrasted the processing of cowhage and histamine itches, emphasized the involvement of a previously under-investigated formation - the claustrum - a "hidden" structure with anatomical connectivity features and functional specializations seemingly fitting for itch processing.²³ The claustrum appears strategically situated to intercept somatosensory information travelling from the thalamus to the cortex, and it is connected with almost all cortical regions. The claustrum and insula registered the cowhage itch more significantly than the histamine itch.²³ The addictive character of the itch-scratch cycle has a profound impact on the networks processing emotional experiences via the cingulate cortex and the Papez circuit. The involvement of itch in modulation of affective states and its correlation with stress are reflected in the involvement of the limbic system, amygdala and the anterior cingulate cortex.

Conclusions

The recent advances made in the study of itch have unveiled new classes of receptors and novel signaling pathways, acting both peripherally and centrally, that can be further explored and utilized. This brings hope that the days of developing specific itch therapies are near.

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