1. Introduction
For decades, the study of itch has received less attention than pain research in neurosciences; nevertheless, we have seen rapid progress in uncovering itch-specific pathways and mediators in the past few years. In particular, the characterization of molecularly defined primary afferents and spinal cord neurons for itch may suggest that the development in the itch field may even have surpassed pain research in some aspects. The relevance of these new developments for neuropathic itch has been recently reviewed in a more clinical context54 and from a more mechanistic perspective.15 This narrative review will focus on the question to which extent the current surge of basic knowledge in itch pathways and mediators can improve our understanding of clinical neuropathic itch. We will also focus on the limitations hampering the translation between basic science and clinical observations.
When considering the problems we have in defining mechanisms of clinical neuropathic itch, it should be noted that also the progress in defining mechanisms and mediators of neuropathic pain has been tedious. Indeed, several basic questions on neuropathic pain mechanisms are still unsolved, such as the relative importance of neuronal vs non-neuronal cells, of peripheral input vs central processing and of spontaneous vs evoked activity. It is therefore not surprising that also the basic mechanisms of neuropathic itch are remaining unsolved to date. Reports that neuropathic itch is common among patients with postherpetic neuralgia20,38 have increased the awareness of the problem, and meanwhile the perspectives on neuropathic itch have broadened and include poststroke, peripheral nerve trauma, or hereditary conditions.13,31 In parallel to this development in clinical research, neuropathic itch has also been integrated conceptually into basic neuroscience research focusing on impaired spinal inhibition in neuropathic pain.7 Considering the clinical overlap between neuropathic itch and pain, it is not surprising that therapeutic options are similar,54 with the major exception of µ-opioids that are analgesic, but induce itch on the spinal level.
Seemingly, it is straightforward to apply the new knowledge accumulated in the itch field to the question of clinical neuropathic itch. However, numerous limitations hamper such a direct translation: our experimental knowledge is mainly based on evoked itch in rodent studies, and chronic itch models mainly focus on chronic inflammatory skin diseases. In addition to these more generic limitations of translation, there is also an itch-specific aspect: to separately assess intensity of itch and pain, scratching vs wiping behavior on injection into the cheek has been successfully established in rodents.49 However, experimental itch models can also elicit a combination of itch- and pain-like behaviors,40,49 suggestive of a mixed sensation. Indeed, patients with small-fiber neuropathy often report concomitant itch and pain sensations9 such as “burning itch” or “itching sting.” The implications of this clinical observation for our basic concepts of itch generation, in particular the mutually exclusive specificity vs pattern or intensity theory of itch, will be discussed in this review. The clinical overlap between pain and itch symptoms in a given patient may be partially masked by the traditional segregation of medical specialties involved: as dermatologists usually encounter itch and neurologists or anesthesiologists mainly pain symptoms, their interpretation may simply be either itch or pain.
2. Discussion
Recently, new major discoveries in the field of mediators and receptors evoking nonhistaminergic itch have been made. These include identification of functional markers for primary pruriceptive afferent neurons in rodents (MrgprA1, MrgprC11, and MrgprD) and man (MrgprX1),24 peripheral mediators that are linked to the itch sensation (interleukin [IL] 13, IL-31, autotaxin, lysophosphatidic acid [LPA], thymic stromal lymphopoietin, and cathepsin S)11,22 and central transmitters and pathways for itch processing (B-type natriuretic peptide [BNP] and gastrin-releasing peptide [GRP]).8,35 Spinal neurons positive for GRP have been found critical for itch, but not for pain3 suggesting specificity, although they are also activated by nociceptive stimuli.55 However, we should avoid oversimplification because many of the itch-related mediators, receptors, or markers are also found in nociceptive pathways. This is obvious for the neurokinin 1 receptor (NK1R),53 TRPV1,19 sodium channel subtypes, such as NaV1.7,13,25 and LPA.57 Moreover, MrgprD-positive neurons originally described as nociceptors62 have recently been implicated in neuropathic pain,58 and neurons carrying the thymic stromal lymphopoietin receptor were described as mediating “itch and/or pain.”59
2.1. Basic concepts for neuropathic itch
In numerous reviews, the neurophysiological basis for the itch sensation has been discussed based on several hypotheses, namely specificity, pattern, and intensity theory.16 Current molecular data provide particular neuronal markers suggestive of the specificity theory, whereas electrophysiological data rather hint to a pattern responsible for itch.12 The key question in this review is: how can we explain neuropathic itch based on these basic concepts?
2.1.1. Specificity
About 20 years ago, mechanoinsensitive (“silent”) histamine-sensitive C nociceptors in human47 and spinothalamic projection neurons in the cat4 have been identified as part of a specific pruritic pathway. More recently, molecular markers of nonhistaminergic itch-specific neurons were identified in the rodent, such as BNP5,33 and members of the mas-related G-protein receptor family (mrgprA3, C11)6,10,41 in primary afferent neurons, but also GRP35,55,56 in dorsal horn neurons. Nonhistaminergic itch signaling has received major interest when mas-related G-protein-coupled receptors (Mrgprs) were identified on presumably itch-related neurons in the mouse,32 ie, MrgprA3,28 D,27 and C11.29 Also, BAM8-22, an activator of MrgrpC11, induces itch in human skin.50 Similarly, intracutaneous injection of beta-alanine—an activator of MrgprD—provokes mainly itch, but also pain in humans.27,60 Chloroquine has often been used in mice to elicit itch-behavior through activation of MrgprA3.2,28,44 Thus, the plethora of new information on pathways and mediators for itch in rodents as described above might imply that the “labeled line” theory for itch has finally been verified.
If the “labeled line” theory of itch was correct for neuropathic itch, the key questions are: which peripheral pruritic mediators are released in neuropathy and which fiber classes are activated by them or how is spinal processing modified. One could hypothesize that on neuronal degeneration, inflammatory mediators, such as interleukin-31 (IL-31), IL-33, LPA, and cathepsin S, are released,42,61 which could selectively activate pruriceptors as schematically shown in Figure 1A. Albeit such a scenario appears plausible, LPA,37 cathepsin S,61 and IL-3318 have also been linked to chronic pain conditions, and thus, might not be optimally suited as itch-specific mediator. Only IL-31 would remain as mediator, mainly associated with itch rather than pain, which would be in line with human data on antipruritic effects of IL-31 receptor antibodies,45 but also coexpression of the IL-31 receptor and natriuretic peptide B in a subpopulation of dorsal root ganglion neurons.26
;)
Figure 1.: Potential mechanisms of neuropathic itch: Transduction of itch in the skin (A–C). (A) Degenerating peripheral nerve fibres (dotted lines) due to peripheral sensorineural injury may release inflammatory mediators such as LPA, IL-31, and IL-33 that activate itch-specific pruriceptors (red line, labeled yellow with “+” at bottom). The pruriceptors cause itch through activation of itch-specific pathways (red “labeled line”). (B) In healthy skin, itch can be caused when punctate stimuli (eg, a plant spine) activate only a few adjacent nociceptive fibers within the epidermis (labeled yellow with “+” at bottom), whereas directly adjacent fibers, including specific pruriceptors (red), remain silent. If instead activated en masse (eg, by trauma), their combined activation will cause pain. (C) The same localised activation can be mimicked after peripheral sensorineural injury (eg, SFPN and herpes zoster) when spontaneous action potentials from the few remaining abnormal epidermal nociceptors (labeled yellow with “+” at bottom) reproduce the discharge profile of nonlesional skin (so-called spatial contrast mechanism of neuropathic itch). (D) Spinal processing of itch based on animal data: Skin and mucosal BNP primary sensory neurons (red) with cell bodies in the dorsal root ganglion (dotted line) stimulate GRP-releasing interneurons in the dorsal horn of the spinal cord that stimulates GRP-receptive interneurons (GRP rec.) and finally projection neurons (STT itch) that send itch signals to the brain through the contralateral STT. Pain neurons (blue) and touch neurons (gray) can inhibit ascending itch signals through GABAergic interneurons, whereas glycinergic interneurons inhibit both itch and pain processing. Peripheral nerve injury (yellow explosion) can induce GRP de novo synthesis that might facilitate spinal itch processing (yellow “GRP”). BNP, B-type natriuretic peptide; cath., cathepsin S; DRG, dorsal root ganglion; GABA, gamma aminobutyric acid; GRP, gastrin-related peptide; IL-31, interleukin 31; IL-33, interleukin 33; LPA, lysophosphatidic acid; Pacinian corpuscles, symbol before the yellow explosion, modified from
Ref. 54; SFPN, small-fiber polyneuropathy; STT, spinothalamic tract.
2.1.2. Spatial contrast type of itch in neuropathy
Electrophysiological data from rodents and monkey did not support a “labeled line” for itch,1,12,43 as no specific subpopulation of itch neurons was found. The results rather support the pattern theory of itch according to which nociceptors can signal itch or pain based on the combination of activated fibers resulting in a population coding.16 On stronger nociceptive stimulation, that causes broad nociceptor activation, the pruritic pattern would be disrupted, and the resulting sensation is pain.
Very focal activation of nociceptors in the skin represents another mechanism, which can explain itch without a “labeled line”: noxious stimulation that is directed only to few cells within the epidermis elicits itch in human skin,51 even when the stimulus is the algogen capsaicin. It has been suggested that local activation of only few epidermal nociceptors can cause itch by a “mismatch signal”46 or “spatial contrast,”36 provided by few activated and many nonactivated nociceptive endings innervating the same skin site, for example, by a minute glass wool fiber (Fig. 1B). Such a discharge pattern indicates that a noxious event is minute and localized within the epidermis. Teleologically, one might conclude that scratching off a part of the epidermis is an adequate response because it will eliminate the threat in this situation. Moreover, scratching will elicit a consistent response of all mechanosensitive polymodal nociceptors innervating this skin and might thereby terminate the “spatial contrast” itch pattern.
Partial skin denervation in peripheral neuropathy will leave some isolated sensory endings within the epidermis (Fig. 1C). Clinically, we use to associate such depletion of skin innervation to reduced sensory function. However, if there is some local inflammation or spontaneous activity of these isolated remaining nerve branches, the resulting discharge pattern would equal the one just described as “spatial contrast.” Thus, a combination of ongoing or evoked activity from sparse surviving or newly regenerating nerve branches could generate neuropathic itch through the “spatial contrast” mechanism.
It is of clinical interest that the same spatial arrangement of isolated epidermal sensory nerve fibers is generated by neurons reinnervating scar tissue, for example, after burns.23 The combination of spatial arrangement and spontaneous activity of regenerating sprouts might underlie the development of itch in this condition. Of note, also scratching itself can lead to reduction in epidermal nerve fiber density39,48; however, it is yet unclear to which extent scratch-induced axotomy might exaggerate chronic inflammatory itch conditions.
It is remarkable that it took only about 10 years to identify an itch-specific spinal pathway in mice: BNP skin afferents in the periphery synapse onto BNP receptor–positive neurons in the superficial dorsal horn that contains GRP. The third neuron expresses GRP receptors and excites pruriceptive neurons that ascend the spinothalamic tract34 (Fig. 1D). Itchiness is one of the most common side effects of administering drugs targeting µ-opioid receptors, and this seems to be related to cross-activation of spinal GRP receptors.30
In mice, peripheral nerve injuries incite broad de novo GRP expression in dorsal root ganglion neurons.52 This response might contribute to neuropathic itch, as nociceptors that typically inhibit itch may undergo a phenotypic switch by this de novo expression. When they become spontaneously active, they could release their GRP in the dorsal horn and contribute to neuropathic itch through volume transmission (Fig. 1D, yellow “GRP”). Thus, in addition to the spatial contrast mechanism described above, peripheral nerve injury could also provoke neuropathic itch through de novo expression of GRP in primary afferent nociceptors.
The “spatial contrast” theory can be easily linked to reduced epidermal innervation and appears to be in line with clinical observations such as itchy scars. However, it is more problematic to explain itch resulting from focal lesions located more proximal in a peripheral nerve. Patients with meralgia paresthetica primarily suffer from pain, whereas patients with notalgia paresthetica or brachioradial pruritus mainly report itch. It is striking that the leading symptom—neuropathic pain vs neuropathic itch—apparently switches dependent on the location of the injured nerve, although one would expect that a mechanical trauma similarly affects all C fibers. The mechanisms leading to the seemingly clear differentiation between neuropathic itch and pain in these 2 conditions remain unclear. Possibly, reporting bias contributes to the differentiation: patients with notalgia paresthetica and brachioradial pruritus are mainly seen by dermatologists, whereas patients with meralgia paresthetica are primary treated by anesthesiologists and neurologists. In dermatology, the symptom of itch is more abundant, whereas it is pain symptoms for neurologists and anesthesiologists. Thus, the different specialists might favor the respective symptom in their documentation, although many patients suffer from both itch and pain.14
2.1.3. Temporal pattern
Specific discharge patterns that differentiate itch and pain have been proposed historically, but there are no data that would identify itch- or pain-specific discharge patterns. Discharges of primary afferents induced by the pruritogen histamine are characterized by lower frequencies as compared to discharges to the algogen capsaicin, and periods of bursting have longer intervals24; however, this difference does not allow for a clear separation. New data have found differential temporal discharge pattern to heat stimuli between potential primary afferents linked to pain or itch processing: polymodal nociceptors were differentiated according to their response to a step-like noxious heat stimulus into quick (“QC”) or delayed/slow fibers (“SC”) in the monkey.60 C nociceptors with immediate phasic heat responses were particularly responsive to the pruritogen β-alanine, suggesting that the QC/SC classification might be helpful to characterize a pruriceptive subpopulation.60 On the other hand, it is not obvious how a differential temporal profile of heat responses could be linked to itch or pain processing. In this respect, there is crucial new information generated by studying temporal characteristics of the second synapse of the itch pathway in the spinal cord between GRP-containing neurons and their GRP receptor expressing counterparts: activity in the GRP-releasing neurons will initially only evoke postsynaptic depolarization without action potentials, and only prolonged activity of the presynaptic GRP-releasing neurons will result in action potentials of the third itch neuron (Prof. Zeilhofer, Pain Mechanisms and Therapeutics Conference, Taormina, 2018). While being interesting in itself, this result has broad implications for our understanding of itch processing: it combines an element of specificity (GRP-releasing neurons) with a temporal discharge pattern (block of short-lasting discharge acting as “low-pass filter”), and thereby represents the first example of a combination of specificity and temporal pattern theory in itch processing.
2.2. Are clinical neuropathic itch conditions based on a combination of specificity, intensity, and pattern?
Basic itch mechanisms are generally discussed in their “pure” form. However, as shown above, there is evidence that physiologic itch processing may combine elements from different basic theories traditionally regarded as mutually exclusive. Under experimental conditions, more of such combinations appear consistent with experimental data: activation of subpopulations of C afferents, such as MrgprA3-positive nociceptors,3,17 might generate itch not only through the assumed specificity but will also activate only a subset of nociceptors innervating a given skin site. Such a combination of active and nonactive nociceptors from the same skin site will thereby mimic a spatial contrast pattern. Another example would be a high number of spontaneously active nociceptors that signal pain; on reduction of this number, for example, by analgesic therapy, the chances to create a spatial contrast pattern by the still active nociceptors are increasing. This would represent a combination of a spatial contrast theory and the old intensity theory. Interestingly, clinical observations indeed support such a development: in patients with postherpetic neuralgia, resolving pain may be combined with an increase in itch.20,21 Thus, based on defined experimental models, we have successfully developed basic theories that can explain differentiation between itch and pain based on specificity in a “labeled line” or the discharge pattern in its temporal or spatial expression (Fig. 2, lower part). These approaches provide us with powerful tools when trying to explain clinical neuropathic itch. However, rather than assuming that in pathological conditions, there is a mutually exclusive explanation for itch purely based on one theory of itch, we rather might adapt our conceptual framework and include mechanisms that borrow aspects from different theories (Fig. 2, upper part).
Figure 2.: Schematic view of mechanisms that have been proposed to explain the generation itch (specificity, pattern, and intensity; black and white boxes). Neuropathy and inflammatory processes can modulate primary afferent discharge and spinal processing such that spatial and temporal patterns are changed (gray arrow). Thereby, discharge that would genuinely be processed as distinct itch may be perceived as partly painful (“stinging itch”) and vice versa (“itching burn”). Rather than strictly following only one of the above theories, the generation of neuropathic itch in patients thereby may be based on a combination of spatial/temporal pattern and specificity.
It will be a major task to translate these basic and theoretic concepts to the clinical context of neuropathic itch. This translational task includes identification of those specific markers found in rodents that are crucially involved in itch processing in patients. In addition, our investigation needs to be open for elements of the intensity and pattern theory, such as spatial contrast, phenotypic switch, and temporal pattern, that all may contribute to the complex clinical complaints consisting of combinations of neuropathic itch and pain. Currently, the traditional separation of chronic itch and chronic pain patients into dermatology vs neurology/anesthesiology still prevails. In this respect, it is important that collaborations on both clinical and institutional levels (IASP and International Forum for the Study of Itch [IFSI]) generate a consented and comprehensive approach.
3. Conclusion
Recent advances in basic itch research have successfully characterized itch-specific pathways on a cellular and molecular level that provides numerous potential targets for antipruritic therapy. However, translation between rodent data and patient complaints is complicated, not only due to species differences but also due to a broad overlap between neuropathic pain and itch in the patients. Moreover, neuropathic itch conditions appear to not solely follow the specificity theory of itch but may also contain elements of the pattern and even intensity theory, such as spatial contrast, temporal pattern, and phenotypic switch of nociceptors. Therefore, on a conceptual level, clinical approaches should combine elements of the current theories of itch rather than treating them as mutually exclusive with only one of them being correct. On a clinical level, the broad overlap between neuropathic itch and pain is contrasting the segregation of diagnostics and therapy between dermatology vs neurology and anesthesiology. Collaborations both on a clinical and institutional level are important to close this gap, to advance our understanding of neuropathic itch, and to develop a consented and comprehensive approach that will improve the treatment of our patients.
Conflict of interest statement
The authors have no conflict of interest to declare.
Acknowledgements
This work was supported by grants from Deutsche Forschungsgemeinschaft (FOR2690) to M. Schmelz and S. Ständer.
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