Abstract
Pain and itch are generally regarded antagonistic as painful stimuli such as scratching suppresses itch. Moreover, inhibition of pain processing by opioids generates itch further supporting their opposing role. Separate specific pathways for itch and pain processing have been uncovered, and several molecular markers have been established in mice that identify neurons involved in the processing of histaminergic and non-histaminergic itch on primary afferent and spinal level. These results are in agreement with the specificity theory for itch and might suggest that pain and itch should be investigated separately on the level of neurons, mediators, and mechanisms. However, in addition to broadly overlapping mediators of itch and pain, there is also evidence for overlapping functions in primary afferents: nociceptive primary afferents can provoke itch when activated very locally in the epidermis, and sensitization of both nociceptors and pruriceptors has been found following local nerve growth factor application in volunteers. Thus, also mechanisms that underlie the development of chronic itch and pain including spontaneous activity and sensitization of primary afferents as well as spinal cord sensitization may well overlap to a great extent. Rather than separating itch and pain, research concepts should therefore address the common mechanisms. Such an approach appears most appropriate for clinical conditions of neuropathic itch and pain and also chronic inflammatory conditions. While itch researchers can benefit from the large body of information of the pain field, pain researchers will find behavioral readouts of spontaneous itch much simpler than those for spontaneous pain in animals and the skin as source of the pruritic activity much more accessible even in patients.
Access provided by Autonomous University of Puebla. Download chapter PDF
Similar content being viewed by others
Keywords
1 Differentiation Between Pain and Itch
Itch and pain can be clearly separated by their distinct sensations and their characteristic reflex patterns. Acute pain evokes withdrawal of the stimulated limb which enables escape from a potentially damaging external stimulus that threatens the organism. In contrast, the scratch reflex directs attention to the stimulated site, and scratching provides the means to remove a potentially damaging stimulus that already has invaded the skin and now poses a threat from inside the body. While virtually all organs of the human body except the brain itself are innervated by nociceptors, itch can be induced only from skin and adjoining mucosae. Actually, only in these locations scratching appears a reasonable approach to remove superficially localized agents. In the respiratory tract, coughing has a very similar protective role and instructively has been termed “airway itch” (Gibson 2004). The clear functional separation between itch and pain could be explained most easily by two specific sensory pathways.
1.1 Specificity for Itch
Specific sets of primary afferent dedicated to pain (“nociceptors”) and to itch (“pruriceptors”) have been hypothesized in the late nineteenth and early twentieth century (Handwerker 2014). Unmyelinated primary afferents that responded to histamine iontophoresis in parallel to the itch ratings of subjects were finally discovered among the group of mechano-insensitive C-fibers (Schmelz et al. 1997). In contrast, the most common type of C-fibers, mechano-heat nociceptors (“polymodal nociceptors”), is either insensitive to histamine or only weakly activated by this stimulus (Schmelz et al. 2003b). Hence, this fiber type cannot account for the prolonged itch induced by the iontophoretic application of histamine. Yet, when histamine is injected intracutaneously, also polymodal nociceptors are activated for several minutes (Johanek et al. 2008). Thus, a contribution of this fiber class to histamine-induced itch cannot be entirely ruled out.
The histamine-sensitive pruriceptors among the mechano-insensitive C-nociceptors are characterized by a particular low conduction velocity, large innervation territories, mechanical unresponsiveness, and high transcutaneous electrical thresholds (Schmelz et al. 1997, 2003b; Schmidt et al. 2002). Interestingly, only these histamine-sensitive afferents were activated by prostaglandin E2 injected intracutaneously in their innervation territory (Schmelz et al. 2003b). In line with the large innervation territories of these fibers, two-point discrimination for histamine-induced itch is poor (15 cm in the upper arm) (Wahlgren and Ekblom 1996). The excellent locognosia for histamine-induced itch in the hand (Koltzenburg et al. 1993) might therefore be based on central processing compensating for low spatial resolution in the periphery. Among the mechano-insensitive afferent C-fibers, only a subset of units shows a strong and sustained response to histamine. They comprise about 20 % of the mechano-insensitive class of C-fibers, i.e., about 5 % of all C-fibers in the superficial peroneal nerve.
In accordance with the existence of dedicated histamine-sensitive primary afferents, cat spinal cord recordings provided evidence for a specific class of dorsal horn neurons projecting to the thalamus which respond strongly to histamine administered to the skin by iontophoresis (Andrew and Craig 2001). These neurons were also unresponsive to mechanical stimulation, and their axons had a lower conduction velocity and anatomically distinct projections to the thalamus. The itch-selective units in lamina I of the spinal cord form a distinct pathway projecting to the posterior part of the ventromedial thalamic nucleus which projects to the dorsal insular cortex (Craig 2002), a region which has been shown to be involved in a variety of interoceptive modalities like thermoception, visceral sensations, thirst, and hunger.
Thus, the combination of dedicated peripheral and central neurons with a unique response pattern to pruritogenic mediators and anatomically distinct projections to the thalamus provides the basis for a specific neuronal pathway for itch.
1.1.1 Molecular Markers for Itch-Processing Neurons
Functional classes of primary afferent neurons are defined primarily on the basis of their response characteristics. However, functional markers are required to identify the neuronal classes also in vitro. For the separation of functional classes among primary afferents, marker proteins have been established that are involved in sensory transduction such as vanilloid receptors (TRPV1, TRPA1) and purinergic receptors (P2X3). Moreover, neuropeptides such as substance P and calcitonin gene-related peptide, receptors for growth factors, and also receptors of yet unknown function such as the family of Mas-related G protein-coupled receptors (Mrgpr) are used. Markers that have been used to characterize neurons involved in itch processing (Akiyama and Carstens 2013) include histamine H1 receptors, the neuropeptides gastrin-releasing peptide and B-type natriuretic peptide, and the several members of the Mrgpr family (A3, D, C11) (LaMotte et al. 2014; Bautista et al. 2014; Braz et al. 2014b). Unfortunately, there are only few examples for a convincing link between the rodent marker and functional neuronal class in primates. For a very special subtype of afferent C-fiber, the very low-threshold so-called C-touch fibers (CT afferents) (Ackerley et al. 2014), links to the expression of MrgprB4 (Vrontou et al. 2013) and to the expression of the glutamate transporter VGLUT3 (Seal et al. 2009) have been described.
In the realm of itch processing, however, we do not have such convincing ties between molecular markers used in rodents and fiber classes in the primate. There is evidence that cowhage induces itch via activation of proteinase-activated receptors (Reddy et al. 2008). Thus, the activation of QC-type mechano-sensitive nociceptors by cowhage (Johanek et al. 2008) might be a possible link to MrgprC11 (Akiyama and Carstens 2013). Beta-alanine, the activator of MrgprD, does provoke itch in humans (Qu et al. 2014; Han et al. 2012; Liu et al. 2012) and activates primarily QC-type mechano-sensitive nociceptors in the monkey (Wooten et al. 2014), but the corresponding fiber type in human is yet unclear. This is similarly true for BAM8-22, activator of MrgprC11, that also provokes histamine-independent itch in humans (Sikand et al. 2011) probably via activating MrgprX1, the human homologue of rodent MrgprC11. Activation of polymodal nociceptors by agonists of receptors thought to be itch specific poses some problems to the concept of specificity of itch and pain (see pattern theory below).
1.1.2 Antagonistic Interaction Between Itch and Pain
Our common experience tells us that pain inhibits itch. Also experimentally, the inhibition of itch by painful stimuli has been demonstrated by the use of various painful thermal, mechanical, and chemical stimuli. Electrical stimulation via an array of pointed electrodes (“cutaneous field stimulation”) has also been successfully used to inhibit histamine-induced itch for several hours in an area around a stimulated site of 20 cm in diameter. The large area of inhibition suggests a central mode of action (Nilsson et al. 1997). Consistent with these results, itch is suppressed inside the secondary zone of capsaicin-induced mechanical hyperalgesia (Brull et al. 1999). This central effect of nociceptor excitation by capsaicin should be clearly distinguished from the neurotoxic effect of higher concentrations of capsaicin which destroy most C-fiber terminals, including fibers that mediate itch (Simone et al. 1998). The latter mechanism, therefore, also abolishes pruritus locally, until the nerve terminals are regenerated.
Not only is itch inhibited by enhanced input of pain stimuli, but vice versa, inhibition of pain processing may reduce its inhibitory effect and thus enhance itch (Atanassoff et al. 1999). This phenomenon is particularly relevant to spinally administered μ-opioid receptor agonists which induce segmental analgesia often combined with segmental pruritus (Andrew et al. 2003), but has also been confirmed in animal experiments (Nojima et al. 2004). Conversely, kappa-opioid antagonists have been found to enhance itch (Kamei and Nagase 2001). In line with these results, the κ-opioid agonist nalbuphine has been shown to reduce μ-opioid-induced pruritus in a meta-analysis (Kjellberg and Tramer 2001). This therapeutic concept has already been tested successfully in chronic itch patients using a newly developed κ-opioid agonist (Kumagai et al. 2010). Recently, GABAergic interneurons harboring the transcription factor Bhlhb5 in the dorsal horn have been found to be crucial to inhibit itch (Ross et al. 2010; Braz et al. 2014a). Most interestingly, these neurons appear to mediate spinal suppression of itch by releasing the κ-opioid agonist dynorphin (Kardon et al. 2014).
Opioid-induced itch has often been linked to peripheral release of histamine from mast cells as intradermally injected opioids can activate mast cells by a non-receptor-mediated mechanism (Ferry et al. 2002). Accordingly, weak opioids, such as codeine, have been used as a positive control in skin prick tests. The consecutive release of histamine and mast cell tryptase can be specifically monitored by measuring tryptase concentration with dermal microdialysis following intraprobe delivery (Blunk et al. 2003). In contrast to morphine, the highly potent μ-opioid agonist, fentanyl, does not provoke any mast cell degranulation, even if applied at concentrations having μ-agonistic effects exceeding those of morphine (Fig. 1). Thus, high local concentrations of opioids are required to degranulate mast cells, and therefore, itch induced by systemic administration of potent μ-opioid agonists in therapeutic doses is based on central mechanisms.
Central inhibition of itch can also be achieved by cold stimulation (Bromm et al. 1995). In addition, cooling has a peripheral inhibitory effect: histamine-induced activation of nociceptors can be reduced by cooling (Mizumura and Koda 1999). Also in humans, cooling of a histamine-treated skin site reduced the activity of the primary afferents and decreased the area of “itchy skin” or “hyperknesis” around the application site (Heyer et al. 1995). Unexpectedly, there is an initial increase of itch intensity upon cooling the histamine application site (Pfab et al. 2006) that can be used as experimental model for central imaging (Napadow et al. 2014). Conversely, tonic warming the skin would lead to an exacerbation of itch. However, as soon as the heating becomes painful, central inhibition of pruritus will counteract this effect (Schmelz 2002).
Recent work on antipruritic effects of subpopulations of primary nociceptive afferents indicates that especially the input from the VGLUT2-positive subpopulation is crucial to explain inhibition of itch behavior by painful stimuli (Lagerstrom et al. 2010; Liu et al. 2010). When VGLUT2 and, thereby, glutamate release in NaV1.8-positive nociceptors was deficient, inflammatory and neuropathic pain responses were grossly abolished, but spontaneous scratching behavior and increased experimental itch were massively enhanced (Liu et al. 2010). Most interestingly, capsaicin-induced pain behavior was changed into scratching behavior in these mice suggesting that the lack of noxious input via VGLUT2-positive nociceptors disinhibited itch (Liu et al. 2010). The exact nature of the crucial nociceptor class is still unclear, as another group did not find increased scratching when VGLUT2 was knocked out in NaV1.8-positive but in TRPV1-positive primary afferent neurons (Lagerstrom et al. 2010). It will be of major interest to further characterize the nociceptor class having a crucial itch-inhibiting spinal effect.
It is important to note that we have so far followed the ideas of two separate populations for itch and pain. This segregation is actually required for the genetic approaches described above. Unfortunately, several aspects of itch generation such as pruritus induced by activation of polymodal nociceptors or spatial stimulus characteristics switching pain to itch cannot be sufficiently explained by this approach.
1.2 Intensity and Pattern Theory of Itch
Numerous neuronal markers that were linked to itch, but not pain processing, support the specificity theory of itch. However, as indicated above, there is evidence that itch can also be induced by activation of nociceptors. Nociceptors could provoke itch either by an intensity coding (“intensity theory”) or by a particular population encoding (“pattern theory”) (Namer and Reeh 2013; Handwerker 2014). Albeit this general question might appear purely academic, it is crucial to provide the most promising research approach to identify pharmacological targets in chronic itch and pain.
1.2.1 Non-histaminergic Itch
Histamine application causes a local wheal response surrounded by an area of vasodilation (“axon reflex erythema”) (Lewis et al. 1927). This vasodilation is induced by neuropeptide release from mechano-insensitive C-fibers (Schmelz et al. 2000; Geppetti and Holzer 1996). The absence of an axon reflex flare therefore suggests that the itch is independent of histamine-sensitive C-fibers. Indeed, itch was induced by papain in an early study in the absence of a flare response indicating a histamine-independent action (Hägermark 1973). Itch without axon reflex flare can also be elicited by weak electrical stimulation (Shelley and Arthur 1957; Ikoma et al. 2005), providing further evidence that the sensation of itch can be dissociated from cutaneous vasodilation.
Cowhage spicules inserted into human skin produce itch in an intensity which is comparable to that following histamine application (LaMotte et al. 2009; Sikand et al. 2009), but is not accompanied by an axon reflex erythema and unresponsive to histamine (H1) blocker (Johanek et al. 2007). The active compound, the cysteine protease muconain, has been identified lately and has shown to activate proteinase-activated receptor 2 (PAR 2) and even more potently PAR 4 (Reddy et al. 2008). Interestingly, mechano-responsive “polymodal” C-fiber afferents, the most common type of afferent C-nociceptors in human skin (Schmidt et al. 1995), can be activated by cowhage in the cat (Tuckett and Wei 1987), in nonhuman primates (Johanek et al. 2007, 2008), and in human volunteers (Namer et al. 2008) (Fig. 2).
Given that cowhage spicules can activate a large proportion of polymodal nociceptors, we face a major problem to explain why activation of these fibers by heat or by scratching actually inhibits itch, whereas activation by cowhage produces it. On the other hand, data from monkey suggest that mechano-heat-sensitive C-nociceptors with a fast response to heating (“QC”) might play a more important role in mediating cowhage-induced itch (Johanek et al. 2008). One might therefore still hypothesize that there is a certain selectivity among mechano-sensitive C-nociceptors for cowhage that would allow the central nervous system to separate nociceptive from pruriceptive stimuli (LaMotte et al. 2014). Along the same lines, in particular QC-nociceptors, but not mechano-insensitive nociceptors, were activated by beta-alanine (Wooten et al. 2014), the activator of MrgprD that provokes itch in humans.
1.2.2 Encoding Itch by Patterns of Activated Nociceptors
Considering nociceptors being involved in generating itch, a population code has been postulated (“pattern theory”) (Handwerker 2014; Akiyama and Carstens 2013; McMahon and Koltzenburg 1992) in which only a subpopulation of nociceptors can also be activated by pruritic stimuli, whereas pure nociceptors are only responsive to algogens. Accordingly, itch will be felt when only the first subpopulation is responding, but pain when both populations are active.
The encoding of itch by nociceptors has also been proposed to be based on a spatial code (Schmelz and Handwerker 2013) based on the itch induced by capsaicin being applied very localized on a cowhage spicule into the epidermis (Sikand et al. 2009). The highly localized stimulation in the epidermis strongly activates some of the local nociceptors, while their immediate neighbors remain silent resulting in a mismatch signal of activation and absence of activation from this site. It has thus been hypothesized that this mismatch might be perceived by the central nervous system as itch (Schmelz and Handwerker 2013; Namer et al. 2008). Interestingly, this result also speaks against capsaicin’s pain specificity (Ross 2011). Teleologically, it is obvious that scratching behavior in the case of a highly localized superficial noxious focus is an adequate response as it can eliminate the presumed cause. Moreover, scratching activates all the mechano-sensitive nociceptors in the stimulated area, and thus, the mismatch signal of activated and nonactivated nociceptors at this site is terminated. Therefore, it needs to be pointed out that pruritus cannot only be explained by itch-specific or itch-selective neurons (LaMotte et al. 2014) along the specificity theory. In addition, the pure spatial pattern of activated nociceptors might similarly underlie the itch sensation without any requirement of itch-specific primary afferent neurons.
2 Central and Peripheral Sensitization in Itch and Pain
Spontaneous itch and pain are of paramount clinical relevance as they correlate to the main complaint of chronic itch and pain patients. It is highly interesting that the patterns of peripheral and central sensitization linked to chronic pain and itch are remarkably similar.
2.1 Central Sensitization
Activity in chemo-nociceptors leads not only to acute pain but, in addition, can sensitize second-order neurons in the dorsal horn, thereby leading to increased sensitivity to pain (hyperalgesia). Two types of mechanical hyperalgesia can be differentiated. Normally painless touch sensations in the uninjured surroundings of a trauma are felt as painful “touch- or brush-evoked hyperalgesia” or allodynia. Though this sensation is mediated by myelinated mechanoreceptor units, it requires ongoing activity of primary afferent C-nociceptors (Torebjörk et al. 1996). The second type of mechanical hyperalgesia results in slightly painful pinprick stimulation being perceived as being more painful in the secondary zone around a focus of inflammation. This type has been called “punctate hyperalgesia” and does not require ongoing activity of primary nociceptors for its maintenance. It can persist for hours following a trauma, usually much longer than touch- or brush-evoked hyperalgesia (LaMotte et al. 1991).
In itch processing, similar phenomena have been described: touch- or brush-evoked pruritus around an itching site has been termed “itchy skin” (Bickford 1938; Simone et al. 1991). Like allodynia, it requires ongoing activity in primary afferents and is most probably elicited by low-threshold mechanoreceptors (Aδ-fibers) (Simone et al. 1991; Heyer et al. 1995). Also, more intense prick-induced itch sensations in the surroundings, “hyperknesis,” have been reported following histamine iontophoresis in healthy volunteers (Atanassoff et al. 1999) (Fig. 3).
The existence of central sensitization for itch can greatly improve our understanding of clinical itch. Under the conditions of central sensitization leading to punctuate hyperknesis, normally painful stimuli are perceived as itching. This phenomenon has already been described in patients suffering from atopic dermatitis, who perceive normally painful electrical stimuli as itching when applied inside their lesional skin (Nilsson et al. 2004; Nilsson and Schouenborg 1999). Furthermore, acetylcholine provokes itch instead of pain in patients with atopic dermatitis (Vogelsang et al. 1995), indicating that pain-induced inhibition of itch might be compromised in these patients.
The exact mechanisms and roles of central sensitization for itch in specific, clinical conditions have still to be explored, whereas a major role of central sensitization in patients with chronic pain is generally accepted. It should be noted that in addition to the parallels between experimentally induced secondary sensitization phenomena, there is also emerging evidence for corresponding phenomena in patients with chronic pain and chronic itch. In patients with neuropathic pain, it has been reported that histamine iontophoresis resulted in burning pain instead of pure itch which would be induced by this procedure in healthy volunteers (Birklein et al. 1997; Baron et al. 2001). This phenomenon is of special interest as it demonstrates spinal hypersensitivity to C-fiber input. Conversely, normally painful electrical, chemical, mechanical, and thermal stimulation is perceived as itching when applied in or close to lesional skin of atopic dermatitis patients (Heyer et al. 1995; Steinhoff et al. 2003).
Ongoing activity of pruriceptors, which might underlie the development of central sensitization for itch, has already been confirmed microneurographically in a patient with chronic pruritus (Schmelz et al. 2003a). Thus, there is emerging evidence, for a role of central sensitization for itch in chronic pruritus.
While there is obviously an antagonistic interaction between pain and itch under normal conditions, the patterns of spinal sensitization phenomena are surprisingly similar. It remains to be established whether this similarity will also include the underlying mechanism which would also implicate similar therapeutic approaches such as gabapentin (Dhand and Aminoff 2014) or clonidine (Elkersh et al. 2003) for the treatment of neuropathic itch.
2.2 Peripheral Sensitization
There is cumulative evidence for a prominent role of nerve growth factor (NGF)-induced sensitization of primary afferents in both chronic itch and pain: increased levels of NGF were found in chronic itch patients suffering from atopic dermatitis or psoriasis (Toyoda et al. 2002, 2003; Tominaga et al. 2009; Yamaguchi et al. 2009). Similarly, there is clear evidence for a major role of NGF in chronic inflammatory pain (Chevalier et al. 2013; Watanabe et al. 2011; Barcena de Arellano et al. 2011). Moreover, blocking NGF by specific antibodies proved to be analgesic in the chronic pain patients (Lane et al. 2010; Sanga et al. 2013). Anti-NGF strategies also were successful in animal models of chronic itch (Tominaga and Takamori 2014). It is therefore not surprising that intradermally injected NGF not only causes hyperalgesia to heat and mechanical stimuli in volunteers (Hirth et al. 2013; Rukwied et al. 2010) but also sensitizes for cowhage-induced itch (Rukwied et al. 2013c). Intracutaneous NGF injection does not induce visual inflammatory responses in human (Rukwied et al. 2010), but interestingly, when combined with an inflammatory pain model (UV-B sunburn), the subjects report of spontaneous pain (Fig. 3) and pronounced hyperalgesia (Rukwied et al. 2013b) that also includes axonal hyperexcitability (Rukwied et al. 2013a). These results nice match the analgesic effects of anti-NGF in chronic inflammatory pain that are not accompanied by reduced signs of inflammation (Lane et al. 2010). Therefore, it emerges that neurotrophic factors such as NGF can change expression patterns of primary afferent nociceptors such that their ability to signal pain or itch by local inflammatory mediators is increased. This increase might be based on higher discharge frequencies linked to sensitized transduction, but also to axonal hyperexcitability.
3 Perspectives: Mechanisms for Itch or Pain in Neuropathy and Chronic Inflammation
Finally, the current concepts differentiating itch and pain need to be evaluated in view of the obvious clinical questions concerning the development of itch or pain after neuropathy or in chronic inflammatory diseases. It is remarkable that some neuropathic conditions such as postherpetic neuralgia and diabetic neuropathy are primarily linked to pain symptoms whereas patients suffering from notalgia paresthetica or brachioradial pruritus mainly report chronic itch (Table 1).
It is important to note that more than 25 % of patients with neuropathic pain conditions such as postherpetic neuropathy also report itch (Oaklander et al. 2003). According to the specificity or selectivity theory, one would hypothesize that the mediators being released in diabetic neuropathy or postherpetic neuralgia determine to which extent itch-selective or itch-specific primary afferents are excited. Moreover, itching neuropathic conditions such as nostalgia paresthetica and brachioradial pruritus should be differentiated from painful meralgia paresthetica by primary activation of pruriceptors rather than nociceptors. However, it is completely unclear how such differentiation could be mediated for very similar peripheral neuropathic conditions. Possibly, specific pruriceptors only play a minor role under these conditions. In contrast, the spatial pattern of nociceptor activation might provide the crucial input: if only few scattered axons are spontaneously active, their input might mimic the one of scattered nociceptors being activated by cowhage spicules in the epidermis, whereas activation of numerous nociceptors of a peripheral nerve would result in pain. Thus, such itch sensation would be generated by the particular spatial code of activated nociceptors (Schmelz and Handwerker 2013; Namer et al. 2008). Accordingly, scattered activation of epidermal nociceptors might also occur in some chronic inflammatory diseases such as atopic dermatitis and explain the difference between itching and painful symptoms. If this hypothesis would be correct, the treatment of neuropathic itch and pain would have essentially identical therapeutic targets and mechanisms rather than itch or pain specific. Thus, the implications of theoretical concepts of itch are, unexpectedly, of major clinical relevance. It will therefore be of major interest for both clinicians and basic researchers to determine which fiber class generates the peripheral input for chronic itch conditions.
References
Ackerley R, Backlund Wasling H, Liljencrantz J, Olausson H, Johnson RD, Wessberg J (2014) Human C-tactile afferents are tuned to the temperature of a skin-stroking caress. J Neurosci 34(8):2879–2883. doi:10.1523/JNEUROSCI. 2847-13.2014
Akiyama T, Carstens E (2013) Neural processing of itch. Neuroscience 250:697–714. doi:10.1016/j.neuroscience.2013.07.035
Andrew D, Craig AD (2001) Spinothalamic lamina 1 neurons selectively sensitive to histamine: a central neural pathway for itch. Nat Neurosci 4:72–77
Andrew D, Schmelz M, Ballantyne JC (2003) Itch—mechanisms and mediators. In: Dostrovsky JO, Carr DB, Koltzenburg M (eds) Progress in pain research and management. IASP Press, Seattle, pp 213–226
Atanassoff PG, Brull SJ, Zhang J, Greenquist K, Silverman DG, LaMotte RH (1999) Enhancement of experimental pruritus and mechanically evoked dysesthesiae with local anesthesia. Somatosens Mot Res 16(4):291–298
Barcena de Arellano ML, Arnold J, Vercellino GF, Chiantera V, Ebert AD, Schneider A, Mechsner S (2011) Influence of nerve growth factor in endometriosis-associated symptoms. Reprod Sci 18(12):1202–1210
Baron R, Schwarz K, Kleinert A, Schattschneider J, Wasner G (2001) Histamine-induced itch converts into pain in neuropathic hyperalgesia. Neuroreport 12(16):3475–3478
Bautista DM, Wilson SR, Hoon MA (2014) Why we scratch an itch: the molecules, cells and circuits of itch. Nat Neurosci 17(2):175–182. doi:10.1038/nn.3619
Bickford RGL (1938) Experiments relating to itch sensation, its peripheral mechanism and central pathways. Clin Sci 3:377–386
Birklein F, Claus D, Riedl B, Neundorfer B, Handwerker HO (1997) Effects of cutaneous histamine application in patients with sympathetic reflex dystrophy. Muscle Nerve 20(11):1389–1395
Blunk JA, Seifert F, Schmelz M, Reeh PW, Koppert W (2003) Injection pain of rocuronium and vecuronium is evoked by direct activation of nociceptive nerve endings. Eur J Anaesthesiol 20(3):245–253
Blunk JA, Schmelz M, Zeck S, Skov P, Likar R, Koppert W (2004) Opioid-induced mast cell activation and vascular responses is not mediated by mu-opioid receptors: an in vivo microdialysis study in human skin. Anesth Analg 98(2):364–370, Table
Braz JM, Juarez-Salinas D, Ross SE, Basbaum AI (2014a) Transplant restoration of spinal cord inhibitory controls ameliorates neuropathic itch. J Clin Invest 124(8):3612–3616. doi:10.1172/JCI75214
Braz J, Solorzano C, Wang X, Basbaum AI (2014b) Transmitting pain and itch messages: a contemporary view of the spinal cord circuits that generate gate control. Neuron 82(3):522–536. doi:10.1016/j.neuron.2014.01.018
Bromm B, Scharein E, Darsow U, Ring J (1995) Effects of menthol and cold on histamine-induced itch and skin reactions in man. Neurosci Lett 187(3):157–160
Brull SJ, Atanassoff PG, Silverman DG, Zhang J, LaMotte RH (1999) Attenuation of experimental pruritus and mechanically evoked dysesthesiae in an area of cutaneous allodynia. Somatosens Mot Res 16(4):299–303
Chevalier X, Eymard F, Richette P (2013) Biologic agents in osteoarthritis: hopes and disappointments. Nat Rev Rheumatol 9(7):400–410
Craig AD (2002) How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci 3(8):655–666
Dhand A, Aminoff MJ (2014) The neurology of itch. Brain 137(Pt 2):313–322. doi:10.1093/brain/awt158
Elkersh MA, Simopoulos TT, Malik AB, Cho EH, Bajwa ZH (2003) Epidural clonidine relieves intractable neuropathic itch associated with herpes zoster-related pain. Reg Anesth Pain Med 28(4):344–346
Ferry X, Brehin S, Kamel R, Landry Y (2002) G protein-dependent activation of mast cell by peptides and basic secretagogues. Peptides 23:1507–1515
Geppetti P, Holzer P (1996) Neurogenic inflammation. CRC, Boca Raton
Gibson PG (2004) Cough is an airway itch? Am J Respir Crit Care Med 169(1):1–2. doi:10.1164/rccm.2310009
Hägermark O (1973) Influence of antihistamines, sedatives, and aspirin on experimental itch. Acta Derm Venereol 53(5):363–368
Han L, Ma C, Liu Q, Weng HJ, Cui Y, Tang Z, Kim Y et al (2012) A subpopulation of nociceptors specifically linked to itch. Nat Neurosci 16(2):174–182
Handwerker HO (2014) Itch hypotheses: from pattern to specificity and to population coding. In: Carstens E, Akiyama T (eds) Itch: mechanisms and treatment. Frontiers in neuroscience. CRC, Boca Raton
Heyer G, Ulmer FJ, Schmitz J, Handwerker HO (1995) Histamine-induced itch and alloknesis (itchy skin) in atopic eczema patients and controls. Acta Derm Venereol 75(5):348–352
Hirth M, Rukwied R, Gromann A, Turnquist B, Weinkauf B, Francke K, Albrecht P et al (2013) NGF induces sensitization of nociceptors without evidence for increased intraepidermal nerve fiber density. Pain 13:10
Ikoma A, Handwerker H, Miyachi Y, Schmelz M (2005) Electrically evoked itch in humans. Pain 113(1–2):148–154. doi:10.1016/j.pain.2004.10.003
Johanek LM, Meyer RA, Hartke T, Hobelmann JG, Maine DN, LaMotte RH, Ringkamp M (2007) Psychophysical and physiological evidence for parallel afferent pathways mediating the sensation of itch. J Neurosci 27(28):7490–7497
Johanek LM, Meyer RA, Friedman RM, Greenquist KW, Shim B, Borzan J, Hartke T, LaMotte RH, Ringkamp M (2008) A role for polymodal C-fiber afferents in nonhistaminergic itch. J Neurosci 28(30):7659–7669
Kamei J, Nagase H (2001) Norbinaltorphimine, a selective kappa-opioid receptor antagonist, induces an itch-associated response in mice. Eur J Pharmacol 418(1–2):141–145
Kardon AP, Polgar E, Hachisuka J, Snyder LM, Cameron D, Savage S, Cai X et al (2014) Dynorphin acts as a neuromodulator to inhibit itch in the dorsal horn of the spinal cord. Neuron 82(3):573–586. doi:10.1016/j.neuron.2014.02.046
Kjellberg F, Tramer MR (2001) Pharmacological control of opioid-induced pruritus: a quantitative systematic review of randomized trials. Eur J Anaesthesiol 18(6):346–357
Koltzenburg M, Handwerker HO, Torebjörk HE (1993) The ability of humans to localise noxious stimuli. Neurosci Lett 150(2):219–222. doi:10.1016/0304-3940(93)90540-2
Kumagai H, Ebata T, Takamori K, Muramatsu T, Nakamoto H, Suzuki H (2010) Effect of a novel kappa-receptor agonist, nalfurafine hydrochloride, on severe itch in 337 haemodialysis patients: a Phase III, randomized, double-blind, placebo-controlled study. Nephrol Dial Transplant 25(4):1251–1257
Lagerstrom MC, Rogoz K, Abrahamsen B, Persson E, Reinius B, Nordenankar K, Olund C et al (2010) VGLUT2-dependent sensory neurons in the TRPV1 population regulate pain and itch. Neuron 68(3):529–542
LaMotte RH, Shain CN, Simone DA, Tsai EFP (1991) Neurogenic hyperalgesia psychophysical studies of underlying mechanisms. J Neurophysiol 66:190–211
LaMotte RH, Shimada SG, Green BG, Zelterman D (2009) Pruritic and nociceptive sensations and dysesthesias from a spicule of cowhage. J Neurophysiol 101(3):1430–1443. doi:10.1152/jn.91268.2008
LaMotte RH, Dong X, Ringkamp M (2014) Sensory neurons and circuits mediating itch. Nat Rev Neurosci 15(1):19–31. doi:10.1038/nrn3641
Lane NE, Schnitzer TJ, Birbara CA, Mokhtarani M, Shelton DL, Smith MD, Brown MT (2010) Tanezumab for the treatment of pain from osteoarthritis of the knee. N Engl J Med 363(16):1521–1531. doi:10.1056/NEJMoa0901510
Lewis T, Harris KE, Grant RT (1927) Observations relating to the influence of the cutaneous nerves on various reactions of the cutaneous vessels. Heart 14:1–17
Liu Y, Abdel Samad O, Zhang L, Duan B, Tong Q, Lopes C, Ji RR, Lowell BB, Ma Q (2010) VGLUT2-dependent glutamate release from nociceptors is required to sense pain and suppress itch. Neuron 68(3):543–556
Liu Q, Sikand P, Ma C, Tang Z, Han L, Li Z, Sun S, LaMotte RH, Dong X (2012) Mechanisms of itch evoked by beta-alanine. J Neurosci 32(42):14532–14537
McMahon SB, Koltzenburg M (1992) Itching for an explanation. Trends Neurosci 15(12):497–501
Mizumura K, Koda H (1999) Potentiation and suppression of the histamine response by raising and lowering the temperature in canine visceral polymodal receptors in vitro. Neurosci Lett 266(1):9–12
Namer B, Reeh P (2013) Scratching an itch. Nat Neurosci 16(2):117–118. doi:10.1038/nn.3316
Namer B, Carr R, Johanek LM, Schmelz M, Handwerker HO, Ringkamp M (2008) Separate peripheral pathways for pruritus in man. J Neurophysiol 100(4):2062–2069
Napadow V, Li A, Loggia ML, Kim J, Schalock PC, Lerner E, Tran TN et al (2014) The brain circuitry mediating antipruritic effects of acupuncture. Cereb Cortex 24(4):873–882. doi:10.1093/cercor/bhs363
Nilsson HJ, Schouenborg J (1999) Differential inhibitory effect on human nociceptive skin senses induced by local stimulation of thin cutaneous fibers. Pain 80(1–2):103–112
Nilsson HJ, Levinsson A, Schouenborg J (1997) Cutaneous field stimulation (CFS): a new powerful method to combat itch. Pain 71(1):49–55
Nilsson HJ, Psouni E, Carstam R, Schouenborg J (2004) Profound inhibition of chronic itch induced by stimulation of thin cutaneous nerve fibres. J Eur Acad Dermatol Venereol 18(1):37–43
Nojima H, Cuellar JM, Simons CT, Carstens MI, Carstens E (2004) Spinal c-fos expression associated with spontaneous biting in a mouse model of dry skin pruritus. Neurosci Lett 361(1–3):79–82
Oaklander AL, Bowsher D, Galer B, Haanpää M, Jensen MP (2003) Herpes zoster itch: preliminary epidemiologic data. J Pain 4(6):338–343
Pfab F, Valet M, Sprenger T, Toelle TR, Athanasiadis GI, Behrendt H, Ring J, Darsow U (2006) Short-term alternating temperature enhances histamine-induced itch: a biphasic stimulus model. J Invest Dermatol 126(12):2673–2678
Qu L, Fan N, Ma C, Wang T, Han L, Fu K, Wang Y, Shimada SG, Dong X, Lamotte RH (2014) Enhanced excitability of MRGPRA3- and MRGPRD-positive nociceptors in a model of inflammatory itch and pain. Brain 137(Pt 4):1039–1050. doi:10.1093/brain/awu007
Reddy VB, Iuga AO, Shimada SG, LaMotte RH, Lerner EA (2008) Cowhage-evoked itch is mediated by a novel cysteine protease: a ligand of protease-activated receptors. J Neurosci 28(17):4331–4335. doi:10.1523/JNEUROSCI. 0716-08.2008
Ross SE (2011) Pain and itch: insights into the neural circuits of aversive somatosensation in health and disease. Curr Opin Neurobiol 21(6):880–887
Ross SE, Mardinly AR, McCord AE, Zurawski J, Cohen S, Jung C, Hu L et al (2010) Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice. Neuron 65(6):886–898
Rukwied R, Mayer A, Kluschina O, Obreja O, Schley M, Schmelz M (2010) NGF induces non-inflammatory localized and lasting mechanical and thermal hypersensitivity in human skin. Pain 148(3):407–413
Rukwied R, Weinkauf B, Main M, Obreja O, Schmelz M (2013a) Axonal hyperexcitability after combined NGF sensitization and UV-B inflammation in humans. Eur J Pain 18(6):785–793
Rukwied R, Weinkauf B, Main M, Obreja O, Schmelz M (2013b) Inflammation meets sensitization—an explanation for spontaneous nociceptor activity? Pain 154(12):2707–2714. doi:10.1016/j.pain.2013.07.054
Rukwied RR, Main M, Weinkauf B, Schmelz M (2013c) NGF sensitizes nociceptors for cowhage- but not histamine-induced itch in human skin. J Invest Dermatol 133(1):268–270
Sanga P, Katz N, Polverejan E, Wang S, Kelly KM, Haeussler J, Thipphawong J (2013) Efficacy, safety, and tolerability of fulranumab, an anti-nerve growth factor antibody, in treatment of patients with moderate to severe osteoarthritis pain. Pain 13:10
Schmelz M (2002) Itch—mediators and mechanisms. J Dermatol Sci 28(2):91–96
Schmelz M, Handwerker HO (2013) Itch. Wall & Melzack’s textbook of pain. Elsevier, Philadelphia
Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjörk HE (1997) Specific C-receptors for itch in human skin. J Neurosci 17(20):8003–8008
Schmelz M, Michael K, Weidner C, Schmidt R, Torebjörk HE, Handwerker HO (2000) Which nerve fibers mediate the axon reflex flare in human skin? Neuroreport 11(3):645–648
Schmelz M, Hilliges M, Schmidt R, Orstavik K, Vahlquist C, Weidner C, Handwerker HO, Torebjörk HE (2003a) Active “itch fibers” in chronic pruritus. Neurology 61(4):564–566
Schmelz M, Schmidt R, Weidner C, Hilliges M, Torebjörk HE, Handwerker HO (2003b) Chemical response pattern of different classes of C-nociceptors to pruritogens and algogens. J Neurophysiol 89(5):2441–2448
Schmidt R, Schmelz M, Forster C, Ringkamp M, Torebjörk HE, Handwerker HO (1995) Novel classes of responsive and unresponsive C nociceptors in human skin. J Neurosci 15(1 Pt 1):333–341
Schmidt R, Schmelz M, Weidner C, Handwerker HO, Torebjörk HE (2002) Innervation territories of mechano-insensitive C nociceptors in human skin. J Neurophysiol 88(4):1859–1866
Seal RP, Wang X, Guan Y, Raja SN, Woodbury CJ, Basbaum AI, Edwards RH (2009) Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors. Nature 462(7273):651–655
Shelley WB, Arthur RP (1957) The neurohistology and neurophysiology of the itch sensation in man. AMA Arch Derm 76:296–323
Sikand P, Shimada SG, Green BG, LaMotte RH (2009) Similar itch and nociceptive sensations evoked by punctate cutaneous application of capsaicin, histamine and cowhage. Pain 144(1–2):66–75
Sikand P, Dong X, LaMotte RH (2011) BAM8-22 peptide produces itch and nociceptive sensations in humans independent of histamine release. J Neurosci 31(20):7563–7567. doi:10.1523/JNEUROSCI. 1192-11.2011
Simone DA, Alreja M, LaMotte RH (1991) Psychophysical studies of the itch sensation and itchy skin (“alloknesis”) produced by intracutaneous injection of histamine. Somatosens Mot Res 8(3):271–279
Simone DA, Nolano M, Johnson T, Wendelschafer-Crabb G, Kennedy WR (1998) Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers: correlation with sensory function. J Neurosci 18(21):8947–8954
Steinhoff M, Neisius U, Ikoma A, Fartasch M, Heyer G, Skov PS, Luger TA, Schmelz M (2003) Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin. J Neurosci 23(15):6176–6180
Tominaga M, Takamori K (2014) Itch and nerve fibers with special reference to atopic dermatitis: therapeutic implications. J Dermatol 41(3):205–212. doi:10.1111/1346-8138.12317
Tominaga M, Tengara S, Kamo A, Ogawa H, Takamori K (2009) Psoralen-ultraviolet A therapy alters epidermal Sema3A and NGF levels and modulates epidermal innervation in atopic dermatitis. J Dermatol Sci 55(1):40–46
Torebjörk HE, Schmelz M, Handwerker HO (1996) Functional properties of human cutaneous nociceptors and their role in pain and hyperalgesia. In: Belmonte C, Cervero F (eds) Neurobiology of nociceptors. Oxford University Press, Oxford, pp 349–369
Toyoda M, Nakamura M, Makino T, Hino T, Kagoura M, Morohashi M (2002) Nerve growth factor and substance P are useful plasma markers of disease activity in atopic dermatitis. Br J Dermatol 147(1):71–79
Toyoda M, Nakamura M, Makino T, Morohashi M (2003) Localization and content of nerve growth factor in peripheral blood eosinophils of atopic dermatitis patients. Clin Exp Allergy 33(7):950–955
Tuckett RP, Wei JY (1987) Response to an itch-producing substance in cat. II. Cutaneous receptor populations with unmyelinated axons. Brain Res 413(1):95–103
Vogelsang M, Heyer G, Hornstein OP (1995) Acetylcholine induces different cutaneous sensations in atopic and non-atopic subjects. Acta Derm Venereol 75(6):434–436
Vrontou S, Wong AM, Rau KK, Koerber HR, Anderson DJ (2013) Genetic identification of C fibres that detect massage-like stroking of hairy skin in vivo. Nature 493(7434):669–673
Wahlgren CF, Ekblom A (1996) Two-point discrimination of itch in patients with atopic dermatitis and healthy subjects. Acta Derm Venereol 76(1):48–51
Watanabe T, Inoue M, Sasaki K, Araki M, Uehara S, Monden K, Saika T, Nasu Y, Kumon H, Chancellor MB (2011) Nerve growth factor level in the prostatic fluid of patients with chronic prostatitis/chronic pelvic pain syndrome is correlated with symptom severity and response to treatment. BJU Int 108(2):248–251
Wooten M, Weng HJ, Hartke TV, Borzan J, Klein AH, Turnquist B, Dong X, Meyer RA, Ringkamp M (2014) Three functionally distinct classes of C-fibre nociceptors in primates. Nat Commun 5:4122. doi:10.1038/ncomms5122
Yamaguchi J, Aihara M, Kobayashi Y, Kambara T, Ikezawa Z (2009) Quantitative analysis of nerve growth factor (NGF) in the atopic dermatitis and psoriasis horny layer and effect of treatment on NGF in atopic dermatitis. J Dermatol Sci 53(1):48–54
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Schmelz, M. (2015). Itch and Pain Differences and Commonalities. In: Schaible, HG. (eds) Pain Control. Handbook of Experimental Pharmacology, vol 227. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-46450-2_14
Download citation
DOI: https://doi.org/10.1007/978-3-662-46450-2_14
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-46449-6
Online ISBN: 978-3-662-46450-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)