Are itch and scratching the nausea and vomiting of skin?

Abstract

The physiologic similarities between itch and nausea may not be evident initially, but they share the role of repelling irritants and toxins from the body by inducting scratching and vomiting, respectively. In addition, itch and nausea frequently occur together in certain conditions such as uraemia. Here we show that the mechanisms underlying itch and nausea overlap and that advances in either field may influence the identification of novel drug targets, particularly for itch.

Itch is a significant problem as it impacts the quality of life to an extent similar to that of pain (1). Most of the advances in the field of itch have been achieved since the turn of the current century. Findings from a range of biomedical fields turn out to impact itch. Advances in understanding pain, which shares pathways with itch, have brought neuroscientists to the field of itch. It is now appreciated that processes that occur in other epithelia, particularly the gut and lung, overlap with those in the skin providing for cross-fertilization of concepts and findings. While itch is defined as an unpleasant sensation that provokes the desire to scratch, nausea is a sensation of abdominal discomfort that provokes the urge to vomit. We discuss parallels between mediators and pathways associated with itch and nausea. We propose that mechanisms underlying itch and nausea tightly overlap. We conclude that advances in either field may influence the identification of novel drug targets, particularly for itch.

Mediators of itch and nausea

Histamine

Histamine is the prototypical itch mediator in human and mice (2–4) (Table 1). Intra-dermal injection of histamine elicits redness, wheal and flare, and the triple response of neurogenic inflammation, most often accompanied by pruritus (2). Antihistamines remain the first-line treatment of urticaria. It was recently reported that not only H₁, but also H₃ and H₄ receptors mediate scratching in mice (5–7). Histamine also activates the neurons in the area postrema (8, 9). H₁, H₂ and H₄ receptors are expressed in human gastrointestinal tract (10, 11). Studies in animal models have demonstrated that histamine provokes gastric contractility through the H₁ receptor (12, 13). H₁ antihistamines, such as diphenhydramine and promethazine, are useful in patients with motion sickness accompanied by nausea and vomiting (14). H₁ antihistamines are also considered the first-line treatment for patients suffering from morning sickness (15), but antihistamines are not effective for chemotherapy-induced nausea (16).

Table 1.

Mediators of itch and nausea

	Scratching and itch	Nausea and vomiting
Neurotransmitter	Receptor	Receptor
Serotonin	5-HT2	5-HT2/5-HT3
Histamine	H1/H3/H4	H1/H2
Acetylcholine	M3	M3/M2
Opioid	μ	μ
Cannabinoid	CB1/CB2?	CB1/CB2
Substance P	NK1?	NK1
Endovanilloid	TRPA1/TRPV1/TRPV2	TRPA1/TRPV1/TRPV2
Cholecystokinin	CCK?	CCK1
Dopamine	?D	D2
GABA	GABA-A/GABA-B	GABAA

Serotonin (5-Hydroxytryptamine)

Serotonin is a neurotransmitter derived from tryptophan. The intra-dermal injection of serotonin into human subjects induces itch. Serotonin has a shorter latency of inducing itch as compared to histamine which indicates a direct effect of serotonin on sensory neurons (17). Studies in mice have demonstrated that 5-HT₂ agonists, but not 5-HT₃ agonists, induce scratching in mice (18). Consistent with this observation, ondansetron, a 5-HT₃ receptor antagonist, does not inhibit serotonin-induced itch in mice (18). In addition, serotonin-induced scratching is not altered in 5-HT₃-deficient mice (19).

Further supporting a role for serotonin in itch, the selective serotonin re-uptake inhibitors (SSRI), paroxetine, sertraline and fluvoxamine have been reported to exert some benefit in the treatment of the itch associated with cholestasis, atopic dermatitis and lymphoma (20–22). Similarly, mirtazapine, a noradrenergic and specific serotonergic antidepressant, decreased itch intensity in an uncontrolled case series (23,24).

Serotonin, acting through 5-HT₃, is strongly associated with nausea (25,26). Enterochromaffin cells are the major source of serotonin in the gut (27). The mainstay of activation of the vomiting centre by serotonin is through the release of serotonin from the gastrointestinal tract into the bloodstream (25,26). Metastatic carcinoid tumors of the skin can be associated with severe itch (28,29) but for reasons that are not known, the incidence of itch in such tumors appears to be less than expected (29). Ondansetron, the specific 5-HT₃ antagonist noted above, is effective in the treatment of chemotherapy-induced nausea and vomiting. In contrast, randomized placebo-controlled trials have failed to demonstrate a beneficial effect for ondansetron in treating the itch associated with systemic disorders such as chronic liver disease or uraemia (30,31).

Opioids

Itch is a classic side effect of mu opioid receptor (MOR) agonists used to treat pain. A placebo-controlled study in 18 patients with chronic pruritic associated with a variety of disorders showed that naltrexone, applied topically, significantly decreased itch (32). In addition, both central and peripheral acting kappa opioid receptor (KOR) agonists decrease chloroquine-induced scratching in mice (33). Furthermore, psoralen + ultraviolet A (PUVA) therapy downregulates the mu opioid system and restores the kappa opioid system in patients with atopic dermatitis, and may contribute to the beneficial effect of phototherapy with respect to decreasing itch (34). Some studies have shown promising results with the MOR antagonists naloxone and naltrexone and the KOR agonist nalfurafine for treating the itch associated with chronic kidney disease, cholestasis and atopic dermatitis (35).

Opioid receptors are expressed in the enteric nervous system, muscle fibres and mucosa of the GI tract (36). Although the exact mechanism of opioid-induced nausea and vomiting is uncertain, studies have shown that stimulation of the MOR and delta opioid receptors (DOR) in the chemoreceptor trigger zone (CTZ) boosts the sensitivity of the vestibular system, resulting in opioid-induced nausea and vomiting (37). The anti-emetic properties of opioid antagonists are attributed to inhibition of the opioid receptors in the CTZ and the nerves of the GI tract that control GI motility. Alvimopan and methylnaltrexone are peripheral acting MOR antagonists approved for treating postoperative ileus and opioid-induced bowel dysfunction (36). Their anti-emetic properties are under investigation.

Substance P

Substance P (SP) belongs to a family of structurally related peptides known as tachykinins (38). Tachykinins are derived from alternative processing of the Tac genes. SP is an endogenous inflammatory neuropeptide. The intra-dermal injection of substance P induces itch in humans and scratching in mice presumably through activation of neurokinin-1 (NK1) (39,40). Substance P has been implicated in many itchy conditions including atopic dermatitis, psoriasis, prurigo nodularis and cutaneous T-cell lymphoma/Sezary syndrome (41–46). SP induces mast degranulation and histamine release from mast cells (40,47,48). Antihistamines may thus be expected to completely block itch, but they do not. SP-induced responses (49) and studies in mast cell deficient mice have shown that SP-induced itch is not significantly decreased (39). These observations implicate pathways independent of histamine and mast cells in SP-induced itch. Mast cells are likely to have a modulatory role as SP induces the release of inflammatory mediators including tumor necrosis factor, IL-3 and granulocyte macrophage colony-stimulating factor from these cells (50). SP is thought to work primarily via activation of the NK1 receptor to contribute to inflammation and itch. NK1 antagonists would thus be expected to be highly effective in the treatment of itch and inflammation. Akin to antihistamines, NK1 antagonists are effective in some, but not all, itchy patients (51,52).

In contrast to itch and inflammation, the NK1 antagonists aprepitant and netupitant are effective for treating chemotherapy-induced nausea and vomiting and approved for this indication (53,54). Aprepitant is an effective inhibitor of nausea and vomiting in all phases of nausea in chemotherapy patients (55). While SP and NK1 are expressed in the peripheral enteric nervous system (25,56), the anti-emetic actions of NK1 receptor antagonists are attributed to central inhibition of this receptor (25).

Cannabinoids

Endogenous cannabinoids are derived from arachidonic acid and bind to cannabinoid (CB) receptors to exert their effects (57). CB1 receptors are expressed on central and peripheral neurons. Activation of these receptors inhibits release of various neurotransmitters that are involved in itch and nausea. CB2 receptors are primarily expressed on immune cells and mediate cytokine release. A recent article reported that S-777469, a novel CB2 receptor agonist, significantly suppressed the scratching behaviour induced by histamine, serotonin and SP in rats (58). CB1 receptors are co-localized with TRPV1 receptors in primary afferent C fibres (59,60), and both receptors are expressed in keratinocytes and skin mast cells (60). Cannabinoid agonists decrease histamine-induced itch in mice (61) and reduce the severity of chronic itch in human subjects (62). Activation of CB2 receptors on keratinocytes induces secretion of β-endorphins in rats. β-endorphins bind mu opioid receptors on nerve endings and inhibit nociception (63).

Nabilone was the first CB1/CB2 agonist available for the treatment of chemotherapy-induced nausea and vomiting (64). Dronabinol, a synthetic analogue of Δ⁹-tetrahydrocannabinol, entered the clinic in 1985 as an anti-emetic and was later approved as an appetite stimulant (64). Recent studies have shown that cannabinoid agonists decrease intestinal motility, predominately through peripheral CB1 receptors (64), but they attenuate nausea by activating CB1 receptors in the nucleus of the solitary tract. Nabiximols (Sativex^®) is prescribed for neuropathic pain, particularly in patients with multiple sclerosis or end-stage cancer (64). Cannabinoid agonists have not yet been approved for the treatment of itch.

Endovanilloids

The transient receptor potential (TRP) ion channels mediate several sensory processes. Certain TRP receptors are required for downstream transmission of signals induced by pruritogens in the periphery. TRPV1 is necessary for the mediation of histamine-induced itch (65). TRPA1 is necessary for the mediation of itch evoked by histamine-independent pruritogens such as BAM8-22 and chloroquine (66). TRPV1 is abundantly expressed on peptidergic DRG neurons (67) and mediates the release of neuropeptides including SP and CGRP (67). SP-induced itch is diminished in TRPA1 deficient mice underscoring the role of TRP channels not only in the release of SP, but also in transmission of SP-induced itch (68). TRPV3 mediates itch at the level of keratinocytes and overexpression of TRPV3 in both human (Olmsted syndrome) and rodents is associated with itch and atopic dermatitis-like skin changes (69–71).

In the GI tract, TRPV₁ is expressed in myenteric ganglia, muscle layers and mucosa in addition to primary sensory afferent neurons (72). TRPV1 is also expressed on the nucleus of the solitary tract, area postrema and dorsal motor nucleus of the vagus nerve (73). Capsaicin, the TRPV1 agonist, induces nausea in the upper gastrointestinal tract of healthy volunteers (74), while resiniferatoxin, an ultrapotent capsaicin analogue, has shown anti-emetic properties on centrally and peripherally acting stimuli in the ferrets (75), by destroying the relevant nerves. TRPA1 is highly expressed in the gastrointestinal tract and its activation on enterochromaffin cells by stimulants such as methyl salicylate and cold, induces the release of 5-HT, which regulates gastrointestinal motility (76). Thienopyridines, including ticlopidine, clopidogrel and prasugrel inhibit ADP and are effective platelet inhibitors. Nausea and vomiting are side effects of this class of drugs and are mediated via TRPA1 (77).

Conclusions and future directions

A comparison of the pathways and mediators involved in itch and nausea reveals fundamental similarities but differences are apparent. For example, gastrin-releasing peptide (GRP) and brain natriuretic peptide (BNP) mediate itch at the level of the spinal cord (78,79) but neither peptide mediates nausea. GRP can, however, indirectly induce release of histamine from enterochromaffin-like cells and alter GI motility (80). In addition to the mediators discussed here, the neurotransmitters acetylcholine, GABA and dopamine are involved in modulating itch and nausea. Overlap in broad neurotransmitter systems is not surprising, as regulatory functions would be expected to be redundant during evolution. Therefore, we appreciate that the similarities between the receptors mediating itch and nausea do not necessarily prove nausea and vomiting to be the itch and scratching of the skin but in terms of evolution, we propose that each may serve a similar physiological purpose: removal of irritating agents or toxins from the body. Itch does so by provoking scratching. Nausea does so by inducing vomiting. A similar phenomenon has been suggested for itch and cough (81). Numerous medications are effective for the treatment of nausea and have been approved for this indication. In contrast, therapeutic options for itch are few, non-targeted and not effective for itches associated with dermatologic or systemic diseases, most of which are histamine-independent. We have shown that itch and nausea have several mediators in common. Most of the newer anti-emetic treatments have not been considered for itch. None of the medications approved for nausea are approved for itch, except for antihistamines. Neurokinin and serotonin receptor antagonists are effective for nausea, but their efficacy for itch is controversial and the studies are limited to small trials. It is appreciated that mediators of itch and nausea may be shared but activate different receptor subtypes. This appears to be the case for serotonin receptors as studies have demonstrated a more prominent role for 5HT3 in nausea when compared to itch as the observations with ondansetron and animal experiments suggest. With respect to the neurokinin inhibitors, the inconsistency between effectiveness extends beyond nausea and itch. In particular, NK1 inhibitors have failed in clinical trials of asthma and pain and nausea remains the only condition that has been successfully treated by NK1 inhibitors (82–84). As with serotonin antagonists, one explanation could be the interaction of SP with NK2 and NK3 receptors in the periphery and skin, but behavioural itch studies with NK2 and NK3 agonists and antagonists do not support a role for these receptors in itch (39). Recent studies have demonstrated that the combination of NK1 inhibitors and 5-HT3 antagonists, aprepitant/ondansetron and netupitant/palonosetron is more effective for the treatment of nausea than either agent alone, but none of these combination medications have been tried on itch (85,86). Studies are required to determine whether differences in the peripheral and central targets of SP could be a key to the development of SP inhibitors that effectively treat itch.

While advances in the field of nausea could be beneficial for itch, recent discoveries in the field of itch can be translated as new targets for gastrointestinal conditions. For example, the expression of certain members of the itch-specific receptors, mas-related G-protein-coupled receptors, or Mrgprs, is elevated in inflammatory bowel disease models (87), suggesting that these receptors may not only serve as targets of anti-itch treatments, but also they may play an important role in inflammatory conditions of the gastrointestinal system. In conclusion, we introduce the hypothesis that the underlying mechanisms that lead to itch and nausea have considerable similarities and that advances in either field could accelerate our understanding of these complex entities.