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Scratching that Itch: HTR7
Department of Biology
Lake Forest College
Lake Forest, Illinois 60045
There is pleasure when an itch is scratched. But to be without an itch is more pleasurable still. – Buddhit Nāgārjuna. Aberrant peripheral serotonin (5-HT) signaling has long been linked to acute and chronic itch disorders. This is the first demonstration of a 5-HT receptor that mediates both acute and chronic itch in the periphery1.
Anyone who has experienced a mosquito bite knows all too well how maddening the relentless itching can be, even if it only lasts a few days. However, for people who suffer from chronic itch that lasts weeks, months, or years, the discomfort can be distracting and often debilitating. Itch (pruritus) is defined as an unpleasant sensation that triggers a desire or reflex to scratch2. Chronic itch is a widespread, multisensory condition that appears in conjunction with a number of skin diseases, systemic conditions, and various neurological disorders3. With so few effective therapies available, people tend to alleviate their discomfort by scratching. Though scratching can provide momentary relief, it often makes the itching worse2. The need to scratch can be so overpowering that it can result in severe self-injury and mutilation. So was the story when an ordinary woman, plagued with an extraordinary facial itch, scratched through her skull during the night – all the way into her brain3, 4. Though her head was later wrapped in layers of gauze to protect the skin graft and she did everything in her power to resist scratching the incessant itch, she managed to scratch off the skin grafts every time4. Anything to reach that gratification. Since an estimated 10-20% of the population will suffer from chronic itch as some point in their life1, understanding the molecular basis of chronic itch is of significant clinical interest. On page 124 of this issue, Morita et al. now show that a peripheral serotonin receptor, HTR7, triggers itch but not pain behaviors, mediates serotonergic and SSRI-evoked itch, and is required for the development of chronic itch in a mouse atopic dermatitis model1.
Itch signals are transduced via a subset of primary afferent sensory neurons that innervate the skin2. TRPA1, inflammatory ion channels found in the plasma membrane of pain- and itch-detecting sensory nerves, have been linked to itch signaling3. Peripheral serotonin, or 5-hydroxytryptamine (5-HT), is a component of the ‘‘inflammatory soup’’ and has been identified as a potent inducer of itch1. 5-HT has long been linked to chronic itch and pain, and somatosensory neurons express ten distinct subtypes of 5-HT receptors1. However, the exact role of each receptor subtype remain undefined, and their role in the transduction of serotonergic itch signals unknown. No evidence exists for any 5-HT receptor transducing serotonergic itch signals in primary afferent neurons.
In order to identify the 5-HT receptor subtypes that mediate itch, Morita et al. examine itch behaviors and sensory neuron gene expression across genetically-distinct inbred mouse strains. These types of mouse strains have been shown to display variable somatosensory behaviors including itch and pain5. Morita et al. transcriptionally profile the dorsal root ganglia (DRG), which contains the neurons responsible for detecting itch, touch and painful stimuli. This allows them to identify the gene whose expression most highly correlates with itch behavior: HTR7, a specific 5-HT receptor. If HTR7 plays a direct role in itch transduction, then one should expect to see significant HTR7 expression in the subset of DRG neurons that detect noxious stimuli and innervate the skin. Using in situ hybridization and immunostaining of hairy skin, Morita et al. confirmed significant presence of Htr7 transcripts in DRG neurons and HTR7 protein in TRPA1-positive fibers, demonstrating that HTR7 is functional and expressed in these sensory neurons.
Figure 1. Schematic Diagram: Roles of HTR7 & TRPA1 Signaling in Acute & Chronic Itch.
Top. Increased 5-HT levels in the skin, triggered by direct injection of 5-HT, SSRI administration, or atopic dermatitis condition activates the 5-HT receptor, HTR7. Injection of selective 5-HT agonist, LP44, also increases 5-HT levels in the skin, activating HTR7. HTR7 signals TRPA1 ion channels to open, promote neuronal depolarization, and trigger itch-evoked scratching.
Bottom: In the peripheral nervous system, itch signals are transduced via a subset of primary afferent sensory neurons that innervate the skin and go through the dorsal root ganglia (DRG) and travel through the central nervous system through the spine to eventually lead to the brain.
The observed correlation between acute itch behavior and HTR7 motivated the researchers to look at the role of HTR7 in serotonergic and chronic itch. Subsets of somatosensory neurons and 5-HT signaling in the somatosensory system have been linked to both acute and chronic itch in addition to pain. Whereas several studies have looked at HTR7 in relation to acute pain6, inflammatory pain7, and mechanical hypersensitivity8, Morita et al. are the first to investigate HTR7 in relation to acute and chronic itch. They use an established mouse cheek model of itch to investigate whether specific activation of peripheral HTR7 triggers itch and/or pain behaviors. Specific activation of HTR7 is accomplished using a HTR7-selective agonist: LP44. Morita et al. observe that LP44, but not vehicle injection, induces scratching behavior in these mice. This response can be blocked by the pre-injection of HTR7 antagonist. In order to support this data with more evidence, the expression and functionality of HTR7 is altered and mouse behavior observed. When the expression or functionality of HTR7 is decreased by genetic ablation and pharmacological inhibition respectively, the scratching of the mice decreases significantly. Furthermore, mice lacking Trpa1 also demonstrate decreased scratching behavior in comparison to WT mice. Taken together, these data show that both HTR7 and TRPA1 are required for LP44-evoked itch behaviors. Previous studies have shown that 5-HT triggers both itch-evoked scratching and pain behaviors9. Interestingly, the activation of HTR7 did not elicit pain behavior in the mouse model. These data demonstrate that acute activation of HTR7 evokes itch but not pain behavior.
Morita et al. next sought out to evaluate the role of HTR7 in serotonergic itch. Since previous studies have shown that selective serotonin reuptake inhibitors (SSRIs) increase 5-HT levels and elevated 5-HT levels promote itch sensations and scratching in humans, Morita et al. investigate whether intradermal injection of SSRIs increase local 5-HT to trigger itch behaviors in mice. Injection of the SSRI sertraline induces a rapid increase in skin 5-HT and induces itch-evoked scratching in WT mice. Predictably, there is significant reduction of SSRI-evoked scratching in Htr7- and Trpa1- mice as compared to WT mice. Interestingly, there is no significant difference in scratching behavior between Htr7+ and Trpa1+ mice. It can thus be ascertained that HTR7 and TRPA1 together mediate some forms of serotonergic and SSRI-mediated itch.
Altered 5-HT signaling is associated with a variety of chronic itch conditions in humans, including atopic dermatitis1, 3. Thus, Morita et al. investigate whether HTR7 plays a role in chronic itch in vivo using an established mouse model of atopic dermatitis. The vitamin D analog, MC903, is used to induce an atopic dermatitis-like phenotype in mice. These mice display lesions, redness, and scabbing. Similar to human atopic dermatitis patients, the MC903-treated mice display high levels of 5-HT in eczematous skin and exhibit significant scratching behavior. Htr7- mice treated with MC903 exhibit less severe lesions and significantly decreased scratching behavior than WT mice. Overall, these findings indicate that HTR7 is a key molecular determinant of atopic dermatitis chronic itch.
Morita et al. cleverly take advantage of the natural variation of gene expression and itch behavior in mice to identify novel molecular determinants of itch in primary afferent sensory neurons. The analysis of HTR7 in serotonergic and SSRI-evoked itch provides interesting data and speculation. Morita et al. show compelling data regarding SSRI-evoked itch. Paradoxically, SSRIs have been found to partially alleviate some forms of chronic itch10. The mechanisms underlying this dual role of SSRIs in alleviating and mediating itch remains unknown. Does SSRI-evoked itch involve different 5-HT signaling molecules under normal and chronic itch conditions? Or are the peripheral and central targets differentially targeted? Furthermore, this is the first study definitively linking the dysregulation of 5-HT in the skin and the significant itch behaviors, both of which are characteristic of the human atopic dermatitis disorder, in the MC903-induced mouse model of atopic dermatitis. However, it is important to note that chronic itch appears in conjunction to a wide range of disorders2, 3. Therefore, it would be beneficial to study the role of HTR7 in other forms of chronic itch in a variety of models exhibiting these conditions. Is HTR7 involved in differential pathways that account for the different forms of itch? Would HTR7 antagonists exhibit efficacy in the selective attenuation of itch that arises from these pathological conditions? In the future, more-detailed analysis of the role of HTR7 in these different pathological itch conditions will reveal regulatory features and therapeutic potential.
- Morita T, et al. HTR7 Mediates Serotonergic Acute and Chronic Itch. Neuron. 2015;87:124–138.
- Ikoma A, Steinhoff M, Ständer S, Yosipovitch G, Schmelz M. The neurobiology of itch. Nat Rev Neurosci. 2006;7:535–547.
- Bautista DM, Wilson SR, Hoon MA. Why we scratch an itch: the molecules, cells and circuits of itch. Nat Neurosci. 2014;17:175–182.
- Gawande, A. The Itch. The New Yorker. 2008.
- Green, A.D., Young, K.K., Lehto, S.G., Smith, S.B., and Mogil, J.S. (2006). Influence of genotype, dose and sex on pruritogen-induced scratching behavior in the mouse. Pain 124, 50–58.
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- Akiyama, T., Carstens, M.I., and Carstens, E. (2010). Facial injections of pruritogens and algogens excite partly overlapping populations of primary and second-order trigeminal neurons in mice. J. Neurophysiol. 104, 2442–2450.
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