Anatomical and functional dichotomy of ocular itch and pain

Anatomical and functional dichotomy of ocular itch and pain

Cheng-Chiu Huang1,7,9, Weishan Yang1,9, Changxiong Guo1, Haowu Jiang1, Fengxian Li 1,2, Maolei Xiao1, Steve Davidson3, Guang Yu 4, Bo Duan5,8, Tianwen Huang5, Andrew J. W. Huang 6 and Qin Liu1,6*

Itch and pain are refractory symptoms of many ocular conditions. Ocular itch is generated mainly in the conjunctiva and is absent from the cornea. In contrast, most ocular pain arises from the cornea. However, the underlying mechanisms remain unknown. Using genetic axonal tracing approaches, we discover distinct sensory innervation patterns between the conjunctiva and cornea. Further genetic and functional analyses in rodent models show that a subset of conjunctival-selective sensory fibers marked by MrgprA3 expression, rather than corneal sensory fibers, mediates ocular itch. Importantly, the actions of both histamine and nonhistamine pruritogens converge onto this unique subset of conjunctiva sensory fibers and enable them to play a key role in mediating itch associated with allergic conjunctivitis. This is distinct from skin itch, in which discrete popu- lations of sensory neurons cooperate to carry itch. Finally, we provide proof of concept that selective silencing of conjunctiva itch-sensing fibers by pruritogen-mediated entry of sodium channel blocker QX-314 is a feasible therapeutic strategy to treat ocular itch in mice. Itch-sensing fibers also innervate the human conjunctiva and allow pharmacological silencing using QX-314. Our results cast new light on the neural mechanisms of ocular itch and open a new avenue for developing therapeutic strategies.

In this work, we establish a role for the bioactive lipid sphingosine 1-phosphate (S1P) and its
receptor S1PR3 in inflammatory thermal pain and itch. S1P injection elicited robust heat hypersensitivity, acute pain, and itch behaviors in mice, which were wholly dependent on S1PR3. S1P-evoked pain was entirely dependent on TRPV1 ion channels, whereas S1P evoked itch was dependent on TRPA1. Consistent with our in vivo findings, we found that S1P activated subsets of both heat- and itch-sensitive dorsal root ganglion (DRG) neurons, and that activation was solely dependent on S1PR3, and not S1PR1. Our data support a model in which S1P elicits neuronal activation via two pathways in distinct subsets of somatosensory neurons. Gβγ-dependent activation of TRPA1 mediates S1PR3-evoked calcium responses in one subpopulation, whereas PLC-dependent activation of TRPV1 mediates S1PR3-evoked calcium responses in the other subpopulation. In the Complete Freund’s Adjuvant (CFA) -induced inflammatory pain model, S1PR3-deficient mice failed to develop heat hypersensitivity, whereas mechanical hypersensitivity developed normally. Pharmacological blockade of S1PR3 activity or S1P production rapidly and selectively ameliorated heat hypersensitivity in wild-type mice treated with CFA. These data definitively identify S1PR3 as a mediator of thermal pain and itch, and, furthermore, demonstrate for the first time that elevated peripheral S1P is an essential driver of chronic inflammatory pain.

BP180 dysfunction triggers spontaneous skin inflammation in mice.

Persistent Extracellular Signal-Regulated Kinase Activation by the Histamine H4 Receptor in Spinal Neurons Underlies Chronic Itch

Kun Huang1,2,5, Dan-Dan Hu1,3,5, Dong Bai1,2,5, Ze-Yang Wu1,3, Yi-Yang Chen4, Yi-Jun Zhang1,3, Xin Lv4, Qing-Xiu Wang2 and Ling Zhang1,3

Persistent Extracellular Signal-Regulated Kinase Activation by the Histamine H4 Receptor in Spinal Neurons Underlies Chronic Itch

Transient extracellular signal-regulated kinase (ERK) activation in the spinal cord triggers histamine-induced acute itch. However, whether persistent ERK activation plays an important role in chronic itch development remains unclear. This study investigated the role of spinal ERK activation in chronic itch. The results showed that repetitive DNFB painting on the nape of mice evoked not only initial scratching but also sustained, spontaneous scratching. In addition, DNFB induced itching rather than nociception, as demonstrated using a cheek model. Furthermore, ERK was persistently activated in the spinal cord of DNFB-treated mice, and the intrathecal inhibition of phosphorylation of ERK suppressed both spontaneous itching and ERK activation. ERK activation was observed in neurons but not in glia cells during chronic itch development. Finally, DNFB- induced spontaneous itching behavior and ERK activation were largely inhibited by the histamine H4 receptor antagonist JNJ7777120 but not by the H1 receptor antagonist chlorpheniramine. Our results indi- cate that persistent ERK activation via the histamine H4 receptor in spinal neurons underlies DNFB-induced chronic itch.
Journal of Investigative Dermatology (2018) -, -e-; doi:10.1016/j.jid.2018.02.019

Upregulation of the human alkaline ceramidase 1 and acid ceramidase mediates calcium-induced differentiation of epidermal keratinocytes.

New mechanism underlying IL-31-induced atopic dermatitis.

Distinct functions of opioid-related peptides and gastrin-releasing peptide in regulating itch and pain in the spinal cord of primates.

Cooling Relief of Acute and Chronic Itch Requires TRPM8 Channels and Neurons
Radhika Palkar1,3, Serra Ongun1,2, Edward Catich1,3, Natalie Li1, Neil Borad1, Angela Sarkisian1 and David D. McKemy1,2,3

1Neurobiology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California; 2Molecular and Computational Biology Graduate Program, Department of Biological Sciences, University of Southern California, Los Angeles, California; and 3Neuroscience Graduate Program, Department of Biological Sciences, University of Southern California, Los Angeles, California
Correspondence: David D. McKemy, Neurobiology Section, Department of Biological Sciences, University of Southern California, 3641 Watt Way, HNB 201, Los Angeles, CA 90089. E-mail: mckemy@dornsife.usc.edu
Abbreviations: Cqx, chloroquine; a-Me5-HT, a-methyl 5-HT
Received 16 August 2017; revised 8 December 2017; accepted 20 December 2017; accepted manuscript published online 27 December 2017; corrected proof published online XXX

Cooling Relief of Acute and Chronic Itch Requires TRPM8 Channels and Neurons

Cooling or the application of mentholated liniments to the skin has been used to treat itch for centuries, yet remarkably little is known about how counter-stimuli such as these induce itch relief. Indeed, there is no clear consensus in the scientific literature as to whether or not cooling does in fact block the transduction of itch signals or if it is simply a placebo effect. This gap in our understanding led us to hypothesize that cooling is antipruritic and, like cooling analgesia, requires function of the cold-gated ion channel TRPM8, a receptor for menthol expressed on peripheral afferent nerve endings. Using a combination of pharmacologic, genetic, and mouse behavioral assays, we find that cooling inhibits both histaminergic and non-histaminergic itch pathways, and that inhibition of itch by cooling requires TRPM8 channels or intact and functional TRPM8-expressing afferent neurons. The cold mimetic menthol is also effective in ameliorating itch in a TRPM8-dependent manner. Moreover, we find that chronic itch can be ameliorated by cooling, demonstrating that this counter-stimulus activates a specific neural circuit that leads to broad itch relief and a potential cellular mechanism for treatment of chronic itch.
Journal of Investigative Dermatology (2018) -, -e-; doi:10.1016/j.jid.2017.12.025