Anatomical and Functional Dichotomy of Ocular Itch and Pain

Fig. 1: Diagram showing the actions of both histamine (His) and non-histamine pruritogens converging onto MrgprA3+ sensory fibers in the conjunctiva to induce ocular itch. NPFF: neuropeptide FF, CQ: chloroquine; 5-HT: serotonin.

Ocular itch is a primary symptom of many ocular conditions and is difficult to treat. Although recent basic and clinical research has led to a better understanding of the immunological mechanisms of ocular conditions, the neural mechanisms underlying ocular itch remain unclear. Ocular itch is generated mainly in the conjunctiva, whereas most ocular pain arises from the cornea. Our study, for the first time, unraveled distinct sensory innervations in the cornea and conjunctiva, and identified a specific neuronal target MrgprA3-expressing sensory fibers in the conjunctiva for mediating ocular itch. This finding provides the neuroanatomical basis for the conjunctival origin of itch. Importantly, the actions of both histamine and non-histamine 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 (Fig. 1). Our discovery offers a new drug target for developing more specific and effective anti-itch medicine that circumvents side-effects of traditional anti-itch drugs (e.g., antihistamines, immunosuppressive corticosteroids and cyclosporine).

Future directions: Intense eye itching is a primary symptom of infectious conjunctivitis caused by virus or bacteria. Consequent eye rubbing/scratching leads to hand-eye contact and promotes person-to-person pathogen transmission. By comparing the sensory innervation patterns between the conjunctiva (the origin of ocular itch) and cornea (the origin of ocular pain), we identified a unique population of sensory fibers in the conjunctiva that mediates both histamine-dependent and -independent ocular itch (see Fig.1). This finding not only provides the neuroanatomical basis for the conjunctival origin of itch, but also paves an avenue for understanding ocular itch associated with infectious conjunctivitis and developing new anti-itch therapies.

Dry eyes and contact lens wear frequently induce abnormal mechanosensation, such as foreign body sensation, and cause mechanical damage to the marginal palpebral conjunctiva (termed “lid wiper”), resulting in “Lid Wiper Epitheliopathy”. The lid wiper spreads tear and senses the shear force (friction) during blinking and ocular saccades. Despite the importance of lid wiper mechanosensitivity in ocular protection, the underlying neural mechanism is unclear due to a lack of information regarding which mechanosensitive neuronal population innervates the lid wiper and senses the shear force during eye movements. By examining the innervation of all known mechanosensitive populations in the conjunctiva, we found only one mechanosensitive population in the lid wiper. We hypothesize that the neuronal population mediates abnormal mechanosensation associated with dry eyes and regulates lacrimation. This project is currently supported by the National Eye Institute.

The neural pathway from the nasal sensory neurons to the brainstem mediates the sneezing reflex

Sneezing is a vital respiratory reflex frequently associated with nasal irritation, allergies, or viral infections. However, its neural circuit remains largely unknown. A sneeze-evoking region was discovered in both cat and human brainstems, corresponding anatomically to the central recipient zone of nasal sensory neurons. Hence, we hypothesize that a neuronal population postsynaptic to nasal sensory neurons mediates sneezing in this region. To test our hypothesis, wescreened major presynaptic neurotransmitters/neuropeptides released by nasal sensory neurons, and found that Neuromedin B (NMB) peptide, instead of glutamate or other neuropeptides, is essential for signaling sneezing. Ablation of NMB-sensitive postsynaptic neurons in the sneeze-evoking region or deficiency in NMB receptor abolished sneezing reflex. Remarkably, NMB-sensitive neurons further project to the caudal ventral respiratory group (cVRG). Chemical activation of NMB-sensitive neurons elicits action potentials in cVRG neurons and leads to sneezing behavior. Our study delineates the first peptidergic pathway mediating sneezing, providing novel insights into the sneezing reflex. This study has been reported by NatureNature Reviews NeuroscienceThe Scientist, French science magazine 

Future directions: Our goal is to understand the sensory regulation of sneezing and other respiratory reflexes. Sneezing can be evoked by a range of nasal sensory stimuli that induce varying sensations in humans. For instance, capsaicin (a pungent compound from chili pepper) evokes intense burning pain and sneezing, whereas histamine causes itch and sneezing. We hypothesize that various sensory stimuli activate a common population of nasal sensory neurons to trigger the sneezing reflex, even though they may activate more other sensory neurons to elicit distinct sensations. We recently identified a highly restricted population of nasal sensory neurons that are sensitive to a variety of sneezing-inducing stimuli. We will test whether this population constitutes the long-sought “sneeze neurons” and mediates the sneezing responses to nasal irritants, allergens, and pathogens such as influenza virus. This project is supported by the National Institute of Allergy and Infectious Diseases.

Lower airway irritations, allergies or infections frequently induce coughing instead of sneezing. We have established a new animal model for coughing. Utilizing genetic mouse tools, we are studying the neural pathways controlling coughing and dissecting its difference from sneezing.

From sensory receptors to parasympathetic effectors

Allergies or infections in the eyes or airway frequently induce glandular secretion (e.g., watery eyes, runny nose), which is essential for clearance of allergens and microbial pathogens. Previous studies have suggested that the superior salivatory nucleus (SSN) controls lacrimation and nasal secretion. However, direct molecular and genetic evidence is lacking. Using molecular, genetic, pharmacological approaches, we are studying the molecular, physiological, and functional diversity of parasympathetic preganglionic neurons in the SSN. We will determine which population(s) of SSN neurons receive sensory inputs from ocular surface or nasal mucosa and mediate lacrimation or nasal secretion. Results from our study will help define the neural circuit from peripheral sensory receptors to parasympathetic effectors and provide foundational knowledge for future studies of excessive cholinergic reflex of glandular secretions in allergy and viral respiratory infections or deficiency associated with ocular or systemic diseases such as dry eyes, primary Sjögren’s syndrome, lupus, and congenital alacrima.