Jiaci

Kuruvilla M, et al.

J Investig Allergol Clin Immunol 2019; Vol. 29(5): 349-356

doi: 10.18176/jiaci.0320

accompanied by irritability and fatigue [3] and patients with

AC have a poor quality of life, irrespective of the severity

of associated nasal symptoms [10].

Neuronal dysregulation is likely to be responsible for at

least some of these symptoms. Exaggerated hyperreactivity

to nonspecific stimuli such as temperature changes, strong

odors, and irritants is known to be a manifestation of neuronal

inflammation in nonallergic and mixed rhinitis [11]. This is

akin to hyperreactivity to heat, sunlight, and wind during the

active phase of vernal keratoconjunctivitis, which may be

reflective of neural involvement [12], as is the nonspecific

increase in reactivity in the conjunctival response to histamine

in AC patients [13]. In addition, exposure to nonspecific

environmental stimuli, pollutants, and cigarette smoke were

reported to be triggers in a substantial proportion of AC

patients [14] and may be similarly attributable to neural

hypersensitivity. The term vasomotor conjunctivitis has been

used to describe this phenomenon [15].

Mechanisms of AC-Induced Neuropathic

Pain

Sensory Nociceptive Innervation of the Ocular

Surface

Peripheral origin:

The ocular surface is innervated by

primary sensory neurons located in the trigeminal ganglion,

most of which (70%) are polymodal nociceptors [16]. The

afferent C fibers express transient receptor potential (TRP)

channels that play a role in many diseases. Pain and itch

also employ largely overlapping transduction machinery.

Transient receptor potential vanilloid 1 (TRPV1) and transient

receptor potential ankyrin 1 (TRPA1) are 2 such TRP channels

that appear to be important in allergic responses. TRPV1 is

known as a capsaicin responder, but also reacts to a host of

other proinflammatory exogenous and endogenous agents. In

addition, it is stimulated by several mediators that are relevant

to the allergic reaction, such as histamine and bradykinin. As

with TRPV1, TRPA1 is activated by inflammatory mediators

including those involved in allergic disease.

TRPV1/TRPA1 receptor activation in the eye induces the

release of neuropeptides such as neurokinins, calcitonin gene-

related peptide (CGRP), and substance P (SP). Furthermore,

activated sensory neurons can themselves directly release

proinflammatory peptides into surrounding tissue (antidromic

release). Other molecules known as neurotrophins (eg, nerve

growth factor [NGF]), act directly on peptidergic C fiber

nociceptors to potentiate TRPV1 receptors and increase

the expression of substance P and TRPV1. This ultimately

translates into nociception and pain [16].

Central representation:

The cell bodies of sensory neurons

innervating the ocular surface are located in the trigeminal

ganglion and terminate in the trigeminal brainstem complex.

There, they establish contact with second-order ocular neurons

that project to the somatosensory cortex, where the original

noxious signal is perceived as pain.

A schematic representation of the pathogenesis of ocular

pain and itch is outlined in Figure 1.

Allergen-Induced Neuromodulation of Sensory Nerves

Under pathological and chronic conditions, dysfunction of

the nervous system itself can generate chronic neuropathic pain

and itch. This is secondary to neural plastic changes in primary

sensory neurons of the peripheral nervous system (peripheral

sensitization) and spinal cord, brainstem, and cortical neurons

in the central nervous system (central sensitization). A

significant body of physiological data suggests that allergy

symptoms may be significantly modulated by the nervous

system. This neural plasticity may be responsible for symptoms

of neuropathic pain and itch in AC. Reflex neural activity

is upregulated in the presence of allergic inflammation and

further amplifies the histamine-mediated immunopathological

response in the conjunctiva.

Peripheral sensitization in allergic inflammation:

During

chronic inflammation, including allergic inflammation, long-

lasting changes develop in the expression and function of

stimulus-transducing ion channels such as TRPV1 and TRPA1.

This results in abnormal hyperexcitability of neurons and may

evoke chronic neuropathic pain.

TRPV1 is believed to be a major cause of neuropathic

pain [17]. It also has a proven role in itch and, in particular,

histamine-induced itch. Chronic allergic inflammation is known

to mediate plasticity of TRPV1 in airway diseases. Inhalation

of allergen by rats or guinea pigs leads to the expression of

TRPV1 in Aδ cough nerves [18]. TRPV1 expression and

substance P levels were found to be significantly higher in

patients with nonallergic rhinitis [19] and asthma, especially

refractory cases [20]. Furthermore, histamine sensitizes the

nociceptor TRPV1 and has been shown to contribute to visceral

hypersensitivity in animals [21]. In addition, other endogenous

inflammatory allergy mediators such as prostaglandin E2 and

bradykinin can markedly enhance the sensitivity of TRPV1

and lower its threshold for activation of sensory nerves [22].

Figure 1.

Schematic representation of neuropathic pain and itch in ocular

surface disease.

Central

sensitization

V1/trigeminal

ganglion

Sensory

cortex

Sensory

plasticity

Increased afferent

excitability

TRPV1

TRPA1

Sub P

NGF

Increased efferent

neural excitability

Noxious

stimulus

Corneal

nociceptors

Peripheral

sensitization

Chronic neuropathic

pain/itch

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