Jiaci

Neuropathic Pain/Itch in Allergic Conjunctivitis

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

doi: 10.18176/jiaci.0320

Inhalation of allergen also upregulates the expression

of genes involved in the production of substance P and

CGRP, both of which act as itch sensation–enhancing

neuropeptides [23,24]. Allergen exposure also enhances

the release of substance P and CGRP from sensory nerve

endings (antidromic pathway). Substance P and CGRP cause

antidromic stimulation of nociceptive fibers, which results in

C-fiber activation and synergistically augments the allergic

inflammatory reaction [24,25]. In 2017, Azimi et al [26]

described the role of substance P–mediated activation of MC

receptors in inducing itching in a mouse model.

Allergic reactions can also lead directly to the release

of neurotrophic factors, especially NGF, from mast cells

and other cells, such as the airway epithelium [27]. NGF

is a complex regulator of neural plasticity that further

sensitizes afferent nerves. It has been found in eosinophils

and peripheral nerves [25,28] and is upregulated by nasal

allergen provocation. Endogenous NGF levels are elevated not

only in certain chronic pain conditions, but NGF serum levels

have also been found to be increased in allergic diseases and

asthma [29], as well as in bronchioalveolar lavage and nasal

lavage fluids from these patients.

All of these factors further stimulate the vascular

endothelial cells or mast cells to release even more chemical

mediators such as histamine, thus producing a vicious circle

of disease exacerbation.

This concept of peripheral sensitization was supported

by a guinea pig model of AC, which demonstrated a reduced

threshold for activation of polymodal nociceptors, as well as an

augmented response to noxious chemical stimuli. The authors

suggested the operation of a comparable pathway in humans.

The overall changes in firing of corneal sensory fibers correlate

with the foreign body and itching sensations reported by AC

patients [30], thus suggesting a possible TRPV1-dependent

pathway in the sensitization stage. However, further studies

must be performed to confirm this finding.

The sensitization of sensory nerves results in augmented

pain sensations and may be responsible for the burning

quality of AC symptoms. Chronic inflammation may also

damage sensory nerve fibers of the ocular surface leading

to formation of neuromas that spontaneously discharge

and cause unpleasant sensations, such as pain, dryness, and

grittiness [16].

Central sensitization in allergic inflammation:

Neuropathic

pain may also result from abnormal function of higher brain

structures, from where ocular trigeminal ganglion neurons

project. Amplification of responses occur in the central

nervous system through sensitization of central pathways,

failure of inhibitory control mechanisms, or both. Central

sensitization can cause secondary hyperalgesia and allodynia,

thus contributing to enhanced inflammatory pain.

Central neural mechanisms are also thought to be involved

in allergic inflammation. Extended exposure to allergen in a

primate model of allergic asthma causes phenotypic changes

in the intrinsic membrane properties of central nervous system

neurons, resulting in their increased excitability [31]. This is

analogous to the increased excitability of spinal neurons during

prolonged neuropathic or inflammatory pain.

Other consequences of central sensitization include

changes in autonomic nerve activity. Allergic inflammation

may enhance autonomic tone, which has been directly observed

in an allergen-sensitized guinea pig model [32].

Loss of inhibitory synaptic transmission (disinhibition) in

the spinal cord has also been attributed to both chronic pain

and chronic itch. This disinhibition of the central nervous

system and, therefore, hyperactivity of trigeminal nociceptive

pathways can produce a much more intense response to

irritants.

Taken together, the evidence supports a model in which

allergic inflammation leads to the release of proinflammatory

mediators that sensitize trigeminal sensory neurons (and their

processes), resulting in a decreased pain/itch threshold. This

may manifest as neuropathic pain and itch. Therefore, there

is a putative positive feedback loop between allergic cells and

neuronal inflammation in the development and maintenance

of the pathophysiology of AC. These, in turn, modulate

ocular responses to allergic and nonallergic stimuli, thus

translating the degree of inflammation into severity of neural

hyperreactivity.

Figure 2outlines neural involvement in allergic conjunctivitis.

Figure 2.

Schematic representation of neural sensitization in allergic conjunctivitis. AC indicates allergic conjunctivitis; TRPV, transient receptor potential

vanilloid; TRPA, transient receptor potential ankyrin; SP, substance P; CGRP, calcitonin gene-related peptide; NGF, nerve growth factor.

CGRP

NGF

• Central sensitization

• Enhanced autonomic tone

• Disinhibition

Increased afferent excitability

Peripheal

sensitization

Antidromic

stimulation

Allergic conjunctivitis

Trigeminal ganglion

CNS

TRPV1/TRPA1 stimulation

NI/neuropathic pain of AC

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