Sensory Nerves, Neurogenic Inflammation and Pain: Missing Components of Alternative Irritation Strategies? A Review and a Potential Strategy

Abstract

The eyes and skin are highly innervated by sensory nerves; stimulation of these nerves by irritants may give rise to neurogenic inflammation, leading to sensory irritation and pain. Few in vitro models of neurogenic inflammation have been described in conjunction with alternative skin and eye irritation methods, despite the fact that the sensory innervation of these organs is well-documented. To date, alternative approaches to the Draize skin and eye irritation tests have proved largely successful at classifying severe irritants, but are generally poor at discriminating between agents with mild to moderate irritant potential. We propose that the development of in vitro models for the prediction of sensory stimulation will assist in the re-classification of the irritant potential of agents that are under-predicted by current in vitro strategies. This review describes the range of xenobiotics known to cause inflammation and pain through the stimulation of sensory nerves, as well as the endogenous mediators and receptor types that are involved. In particular, it focuses on the vanilloid receptor, its activators and its regulation, as these receptors function as integrators of responses to numerous noxious stimuli. Cell culture models and ex vivo preparations that have the potential to serve as predictors of sensory irritation are also described. In addition, as readily available sensory neuron cell line models are few in number, stem cell lines (with the capacity to differentiate into sensory neurons) are explored. Finally, a preliminary strategy to enable assessment of whether incorporation of a sensory component will enhance the predictive power of current in vitro eye and skin testing strategies is proposed.

A Scientific and Animal Welfare Assessment of the OECD Health Effects Test Guidelines for the Safety Testing of Chemicals under the European Union REACH System

“…However, the successful validation of tests for corrosivity (58) has resulted in the acceptance by the OECD of a revised guideline, TG 405 (acute eye irritation/corrosion), which incorporates a tiered-testing strategy for eye irritation and corrosion. It is very likely that a battery of complementary tests will be required for modelling eye irritation, since it is caused by several different mechanisms, and these tests might need to include cell cultures incorporating neural cells (59). It is fortunate that tests have at least been developed and accepted for corrosivity, so that corrosive materials can be eliminated prior to animal testing (TG 430; Figure 1).…”

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“…A similar model involving human corneal epithelium cell cultures, developed by Sladowski et al (27), involves the measurement of cell viability and measures IL-1β release. Since the corneal epithelium in vivo is a highly innervated tissue, the development of models that include a neuronal component for detecting irritation is considered to be an important consideration for their overall improvement (28). In this regard, it is of interest that the innervation of a corneal model is being achieved by the incorporation of ND7/23 sensory neurons into an immortalised, multilayered human model of the cornea (29).…”

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