title: 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.
authors.affiliation: Division of Gastroenterology, School of Medical and Surgical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Garle
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Fry
mesh_terms: D023401:Animal Use Alternatives / Q000379:methods*; D000818:Animals; D002460:Cell Line; D007509:Irritants / Q000633:toxicity*; D008954:Models, Biological; D020078:Neurogenic Inflammation / Q000139:chemically induced / Q000503:physiopathology; D009475:Neurons, Afferent / Q000187:drug effects; D010146:Pain / Q000139:chemically induced; D011955:Receptors, Drug / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D023422:Skin Irritancy Tests / Q000379:methods*; D013045:Species Specificity; D013234:Stem Cells; D013268:Stimulation, Chemical; D015262:Xenobiotics / Q000633:toxicity*
chemical_list: D007509:Irritants; D011955:Receptors, Drug; D015262:Xenobiotics