Trigeminal pathways for hypertonic saline- and light-evoked corneal reflexes
Introduction
Corneal reflexes are involuntary eyelid closures that can be evoked by mechanical or electrical stimulation of the ocular surface or by light flashes that serve mainly a protective function (Ongerboer de Visser, 1980, Mukuno et al., 1983, Cruccu et al., 1986). By contrast, eyeblink reflexes are critical for maintaining tear film integrity and can occur spontaneously, be evoked by diverse inputs of trigeminal or spinal origin as well as by conditioning stimuli (Evinger et al., 1991, Gruart et al., 1995, Delgado-Garcia et al., 2003, Dauvergne and Evinger, 2007, Kaminer et al., 2011). Although corneal reflexes and eyeblinks share several features and each results in excitation of orbicularis oculi (OO) motor units and lid closure, several lines of evidence suggest that the brain circuitry for corneal and blink reflexes are organized differently (Ongerboer de Visser, 1983, Berardelli et al., 1985, Cruccu et al., 1991).
Animal studies of brain pathways for cornea-evoked eyelid closure have relied mainly on results from electrical stimulation of the ocular surface (Henriquez and Evinger, 2005, Henriquez and Evinger, 2007). While this approach allows for detailed analysis of the timing and pattern of orbicularis oculi electromyographic (OOemg) activity, electrical stimuli necessarily by-pass normal sensory transduction mechanisms. Tear osmolarity is a key factor in predicting severity in dry eye disease (Sullivan et al., 2010, Alex et al., 2013), while abnormal light sensitivity is a common symptom in dry eye (Pflugfelder, 2011) and blepharospasm (Adams et al., 2006, Hallett et al., 2008), conditions well associated with abnormal control of eyeblinks. Trigeminal sensory nerves that supply the eye and periocular tissues project centrally to terminate in two spatially discrete regions, the trigeminal subnucleus interpolaris/caudalis transition (Vi/Vc) and the trigeminal subnucleus caudalis/upper cervical cord junction (Vc/C1) regions (Marfurt, 1981, Marfurt and Del Toro, 1987, Marfurt and Echtenkamp, 1988, Panneton et al., 2010). Previously we reported that ocular neurons at the Vi/Vc and Vc/C1 regions encoded the concentration of hypertonic saline (Tashiro et al., 2010) and light intensity (Okamoto et al., 2010, Okamoto et al., 2012), whereas others have used electrical stimulation of the ocular surface and supraorbital nerve to assess the role of the Vi/Vc and Vc/C1 regions on corneal and blink reflexes, respectively (Pellegrini et al., 1995, Henriquez and Evinger, 2005, Henriquez and Evinger, 2007). To better understand the organization of trigeminal pathways that mediate corneal reflexes evoked by physiological stimuli, OOemg activity was recorded in response to hypertonic saline or bright light before and after selective blockade of trigeminal sensory nerves or second-order trigeminal brainstem neurons at the Vi/Vc transition and Vc/C1 regions.
Section snippets
Experimental procedures
The animal protocol was approved by the Institutional Animal Care and Use committee of the University of Minnesota and conformed to the established guidelines set by The National Institute of Health guide for the care and use of laboratory animals (PHS Law 99-158, Revised 2002). All efforts were made to minimize the number of animals used for experiments and their suffering.
Stimulus intensity and OOemg activity
Normal and hypertonic saline applied to the ocular surface caused increases in OOemg activity (Fig. 1A). The magnitude of the AUC increased with greater NaCl concentrations (Fig. 1B, F2,10 = 24.9, p < 0.001), while the response latency was reduced significantly (Fig. 1C, F2,10 = 23.8, p < 0.001). Although the timing for NaCl-evoked OOemg activity was much delayed compared to that seen after electrical stimuli (Henriquez and Evinger, 2005), the pattern of the response to hypertonic saline (i.e., 2.5 and
Discussion
The main finding in this study was that OOemg activity evoked by ocular stimuli that cause pain and discomfort in humans required a relay through both the Vi/Vc transition and the Vc/C1 junction regions. This held true for two very different types of ocular stimuli, hypertonic saline and bright light. In the case of hypertonic saline, blockade of ocular surface nerve endings by topical application of lidocaine or by intra-ganglionic injection in the TG prevented the evoked OOemg response. By
Conclusions
Eyeblinks and corneal reflexes have been widely used as diagnostic tools to assess neurological conditions (Ongerboer de Visser, 1980, Agostino et al., 1987, Basso and Evinger, 1996, Cruccu et al., 1997, Kofler and Halder, 2014). The present study suggests that protocols using natural physiological stimuli can be adapted for use in anesthetized animals to provide new information on trigeminal pain circuitry.
Acknowledgments
The authors have no financial or other relationship to report that might lead to a conflict interest. This study was supported by ‘NIH’ – ‘United States’ grant EY 021447.
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