Elsevier

Neuroscience

Volume 277, 26 September 2014, Pages 716-723
Neuroscience

Trigeminal pathways for hypertonic saline- and light-evoked corneal reflexes

https://doi.org/10.1016/j.neuroscience.2014.07.052Get rights and content

Highlights

  • Corneal reflex evoked by natural physiological stimuli (hypertonic saline and bright light).

  • Hypertonic saline and bright light selectively activate ocular surface and intraocular trigeminal nerves, respectively.

  • Corneal reflex evoked by physiological stimuli depends on the relay in both Vi/Vc transition and Vc/C1 junction regions.

Abstract

Cornea-evoked eyeblinks maintain tear film integrity on the ocular surface in response to dryness and protect the eye from real or potential damage. Eyelid movement following electrical stimulation has been well studied in humans and animals; however, the central neural pathways that mediate protective eyeblinks following natural nociceptive signals are less certain. The aim of this study was to assess the role of the trigeminal subnucleus interpolaris/caudalis (Vi/Vc) transition and subnucleus caudalis/upper cervical cord (Vc/C1) junction regions on orbicularis oculi electromyographic (OOemg) activity evoked by ocular surface application of hypertonic saline or exposure to bright light in urethane anesthetized male rats. The Vi/Vc and Vc/C1 regions are the main sites of termination for trigeminal afferent nerves that supply the ocular surface, while hypertonic saline (saline = 0.15–5 M) and bright light (light = 5k–20k lux) selectively activate ocular surface and intraocular trigeminal nerves, respectively, and excite second-order neurons at the Vi/Vc and Vc/C1 regions. Integrated OOemg activity, ipsilateral to the applied stimulus, increased with greater stimulus intensities for both modalities. Lidocaine applied to the ocular surface inhibited OOemg responses to hypertonic saline, but did not alter the response to light. Lidocaine injected into the trigeminal ganglion blocked completely the OOemg responses to hypertonic saline and light indicating a trigeminal afferent origin. Synaptic blockade by cobalt chloride of the Vi/Vc or Vc/C1 region greatly reduced OOemg responses to hypertonic saline and bright light. These data indicate that OOemg activity evoked by natural stimuli known to cause irritation or discomfort in humans depends on a relay in both the Vi/Vc transition and Vc/C1 junction regions.

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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