The Parasympathetic Nervous System and DED
The connection between the two suggests dry eye is more than just a disease of the eye.
Hardeep K. Kataria, OD, FAAO, and Mila Ioussifova, OD, FAAO, CNS
Modern Optometry 
The parasympathetic nervous system (PNS), involved in the “rest and digest” response, and the sympathetic nervous system, involved in the “fight or flight” response, are the two main divisions of the autonomic nervous system. The PNS operates in the craniosacral and sacral segments of the central nervous system, and involves the oculomotor (III), facial (VII), glossopharyngeal (IX), and vagus (X) nerves. The primary neurotransmitters used by these nerves, acetylcholine (ACh) and vasoactive intestinal peptide (VIP), work together to promote the “rest and digest” functions of the body (eg, constricting pupils, slowing heart rate, and maintaining gut motility for digestion).1 The motor branch of the seventh nerve serves as part of the postganglionic parasympathetic pathway that innervates the lacrimal functional unit for tear production, distribution, and clearance. The lacrimal gland has mainly muscarinic ACh receptors, and the primary neurotransmitter responsible is ACh. Therefore, if we want to stimulate tear production in conditions such as aqueous-deficient dry eye disease (DED), we should focus on targeting the lacrimal gland tissue, nerve, receptor, and/or neurotransmitter.2 HOW ARE THE PNS AND DED CONNECTED? Because the PNS is mainly responsible for tear production in the lacrimal gland, when the superficial petrosal nerve is denervated, tear production is reduced by 70%. Conversely, when we stimulate the PNS, we can increase tear production.2 Additionally, the PNS plays a role in immune modulation, with the cholinergic antiinflammatory pathway linking the autonomic nervous system and the immune system, primarily through the parasympathetic nerves, especially the vagus nerve, along with ACh and its receptors. This pathway can activate and regulate immune cell functions, contributing to its antiinflammatory role and affecting the development of various autoimmune diseases.3 Anticholinergic medications, such as antihistamines and antidepressants, also downregulate the binding of ACh to its muscarinic receptor in the lacrimal gland, leading to overall reduced tear production.2 In conditions such as Sjögren syndrome, inflammation further reduces ACh release and tear production. Furthermore, the presence of muscarinic receptor antibodies that block ACh binding to the receptors may also lead to decreased tear production.4 It has been suggested that serum autoantibodies against muscarinic ACh may even serve as an early marker for Sjögren syndrome.5 Because serum ACh cannot be measured successfully, clinicians must use signs and symptoms to help guide treatment for these patients. It is worth mentioning that studies have confirmed the presence of VIP receptors in human meibomian gland acini that may be indicated in cell proliferation, and that exogenous application of VIP can stimulate goblet cell secretion; however, further data are needed to confirm the exact role of VIP in DED.6 Overall, the role of the PNS in aqueous-deficient dry eye is well established (its role in evaporative dry eye and the meibomian glands is less so).
