Reflex tear secretion is a fundamental protective mechanism of the ocular surface, triggered by a variety of stimuli that engage a complex neurocircuitry to elicit a rapid and graded lacrimal gland response. This process is distinct from basal and emotional tearing, relying on a well-defined reflex arc involving sensory afferents, central processing units within the brainstem, and efferent autonomic pathways that ultimately innervate the lacrimal gland (1, 2). The integrity of this circuit is paramount for maintaining ocular surface health, as it serves to dilute and remove irritants, foreign bodies, and pathogens, as well as to respond to environmental challenges such as cold air or bright light (1, 2).

The afferent limb of the reflex tear secretion pathway originates from sensory nerve endings densely populating the cornea and conjunctiva (1, p. 156, Fig 1; 2, Section: “Anatomy and physiology of the lacrimal system”). These sensory receptors are primarily free nerve endings of trigeminal origin, specifically supplied by the ophthalmic division (V1) of the trigeminal nerve (CN V) (1, p. 160). The receptor population is diverse, encompassing polymodal nociceptors, which respond to noxious chemical, mechanical, and thermal stimuli, and mechanoreceptors that detect touch and pressure (1, p. 160-161). Changes in tear film osmolarity and temperature can also activate these sensory afferents (1, p. 161). Upon stimulation, action potentials are generated and conveyed along these trigeminal fibers, whose cell bodies reside in the trigeminal ganglion. From the ganglion, central axons project to the trigeminal sensory nuclear complex in the brainstem, with the principal relay for nociceptive and irritant information occurring in the spinal trigeminal nucleus, particularly its pars caudalis and pars interpolaris (1, p. 161). [IMAGE: Diagram illustrating the sensory innervation of the cornea and conjunctiva by branches of the trigeminal nerve, and their projection to the trigeminal sensory nucleus.]

Central processing of these afferent signals is crucial for orchestrating the appropriate efferent response. Second-order neurons from the trigeminal sensory nucleus, particularly the spinal trigeminal nucleus, ascend to synapse within the superior salivatory nucleus (SSN), located in the pontine tegmentum (1, p. 161, Fig 4; 2, Section: “Anatomy and physiology of the lacrimal system”). The specific portion of the SSN responsible for lacrimal gland control is often referred to as the lacrimal nucleus (1, p. 161). This nucleus serves as the primary parasympathetic preganglionic center for reflex tearing. While the reflex arc is relatively direct, the lacrimal nucleus also integrates inputs from other central nervous system regions, including the hypothalamus and limbic structures, which are more prominently involved in emotional tearing, and pathways mediating responses to light (1, p. 156, p. 161; 2, Section: “Neuroanatomical correlates of emotional crying”). The output from the lacrimal nucleus is graded, allowing for tear secretion to be modulated from basal levels to copious reflex flow depending on the intensity and nature of the afferent stimulus (1, p. 156).

The efferent control of reflex tear secretion is predominantly mediated by the parasympathetic nervous system, with a modulatory role played by the sympathetic system (1, 2). Preganglionic parasympathetic fibers originate from neurons within the lacrimal nucleus (SSN) (1, p. 161, Fig 4; 2, Section: “Anatomy and physiology of the lacrimal system”). These axons travel within the nervus intermedius, a component of the facial nerve (CN VII), and subsequently course through the greater petrosal nerve. The greater petrosal nerve then joins with the deep petrosal nerve (carrying sympathetic fibers) to form the nerve of the pterygoid canal (vidian nerve), which traverses the pterygoid canal to reach the pterygopalatine fossa (1, p. 161-162, Fig 4). Within the pterygopalatine ganglion (PPG), these preganglionic parasympathetic fibers synapse with postganglionic neurons (1, p. 162; 2, Section: “Anatomy and physiology of the lacrimal system”). [IMAGE: Schematic of the parasympathetic efferent pathway from the superior salivatory nucleus to the lacrimal gland via the pterygopalatine ganglion.] Postganglionic parasympathetic fibers originating in the PPG are then conveyed to the lacrimal gland. The precise route involves fibers joining the zygomatic nerve (a branch of the maxillary division of the trigeminal nerve, V2), which then communicates with the lacrimal nerve (a branch of the ophthalmic division, V1) via an anastomotic branch; the lacrimal nerve ultimately delivers these secretomotor fibers to the acinar and ductal cells of the lacrimal gland (1, p. 162, Fig 4). The principal neurotransmitter released by these postganglionic parasympathetic terminals is acetylcholine (ACh), which acts upon muscarinic acetylcholine receptors (mAChRs), primarily of the M3 subtype, located on lacrimal gland cells (1, p. 162, p. 164). Activation of these M3 receptors is the main driver for the secretion of water, electrolytes, and proteins that constitute reflex tears. Vasoactive intestinal peptide (VIP) is an important co-transmitter released alongside ACh from these parasympathetic nerves. VIP, acting through its own receptors (VPAC1 and VPAC2), potentiates the secretory effects of ACh, particularly enhancing protein secretion, and also contributes to vasodilation within the gland (1, p. 162, p. 165).

Sympathetic innervation also reaches the lacrimal gland and can modulate its secretory activity, although its role in reflex tearing is generally considered secondary to the parasympathetic drive (1, p. 163; 2, Section: “Anatomy and physiology of the lacrimal system”). Preganglionic sympathetic neurons involved in this pathway are located in the intermediolateral cell column of the upper thoracic spinal cord segments (typically T1-T3) (1, p. 163, Fig 4). Their axons ascend in the sympathetic chain to synapse in the superior cervical ganglion (SCG) (1, p. 163). Postganglionic sympathetic fibers from the SCG form a plexus around the internal carotid artery and enter the skull. These fibers contribute to the deep petrosal nerve, which, as mentioned, joins the greater petrosal nerve. Sympathetic fibers pass through the PPG without synapsing and travel with branches of the maxillary and ophthalmic nerves, or along blood vessels, to reach the lacrimal gland (1, p. 163, Fig 4). [IMAGE: Overview of the sympathetic efferent pathway from the thoracic spinal cord to the lacrimal gland via the superior cervical ganglion.] The primary neurotransmitter released by sympathetic terminals is norepinephrine (NE), which acts predominantly on alpha1-adrenergic receptors (specifically alpha1A and alpha1D subtypes have been identified in lacrimal tissue) to stimulate protein secretion and, to a lesser extent, electrolyte and water secretion (1, p. 163, p. 167). Beta-adrenergic receptors are also present in the lacrimal gland, but their functional significance in tear secretion is less clearly defined (1, p. 167). Neuropeptide Y (NPY) is often co-released with NE from sympathetic nerves and can modulate both secretory responses and blood flow within the gland (1, p. 163). The interplay between parasympathetic and sympathetic inputs allows for fine-tuning of the lacrimal gland’s output in response to various physiological demands. Furthermore, hormonal influences, such as those exerted by androgens and estrogens, can modulate lacrimal gland structure, innervation, and function, thereby impacting tear secretion processes, including reflex tearing (1, p. 170-171).

In summary, reflex tear secretion is mediated by a sophisticated neurocircuitry that begins with sensory detection at the ocular surface by trigeminal afferents. These signals are relayed through the trigeminal sensory nucleus to the superior salivatory (lacrimal) nucleus in the pons. From here, predominantly parasympathetic efferent pathways, with ACh and VIP as key neurotransmitters, project via the pterygopalatine ganglion to stimulate the lacrimal gland. Sympathetic pathways, utilizing NE and NPY, provide additional modulatory input. This intricate system ensures a rapid and appropriate secretory response to protect and maintain the health of the eye.