Abstract
Persistent ocular pain caused by corneal inflammation and/or nerve injury is accompanied by significant alterations along the pain axis. Both primary sensory neurons in the trigeminal nerves and secondary neurons in the spinal trigeminal nucleus are subjected to profound morphological and functional changes, leading to peripheral and central pain sensitization. Several studies using animal models of inflammatory and neuropathic ocular pain have provided insight about the mechanisms involved in these maladaptive changes. Recently, the advent of new techniques such as optogenetics or genetic neuronal labelling has allowed the investigation of identified circuits involved in nociception, both at the spinal and trigeminal level. In this review, we will describe some of the mechanisms that contribute to the perception of ocular pain at the periphery and at the spinal trigeminal nucleus. Recent advances in the discovery of molecular and cellular mechanisms contributing to peripheral and central pain sensitization of the trigeminal pathways will be also presented.
Highlights
Ocular pain is produced by stimulation of primary sensory neurons at the eye surface or by alterations along the ocular pain pathway
Corneal sensory fibers are mainly associated with pain: psychophysical studies in humans have demonstrated that corneal mechanical, chemical or thermal stimulation produces aversive or nociceptive sensations (Kenshalo et al, 1960; Beuerman and Tanelian, 1979; Belmonte et al, 1999), except for the purely cold sensations provoked by low-temperature stimuli of moderate intensity (Acosta et al, 2001)
Mechanonociceptors (MNs) represent about 10% of corneal fibers and are activated exclusively by noxious mechanical forces generated by external objects, presence of foreign bodies, air pressure or distortion of epithelium layer caused by drying ocular surface
Summary
Ocular pain is produced by stimulation of primary sensory neurons at the eye surface or by alterations along the ocular pain pathway. Corneal transduction of mechanical stimuli is mainly performed by PIEZO2 channels, large membrane proteins with a homotrimeric propeller-shaped structure, comprising a central ion-conducting pore module and three peripheral mechanosensing blades with 38 transmembrane domains. Mechanical activation of this channel generates a cationic current, that depolarizes excitable cells (Coste et al, 2010; Coste et al, 2012). The repetitive reinjury of PIEZO2 channels could cause chronic pain even in the absence of secondary harsher tissue injury (Sonkodi et al, 2021a; Sonkodi et al, 2021b) Both TRPV1 and TRPA1 channels, belonging to the transient receptor potential (TRP) family of ion channels, are involved in corneal pain transduction. Peripheral sensitization is defined as the increased responsiveness and reduced threshold of nociceptive neurons in the periphery of the sensory system, induced by local inflammation or by peripheral nerve injury
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