Mechanisms of Peripheral and Central Pain Sensitization: Focus on Ocular Pain

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.

Keywords: cornea; descending modulation; ocular pain; peripheral and central sensitization; synaptic transmission; trigeminal ganglion.

FIGURE 1

Schematic representation of sensory pathways involved in corneal pain transmission. (A) Sensory pathways conveying corneal nociceptive input to the central nervous system. Corneal sensory input is transmitted by corneal nociceptors, whose cell bodies are located in the trigeminal ganglion (TG). Central terminals of nociceptors project to the spinal trigeminal nucleus (Sp5) in the brain stem. Projection neurons in these regions send ascending pathways to several areas, including the parabrachial nucleus (PBN) and the thalamus, that in turn project to higher centers. (B) Principal ion channels involved in corneal sensory transduction on the nociceptor peripheral terminals. During peripheral sensitization, TRPV1 and TRPA1 are usually upregulated, while TRPM8 function is enhanced in neuropathic pain and decreased during inflammation.

FIGURE 2

Modulation and sensitization of sensory input in the spinal trigeminal nucleus (Sp5). (A) Corneal sensory input is processed in Sp5, mainly at the transition between the subnuclei interpolaris and caudalis (Vi/Vc) and at the junction between the subnucleus caudalis and the upper cervical spinal cord (Vc/C1). Sp5 activity is controlled by descending modulation, comprising serotoninergic pathways. Serotoninergic neurons are located in rostral ventral medulla (RVM) and are activated by projection neurons in periaqueductal grey area (PAG). (B) Hypothetical mechanisms sustaining central ocular pain sensitization in Sp5. Persistent corneal nociceptive input may induce a general increase of synaptic excitation (mostly mediated by glutamate and peptides) and a decrease of synaptic inhibition (mediated by GABA and glycine). As reported for several forms of spinal and trigeminal pain, glutamate receptors could be potentiated by increased phosphorylation and participate to plasticity phenomena, such as wind-up and LTP. Synaptic inhibition could be depressed through changes of chloride equilibrium potential, LTD, neuronal loss, decrease of transmitter release, and presynaptic facilitation. Furthermore, a switch in the function of serotoninergic modulation from anti-to pro-nociceptive could contribute to the hyperexcitability state. Further studies are needed to confirm these mechanisms in the ocular pain system.