Role of glutamate in corneal nociception

Abstract

Scope and Method of Study: At sensory peripheral nerve terminals, glutamate is released into tissues, e.g., skin, where it sensitizes surrounding afferent nerves and resident cells. Sensitization of peripheral sensory afferents causes hyperalgesia and allodyna. Although neurotransmitters like glutamate are released into the cornea in response to triggering stimuli, neither the mechanism of release nor the presence of glutamate receptors in the cornea has been studied in detail. In this study the following projects were performed: (1) immunohistochemistry, Western blot, and retrograde tracing were used to demonstrate synaptophysin I and vesicular glutamate transporter 2 (VGLUT2) in rat cornea sensory nerve fibers and trigeminal neuronal cell bodies; (2) immuno-histochemistry and retrograde tracing were used to localize ionotropic glutamate receptor subunits in rat cornea sensory nerve fibers and trigeminal neuronal cell bodies; (3) nocifensive behavioral analysis was used to determine the role of glutamate receptors in the rat cornea.

Findings and Conclusions: VGLUT2, synaptophysin I, and ionotropic glutamate receptor subunits for NMDA (N-methyl-D-aspartate), AMPA (2-amino-3-(5-methyl-3-oxo-1, 2- oxazol-4-yl) propanoic acid) and kainate are present in intact rat cornea. Glutamate, AMPA, and kainate interact with corneal glutamate receptors to cause nociception/irritation. NMDA did not induce corneal irritation possibly due to magnesium block of the receptor. Ionotropic glutamate receptor antagonists: AP5, (D-(-)-2-amino-5-phosphonopentanoic acid), NBQX (2, 3-aioxo-6-nitro-1, 2, 3, 4-tetrahydrobenzo-[f]quinoxaline-7-sulfonamide disodium salt), and CNQX, (6-cyano-7-nitroquinoxaline-2, 3-dione disodium) blocked glutamate-, AMPA-, and kainate-induced corneal irritation, respectively, in a dose dependent fashion. This study suggests that: 1) there is a potential for vesicular glutamate release from corneal afferent nerves, 2) ionotropic glutamate receptors are expressed in corneal afferent nerves and epithelial cells, 3) glutamate interacts with its receptors in the cornea to cause nociception. This suggests that blockade of these receptors may help in controlling inflammatory or maladaptive pain from the cornea.