Our long-term goal is to understand the mechanisms that control the excitability of pain-receptor neurons in the cornea. The cornea is innervated by nerve fibers expressing cold receptors (TRPA1 and TRPM8 ion channels), mechanoreceptors (molecular identity unknown), and polymodal receptors that respond to noxious chemical and thermal stimuli (TRPV1 ion channels). Sensory transduction of noxious stimuli protects the cornea from further damage by inducing protective blink reflexes and lacrimal secretions, whereas inflammatory hyperalgesia has a role in protecting injured tissue from repeated unintentional damage. Additionally, corneal nerves and their associated neurotrophins are important for corneal health and wound healing;dysfunction of the corneal nerves or damage during surgery may produce neurotrophic keratitis, characterized by corneal anesthesia and increased risk for corneal ulcers and perforation. TRPV1 is expressed in small-diameter corneal nerve fibers of the ophthalmic branch of the trigeminal ganglia. In response to tissue injury, TRPV1 undergoes sensitization in the presence of pro-inflammatory agents such as Nerve Growth Factor (NGF) and other neurotrophins. NGF induces neuritogenic and trophic signals when bound to the extracellular domain of its receptor, tropomyosin-receptor-kinase subtype A (TrkA). This catalytic receptor activates three enzymatic pathways inside the sensory nerve fiber: the phospholipase C (PLC) pathway, the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase (PI3K) pathway. The hyperalgesia induced by NGF and other trophic factors is due to an increase in the number of TRPV1 ion channels in the plasma membrane of sensory neurons. We and others have shown that the mechanism involves the PI3K signaling pathway downstream of TrkA. Furthermore, a direct interaction between a regulatory subunit of PI3K and TRPV1 channels appears to control the localization of the increase in pain receptors within sensory neurons. It is important to understand the sensitization of TRPV1 that occurs in response to NGF: interrupting this hyperalgesic sensory pathway would be of great utility in the clinical setting. In addition, understanding the converse pathway - desensitization of TRPV1 ion channels - may lead to new approaches for treating the pain of injury and disease and may open up therapeutic options that would otherwise be limited due to pain-inducing side effects. In this proposal we will study both hyperalgesia and desensitization. Combining new optical methods with electrophysiology, we will elucidate the role of the membrane lipid PIP2 in desensitization. We will also determine whether the product of PI3K activity, the membrane lipid PIP3, is sufficient for cellular hyperalgesia. By the end of the funding period, we will have gained a detailed understanding of how phosphoinositides (PIP2 and PIP3) tune the excitability of TRPV1-expressing pain receptor neurons.
In the cornea and periphery, pain-receptor neurons become hypersensitive to pain when tissue is injured or inflamed. We will determine how hypersensitivity to pain develops in pain-receptor neurons. Our goal is to identify targets for improved pain therapies.
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