Understanding of anatomical and physiological relationships within the neural networks driving craniofacial pain is a key step in developing effective therapeutic treatments. Many studies evaluating such networks focus on peripheral mechanisms of trigeminal nociception and on homologies between trigeminal and spinal nociceptive processing. The extended goal of this work is to investigate the cellular mechanisms underlying synaptic transmission between the central terminals of the trigeminal nerve (trigeminal afferents) and neurons located in the spinal trigeminal nucleus caudalis (Vc), a brainstem region implicated in nociceptive processing for the face. We hypothesize that synaptic connectivity of individual trigeminal afferents and neurons in the Vc is mediated by glutamate acting at non-NMDA and NMDA receptors and may be modulated by select ion channels, specifically the Transient Receptor Potential Vanilloid type 1 (TRPV1). We also believe that these functional connections may have distinct anatomical features. Both NMDA and non-NMDA receptors are observed in Vc, although their roles in mediating excitatory synaptic transmission in this region are ill-defined. TRPV1 is expressed on both peripheral and central termini of trigeminal neurons and upregulation of TRPV1 is closely associated with abnormal pain. Peripherally, TRPV1 has been characterized extensively as a molecular transducer of nociceptive information;however, the roles of centrally trafficked TRPV1 channels in pain processing remain unclear.
Aim 1 will determine the functional connectivity of trigeminal afferents and Vc neurons with in vitro electrophysiological techniques assessing: synaptic latency variability as a measure of synaptic order, glutamate-mediated responses at NMDA and non-NMDA channels, and if TRPV1 modulates glutamatergic responses in Vc using brainstem synaptic transmission (e.g. NTS) as a model. Preliminary data demonstrate that individual trigeminal afferents can be identified using measures of synaptic latency variability, and chemical activation of central TRPV1 induces measurable responses.
Aim 2, will determine the morphological features of Vc neurons related to synaptic latency variability and evaluate the anatomical connectivity between trigeminal afferents and Vc neurons with respect to TRPV1. The results will be integrated with findings from Aim 1 to provide a more specific understanding of the relationship between trigeminal afferent and Vc neuron subpopulations and the cellular mechanisms underlying synaptic transmission. These results will provide important, complementary anatomical and functional information about the neural networks that relay sensory information from the face to the brain, including the role of TRPV1 in the trigeminal pain pathway, and identify potential mechanisms for both neural plasticity and modulation of craniofacial pains.

Public Health Relevance

According to the National Institute of Dental and Craniofacial Research's Panel on Pain Research 2003, 22% of the American population reports having orofacial pain, the most common type of craniofacial pain. Facial tissues are innervated by neurons which comprise the trigeminal nerve. These neurons branch both peripherally to the face and centrally to the brain creating a relay network for processing of nociceptive sensory information. The current proposal seeks to understand the cellular mechanisms driving neural integration of pain sensations transmitted from the face to the brain with the potential to identify therapeutic targets for modulation of craniofacial pain.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Postdoctoral Individual National Research Service Award (F32)
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NIDCR Special Grants Review Committee (DSR)
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Frieden, Leslie A
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Oregon Health and Science University
Schools of Medicine
United States
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Fawley, Jessica A; Hofmann, Mackenzie E; Largent-Milnes, Tally M et al. (2015) Temperature differentially facilitates spontaneous but not evoked glutamate release from cranial visceral primary afferents. PLoS One 10:e0127764
Hofmann, Mackenzie E; Largent-Milnes, Tally M; Fawley, Jessica A et al. (2014) External QX-314 inhibits evoked cranial primary afferent synaptic transmission independent of TRPV1. J Neurophysiol 112:2697-706
Hegarty, Deborah M; Hermes, Sam M; Largent-Milnes, Tally M et al. (2014) Capsaicin-responsive corneal afferents do not contain TRPV1 at their central terminals in trigeminal nucleus caudalis in rats. J Chem Neuroanat 61-62:1-12
Largent-Milnes, Tally M; Hegarty, Deborah M; Aicher, Sue A et al. (2014) Physiological temperatures drive glutamate release onto trigeminal superficial dorsal horn neurons. J Neurophysiol 111:2222-31