Chronic orofacial pain syndromes affect approximately one fourth of the population and are believed to be frequently related to trigeminal nerve damage as a result of trauma or dental surgery. Trigeminal neuropathic pain is usually characterized by primary hyperalgesia at the site of injury and widespread or secondary hyperalgesia outside the injured zone, and presents a difficult therapeutic challenge. It is recognized that the development of primary hyperalgesia involves both sensitization of primary afferent nociceptors and neuronal hyperactivity referred to as central sensitization at the levels of the spinal dorsal horn and supra-spinal structures after nerve injury. Secondary hyperalgesia is also attributed to central sensitization. Recently, primary and secondary hyperalgesia demonstrated in a rat trigeminal neuropathic model involving the chronic constriction injury of the infraorbital nerve have been developed to investigate the mechanisms of transition of acute to chronic neuropathic pain. The findings indicate that descending 5-HT and dorsal horn 5-HT3A receptors (5- HT3AR) are involved in central mechanisms underlying the maintenance of secondary hyperalgesia. Transient Receptor Potential Vanilloid Type 1 (TRPV1) is a non-selective cation channel and is primarily expressed in peripheral and central terminals of primary nociceptive neurons. Peripheral terminal TRPV1 detects a variety of noxious, physical and chemical stimuli as peripheral sensory integrators and accounts for peripheral sensitization and inflammatory pain amplification. However, the physiological relevance and function of central terminal TRPV1 in pain transmission and modulation are poorly understood. As the only excitatory ligand-gated ion channel of the 5-HT receptor family, 5-HT3Rs are expressed in central terminals of primary nociceptors. It is unclear whether active descending facilitation drives central terminal TRPV1 sensitization via activation of presynaptic 5-HT3ARs and contributes to the maintenance of the neuropathic pain state. In this proposal, by combining molecular, genetic, newly developed terminal calcium imaging, electrophysiological recording and behavioral pharmacological approaches, we will focus on studying CNS modulation of primary afferent central terminal sensitization and hyperexcitability underlying the maintenance of pain amplification after trigeminal nerve injury. We hypothesize that nerve injury in the orofacial region can lead to the maintenance of secondary hyperalgesia that involves sensitization of central terminal TRPV1 of primary afferent nociceptors and its modulation by activation of descending 5-HT and presynaptic 5-HT3R mechanisms. The three aims will test these hypotheses: 1) To determine whether dynamic change of TRPV1 expression exists in the Vc after nerve injury and its involvement in the maintenance of secondary hyperalgesia. 2) To determine whether central terminal TRPV1 sensitizes after nerve injury and is involved in enhanced synaptic excitatory input during the maintenance of secondary hyperalgesia. 3) To determine the involvement of descending 5-HT and Vc 5- HT3ARs in central terminal TRPV1 sensitization and presynaptic hyperexcitability underlying persistent secondary hyperalgesia. A thorough understanding of the mechanisms of primary afferent central terminal sensitization and its CNS modulation after nerve injury will be important for the development of new strategies to prevent chronicity of neuropathic pain.

Public Health Relevance

The major goal of the proposed research is to study the central terminal TRPV1 sensitization of primary nociceptive afferents and its modulation of descending facilitation that accounts for the maintenance of neuropathic pain states including widespread hyperalgesia and allodynia after trigeminal nerve injury. Although it is now commonly recognized that the development of inflammatory pain and resultant pain amplification is dependent upon peripheral TRPV1 sensitization of primary sensory nociceptors, it is unclear whether peripheral afferent central terminal TRPV1 sensitization is involved in the maintenance of neuropathic pain state and whether 5-HT-dependent descending facilitation drives central terminal sensitization and enhanced excitatory synaptic transmission by the involvement of presynaptic 5-HT3 receptors on central terminals of primary afferents. Our finding will lead to a transformative shift in the search for new treatment strategies and innovative approaches for chronic pain.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
High Priority, Short Term Project Award (R56)
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Somatosensory and Chemosensory Systems Study Section (SCS)
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Kusiak, John W
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University of Maryland Baltimore
Other Basic Sciences
Schools of Dentistry
United States
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