Chronic pain is a major public health problem and offers a most difficult challenge to therapy. Although chronic pain has been increasingly recognized as a disease of the nervous system, the underlying mechanisms remain largely unclear. Recently studies suggest that enhanced descending facilitation or reduced descending inhibition from the rostral ventromedial medulla (RVM), a pivotal structure of descending modulation of trigeminal and spinal nociceptive transmission, contribute to supraspinal mechanisms of chronic pain. New evidence shows that 5-HT-dependent descending facilitation from the RVM is responsible for the transition of acute pain to chronicity after nerve injury. However, the synaptic and cellular signaling mechanisms accounting for 5-HT-dependent descending facilitation are poorly understood. Transient receptor potential vanilloid type 1 (TRPV1) channels are ligand-gated nonselective cation channels with high Ca++ permeability and are prominently expressed in primary nociceptive sensory neurons as molecular sensors for noxious heat and inflammatory mediators. More recently, TRPV1 channels are also found to express in the brain, cross-talk with other synaptic proteins and act as an integrator for downstream signaling to mediate long-lasting synaptic plasticity. Although TRPV1 channels are distributed in the RVM, their potential physiological and pathological significance in descending pain modulation remains unknown. We have explored glia-cytokine-neuronal interaction in the RVM underlying descending pain facilitation and the maintenance of hyperalgesia after nerve injury. Thus, we will further study the functional signature of TRPV1 channels in the RVM, expanding our study of distinct signaling mechanisms involved in hyperexcitability of 5-HT-containing RVM neurons and behavioral hypersensitivity. Our hypothesis is that calcium-permeable TRPV1 channels are functionally expressed in RVM 5-HT-containing neurons and modulate excitatory synaptic transmission and neuronal activity in the RVM. We further hypothesize that the long-lasting upregulation and sensitization of RVM TRPV1 is induced after nerve injury and facilitate intracellular signal transduction between glial hyperactivity and neuronal hyperexcitability. Through integrating downstream signaling relevant to cytokine receptor activation and subsequent increase of NMDA receptor activity, TRPV1 sensitization in 5-HT-containing neurons maintains neural hyperexcitability and contributes to 5-HT-dependent descending pain facilitation underlying the maintenance of neuropathic pain. The following Specific Aims will test these hypotheses using multidisciplinary approaches. #1: To test the hypothesis that central TRPV1 channels are present in the RVM and functionally expressed in 5-HT-containing RVM neurons projecting to the dorsal horn. #2: To test the hypothesis that long-term upregulation and sensitization of TRPV1 in the RVM occur after nerve injury and mediate descending facilitation underlying the development of neuropathic pain. #3: To test the hypothesis that proinflammatory cytokines released upon glial hyperactivity in the RVM sensitize local TRPV1 function after nerve injury, which is dependent on long-lasting upregulation of intracellular atypical protein kinase C/Mzeta signaling. #4: To test the hypothesis that TRPV1 activation is involved in descending pain modulation through potentiation of glutamatergic synaptic transmission in RVM neurons and hyperexcitability of 5-HT-containing neurons. The findings from this proposal will expand our appreciation of a novel role of central TRPV1 channels in supraspinal mechanisms of 5-HT-dependent descending facilitation and provide new therapeutic targets for the treatment of neuropathic pain.

Public Health Relevance

Transient receptor potential channels (TRPV1 receptors) are early found to be primarily expressed in primary nociceptive sensory neurons and respond to a diverse range of stimuli including thermal stimuli and chemical irritant such capsaicin, a pungent ingredient of red hot chili peppers, causing peripheral inflammation and hyperalgesia. Although increasing evidence indicate their widespread distribution in the brain, the functional significanc of TRPV1 receptor expression in the CNS remains elusive. The proposed study aims at investigating the functional expression of supraspinal TRPV1 receptors and its role in descending pain modulatory circuitry in the development of persistent orofacial pain after trigeminal nerve injury. The finding will provide novel central mechanisms underlying persistent pain and useful drug targets for chronic pain.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Mohapatra, Durga Prasanna
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Maryland Baltimore
Other Basic Sciences
Schools of Dentistry/Oral Hygn
United States
Zip Code
Guo, Wei; Imai, Satoshi; Yang, Jia-Le et al. (2018) NF-KappaB Pathway Is Involved in Bone Marrow Stromal Cell-Produced Pain Relief. Front Integr Neurosci 12:49
Wang, Sheng; Lim, Jongseuk; Joseph, John et al. (2017) Spontaneous and Bite-Evoked Muscle Pain Are Mediated by a Common Nociceptive Pathway With Differential Contribution by TRPV1. J Pain 18:1333-1345
Wang, Sheng; Wang, Sen; Asgar, Jamila et al. (2017) Ca2+ and calpain mediate capsaicin-induced ablation of axonal terminals expressing transient receptor potential vanilloid 1. J Biol Chem 292:8291-8303
Guo, Wei; Imai, Satoshi; Yang, Jia-Le et al. (2017) In vivo immune interactions of multipotent stromal cells underlie their long-lasting pain-relieving effect. Sci Rep 7:10107