Chronic inflammatory and neuropathic pain is a problem of considerable clinical relevance. Understanding the mechanisms underlying development and maintenance of chronic pain would be a major step towards rational treatment of such pain conditions. Considerable evidence links chronic pain of neuropathic origin with increased excitability and abnormal signal generation in primary afferent neurons within sensory ganglia. Chemically-mediated cross-excitation between neurons in sensory ganglia has been proposed as one major mechanism by which abnormal discharges can be generated in pathological pain states. However, the identity of the chemical mediator of cross-excitation is unknown. Adenosine triphosphate (ATP) is released within sensory ganglia following neuronal activation and was shown to activate receptors on somata of sensory neurons. The overall goal of this proposal is to directly test the hypothesis that ATP is the chemical mediator of cross-excitation and to determine how release of ATP changes in pathological pain states.
The specific aims are to: 1) determine the involvement of released ATP in cross-excitation of neurons within sensory ganglia, 2) determine the changes in basal and stimulus-evoked ATP release after peripheral inflammation, 3) determine the changes in basal and evoked ATP release after induction of sciatic neuropathy, 4) compare ATP release from different types of isolated and labeled DRG neurons. Cross-depolarization evoked by peripheral nerve stimulation will be measured during intracellular recordings from neurons in dorsal root ganglia (DRG). ATP receptors on sensory neurons will be manipulated by application of selective agonists and antagonists to influence evoked cross-depolarization. ATP release will be measured by the luciferin-luciferase assay in DRG perfusates. ATP release from acutely isolated DRG neurons will be measured using detector patches. These studies will be carried out first under normal conditions and then compared to results obtained after induction of a) peripheral inflammation, and b) peripheral neuropathy in rats. The acquired knowledge may lead to the development of novel therapeutics targeting abnormal excitability changes in sensory neurons.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Clinical Investigator Award (CIA) (K08)
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NIDCR Special Grants Review Committee (DSR)
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Hardwick, Kevin S
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University of California Los Angeles
Schools of Dentistry
Los Angeles
United States
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Thakor, Devang Kashyap; Lin, Audrey; Matsuka, Yoshizo et al. (2009) Increased peripheral nerve excitability and local NaV1.8 mRNA up-regulation in painful neuropathy. Mol Pain 5:14
Matsuka, Yoshizo; Ono, Takeshi; Iwase, Hirotate et al. (2008) Altered ATP release and metabolism in dorsal root ganglia of neuropathic rats. Mol Pain 4:66
Mitrirattanakul, Somsak; Lopez-Valdes, Hector E; Liang, Jing et al. (2007) Bidirectional alterations of hippocampal cannabinoid 1 receptors and their endogenous ligands in a rat model of alcohol withdrawal and dependence. Alcohol Clin Exp Res 31:855-67
Matsuka, Y; Edmonds, B; Mitrirattanakul, S et al. (2007) Two types of neurotransmitter release patterns in isolectin B4-positive and negative trigeminal ganglion neurons. Neuroscience 144:665-74
Mitrirattanakul, Somsak; Ramakul, Navapoln; Guerrero, Andre V et al. (2006) Site-specific increases in peripheral cannabinoid receptors and their endogenous ligands in a model of neuropathic pain. Pain 126:102-14
Matsuka, Yoshizo; Spigelman, Igor (2004) Hyperosmolar solutions selectively block action potentials in rat myelinated sensory fibers: implications for diabetic neuropathy. J Neurophysiol 91:48-56