With the discovery that the amino acid glutamate functions as a specific excitatory neurotransmitter within the central nervous system (CNS), much attention has been given to the characterization of the central systems which it may modulate. Several lines of experimental evidence support the hypothesis that glutamate is involved in the development of pain and hyperalgesia at the level of the spinal cord. While the mechanisms of pain and hyperalgesia mediated by glutamate within the CNS have been well characterized, relatively little is known about glutamate's possible activation of the peripheral terminals of nociceptors, nerves responsible for facilitating pain within peripheral tissue. Our specific aims have used a multimethodologic approach to explore the hypothesis that the excitatory amino acid glutamate participates in the activation of a select populations of nociceptors. The results of our in vitro superfusion experiments have demonstrated that glutamate is capable of activating nerve fibers within dental pulp in a concentration-and receptor-dependent manner, as measured by evoked release of peptide markers of neuronal activation (Jackson et al., Abs. Soc. Neurosci. 19:996,1993). Additionally, data from dental pulp suggests that glutamate is released from pulp tissue when it is stimulated with noxious agents. The results of animal behavior experiments have also supported the hypothesis that glutamate has a peripheral site of action in the activation of peripheral nociceptors (Jackson et al. Ear. J. Pharmacal. 284:321-325,1995; Jackson et al., Aba. Sac. Neurosci. 20:1390, 1994). The injection of glutamate into the hindpaws of rats produces a dose- and receptor-dependent decrease in the time to withdrawal the paw from a noxious heat stimulus. Additionally, the local administration of specific antagonists to glutamate receptor subtypes into the inflamed hindpaws of rats results in an increase in the paw withdrawal latency relative to vehicle treated animals (Graff et al., J. Dent Res. 74:175,1995; Graff et al., J. Dent. Res. 75:137,1996). Collectively, these findings are of physiologic and pharmacologic significance because activation of excitatory amino acid receptors in peripheral tissue may partially contribute to inflammatory mediated pain states. Accordingly, peripheral glutamate receptors may represent an additional target for analgesic therapies in the future. The source of endogenous glutamate released into inflamed tissue and the cellular location and characterization of peripheral glutamate receptors are among the research objective to be explored in the future (recently funded NIDR RO1 DE11659).