The dorsal horn of the spinal cord constitutes the first level in the central nervous system where input from sensory fibers innervating the body is integrated. As the neurons of the dorsal horn are responsible for the relay of nociceptive information to higher brain structures, their level of excitability critically influences our sensory experience. Thus, a thorough understanding of the inhibitory control regulating the excitability of dorsal horn neurons is crucial for the development of new drugs and strategies for the treatment of sensory dysfunction, including allodynia, secondary hyperalgesia, chronic and phantom limb pain. The long term goal of this research is therefore to understand how inhibitory mechanisms regulate the integrative properties of the dorsal horn by controlling neuronal excitability. The more immediate goal is to study, at the cellular and molecular level, the properties of the inhibition imposed upon dorsal horn neurons by the dominant inhibitory amino acid transmitters gamma-aminobutyric acid (GABA) and glycine. The whole-cell patch clamp technique will be used to obtain high resolution recordings of inhibitory postsynaptic currents (IPSCs) occurring in dorsal horn neurons maintained in adult rat spinal cord slices at physiological temperature. Taking advantage of the level of resolution provided by these recordings, advanced quantitative analytical tools such as non- stationary noise analysis will be used to study spontaneously occurring and monosynaptically evoked IPSCs in isolation. This approach will provide detailed insights into the basic physiology and pharmacology of inhibitory synapses and direct information on the behavior of individual receptor/channel molecules underlying synaptic events. Thus, without the need to extract these molecules from the nervous tissue, it will be possible to obtain valuable information on their properties in a preparation which maintains intact the connections between cells in fully differentiated tissue. The specific objectives of the present proposal will be: 1) to characterize the ligand-gated channels underlying IPSCs in the marginal zone and substantia gelatinosa of the dorsal horn in terms of their pharmacology, conductance, kinetics, modulation, and distribution among distinct types of identified neurons and 2) to determine whether neurokinin and opioid peptides, which play an important role in the regulation of nociception, modulate inhibition by affecting the frequency of occurrence, the conductance, or the kinetics of miniature (action potential independent) IPSCs in this area of the spinal cord.