The long-term objective is to understand how multiple serotonin receptors, present on the same dorsal root ganglion cell, interact to synthesize a meaningful signal. To date, evidence indicates that 5-HT2 and 5-HT3 receptors co-occur on A-type cells, and that 5-HT1A and 5-HT(2 or 3) receptors are colocalized on C-type cells of the primary sensory neurons. The problem to be solved is how seemingly conflicting effects (e.g. co-occurrence of receptors that increase and decrease membrane conductance, or that depolarize and hyperpolarize the membrane) are integrated into a coherent signal. It is hypothesized that integration of multiple receptor signals is accomplished by second messenger cross-talk. Using a combination of current-clamp, voltage-clamp and patch-clamp methodologies on acutely isolated dorsal root ganglia or their dissociated cells, the ion currents affected by each 5-HT receptor subtype will be identified. Then, by use of pharmacological probes, the role of various known second messengers in transducing or modulating the ion current(s) associated with each receptor subtype will be characterized. Once the ion current(s) and the second messenger roles have been described for each receptor subtype, the interactions between receptor subtypes will be explored. Whenever it is observed that one receptor subtype will augment or impede the effect of another receptor subtype present on the same cell, the role of second messengers in that interaction will be characterized. The understanding of how one receptor subtype modulates the response of another receptor subtype on the same cell would markedly increase our ability to pharmacologically manipulate that cells responsiveness. With respect to the dorsal root ganglion cells, this understanding would increase opportunities for gaining selective pharmacological control over sensory input, including pain and motor reflexes. In addition, other cell systems in the brain contain multiple 5-HT receptor subtypes, and the principles established by this investigation have potential application in the larger area of serotonin pharmacology.
