Modulation of Substance P Release in Primary Sensory Neurons by Misoprostol and Prostaglandins

Pain is one of the cardinal signs of inflammation. A number of inflammatory mediators have been shown in animal models to induce or augment pain. Of particular interest are the prostaglandins (PGs), which are arachidonic acid metabolites and can be pharmacologically regulated by cyclooxygenase inhibitors, the nonsteroidal anti-inflammatory drugs (NSAIDs). Indeed, NSAIDs are potent modulators of pain sensitivity. They are thought to mediate their hypoalgesic action through inhibition of prostaglandin production. However, indiscriminate inhibition of prostaglandin synthesis also creates a significant number of clinical side effects, among them gastrointestinal toxicity. With the introduction of misoprostol, a PGE(1) analog, a large number of investigative possibilities are opened. We have proposed to study the effect of misoprostol in an in vitro pain model. Our model, created by culturing primary sensory neurons isolated from dorsal root ganglions, was then differentiated by nerve growth factor and subjected to electrical stimulation. Substance P release following electrical stimulation was quantitated by radioimmunoassay. We found that misoprostol augmented substance P release in a dose-related manner. With 100 ng/ml of misoprostol added, there was a 45% increase in substance P release as compared to control. PGE(1) and PGE(2) addition at similar concentration caused a similar degree of increase in substance P release. Thus, acute addition of misoprostol to cultured sensory neurons appears to sensitize them to release more substance P. Our result does not necessarily imply that misoprostol will cause pain clinically. In our study, misoprostol at 10 ng/ml has no effect on substance P release. Because the plasma concentration of misoprostol is in the picogram per milliliter range, misoprostol most likely does not have a pain potentiation effect at the recommended therapeutic dose. Our data indicated that misoprostol at therapeutic dose has an insignificant effect on substance P release from primary sensory neuron.