The pain and hyperalgesia, associated with tissue injury and inflammation is among the most common reasons people seek medical treatment. Hyperalgesia is associated with the sensitization of primary afferent nociceptors. Hyperalgesic inflammatory mediators (HIM's) released following injury act on nociceptor terminals to increase their excitability. HIM's such as Prostaglandin E2 sensitize nociceptors both in vivo and in vitro. Evidence suggests that HIM-induced sensitization may involve the activation of either protein kinase A- or protein kinase C-dependent second messenger pathways. Using a model for the nociceptor terminal in vitro, it has been demonstrated that HIM's modulate a tetrodotoxin resistant voltage-gated Na current (TTX-R Ina) in a manner consistent with nociceptor sensitization. Thus, changes in this current constitute a final step in the transduction pathway underlying the effects of inflammatory mediators in nociceptors. Using patch clamp electrophysiology and Ca imaging techniques in combination with a series of specific pharmacological agents to identify the cellular components, and therefore second messenger pathway utilized by HIM's, the following hypotheses will be tested: 1) HIM-induced modulation of TTX-R I involves the activation of a protein kinase A-dependent second messenger pathway: 2) HIM-induced modulation of TTX-R Ina involves the activation of a protein kinase C dependent second messenger pathway; 3) HIM-induced modulation of TTX-R Ina involves an interaction between PKA- and PKC-dependent second messenger pathways. These studies will provide the first detailed analysis of the second messenger pathway underlying inflammatory mediator-induced nociceptor sensitization. By increasing our understanding of the neurobiology of nociceptor sensitization, results from these studies have the potential to facilitate the development of novel therapeutic approaches to the treatment of pain. This is particularly true with respect to TTX-R Ina, because this current appears to be unique to primary afferent nociceptors. Thereby, manipulations targeting TTX-R Ina have the potential for providing the most effective pain relief known, with the smallest number of side effects.
