NOCICEPTIVE MEMORY: MECHANISMS OF HYPEREXCITABILITY

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Central memory of peripheral injury relies on mechanisms that are likely prototypes of other transcription-dependent forms of long-term memory, and which directly contribute to the clinical problems of persistent hyperalgesia and neuropathic pain. In addition, derangements of these fundamental plasticity mechanisms may contribute to problems of memory and learning in humans. The invertebrate, Aplysia, contains nociceptive sensory neurons with defined roles in defensive behavior and which display long-term hyperexcitability (LTH) of their central as well as peripheral components lasting for days to months after intense noxious stimulation. These sensory neurons are particularly favorable for investigating long-term memory mechanisms because they can be manipulated and tested individually before, during, and after memory induction -- in ways not possible with vertebrate neurons. The proposed studies will test a multiphase hypothesis about the cellular signaling pathways and transcription factors responsible for induction of LTH in these neurons, focusing on the phases that depend upon signals evoked by intense neural activity. A number of specific questions will be systematically addressed. What ionic mechanisms underlie the expression Of LTH? During LTH are there changes in the mRNA levels of any ion channels that have been cloned from Aplysia? How long do different phases of LTH induction last? How do they depend upon NO and cGMP signals? Do NO and PKG act through activation of MAPK? Is prolonged or repeated elevation of intracellular Ca2+ necessary or sufficient to induce LTH? Is prolonged PKA activation important for LTH induction? Is there simultaneous or sequential synergism between cAMP and either Ca2+ or cGMP signals during the induction of LTH? How does the activity of protein kinases potentially important for LTH (e.g. PKG, MAPK IAK-1, PKA, PKC, CaMK, SAPK) change during different phases of the induction and maintenance of LTH? Which transcription factors are required for the rapid induction of LTH? Are any phases of LTH prevented by injection of decoy oligonucleotides encoding response elements such as CRE, SRE and ERE? Can LTH be induced by injection of activated transcription factors? As is evident by the detailed nature of these questions, the proposed experiments directly probe specific pathways that are important for the induction of LTH. Our findings will provide significant insights into fundamental mechanisms important for both memory formation and persistent pain.