Amygdala, CREB, and Neuropathic Pain Facilitation

Tulane University Of Louisiana, New Orleans LA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): It is well known that pain can be modulated by the brain. This has clinical relevance to those suffering from chronic pain. This proposal is designed to examine the contribution of the central nucleus of the amygdala (CeA) to facilitation of chronic neuropathic pain. Using the spared nerve injury (SNI) model of peripheral mononeuropathy, the experiments in this proposal will test hypotheses that NMDA- and CREB-dependent mechanisms in the CeA contribute to chronic neuropathic pain. In Specific Aim 1, the local anesthetic lidocaine will be used to test the hypothesis that disruption of neural activity in the CeA but not the basolateral amgdaloid nucleus (BLA) reduces allodynia and hyperalgesia associated with SNI. Specific Aim 2 will test the hypothesis that excitatory neurotransmission in the amygdala contributes to neuropathic pain behavior. Aim 2A will test the hypothesis that nerve injury increases basal and stimulus-induced glutamate release in the CeA, measured by in vivo microdialysis (Aim 2A). Aim 2B will test the hypothesis that NMDA receptor-blockade in the CeA reduces allodynia and hyperalgesia associated with SNI. Specific Aim 3 will test the hypothesis that CREB in the amygdala contributes to neuropathic pain behavior by 1) determining if behavioral signs of neuropathic pain are correlated with increased levels of phosphorylated CREB in the CeA (Aim 3A), 2) determining if CRE-dependent genes are increased in the CeA in SNI rats relative to controls (Aim 3B), and 3) determining if blockade of CREB function in the CeA reduces allodynia and hyperalgesia associated with SNI (Aim 3C). This will be accomplished using herpes simplex viral vector- mediated gene transfer of a mutant form of CREB as well as through RNA interference to downregulate endogenous CREB mRNA. Chronic pain affects millions of people in the United States and currently available pain killers (e.g. opioids, NSAIDS, acetaminophen) do not alleviate pain for many of these patients, often having undesirable side effects such as dependency. The inefficacy of these drugs may be due to a lack of understanding of pain modulation by the brain. A region of the brain most known for its role in regulating emotion, the amygdala, has recently been implicated in pain enhancement. Thus, the experiments in the current proposal investigating the role of the amygdala in chronic pain are timely and may lead to more effective drug targets. [unreadable] [unreadable] [unreadable]