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Browsing by Author "Feldman, Polina"
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Item Challenging the catechism of therapeutics for chronic neuropathic pain: targeting CaV2.2 interactions with CRMP2 peptides(Elsevier, 2013-12-17) Feldman, Polina; Khanna, Rajesh; Department of Pharmacology and Toxicology, IU School of MedicineChronic neuropathic pain management is a worldwide concern. Pharmaceutical companies globally have historically targeted ion channels as the therapeutic catechism with many blockbuster successes. Remarkably, no new pain therapeutic has been approved by European or American regulatory agencies over the last decade. This article will provide an overview of an alternative approach to ion channel drug discovery: targeting regulators of ion channels, specifically focusing on voltage-gated calcium channels. We will highlight the discovery of an anti-nociceptive peptide derived from a novel calcium channel interacting partner – the collapsin response mediator protein 2 (CRMP2). In vivo administration of this peptide reduces pain behavior in a number of models of neuropathic pain without affecting sympathetic-associated cardiovascular activity, memory retrieval, sensorimotor function, or depression. A CRMP2-derived peptide analgesic, with restricted access to the CNS, represents a completely novel approach to the treatment of severe pain with an improved safety profile. As peptides now represent one of the fastest growing classes of new drugs, it is expected that peptide targeting of protein interactions within the calcium channel complex may be a paradigm shift in ion channel drug discovery.Item Identification of a functional interaction of HMGB1 with Receptor for Advanced Glycation End-products in a model of neuropathic pain(Elsevier, 2014-11) Allette, Yohance M.; Due, Michael R.; Wilson, Sarah M.; Feldman, Polina; Ripsch, Matthew S.; Khanna, Rajesh; White, Fletcher A.; Department of Anesthesia, IU School of MedicineRecent studies indicate that the release of high mobility group box 1 (HMGB1) following nerve injury may play a central role in the pathogenesis of neuropathic pain. HMGB1 is known to influence cellular responses within the nervous system via two distinct receptor families; the Receptor for Advanced Glycation End-products (RAGE) and Toll-like receptors (TLRs). The degree to which HMGB1 activates a receptor is thought to be dependent upon the oxidative state of the ligand, resulting in the functional isoforms of all-thiol HMGB1 (at-HMGB1) acting through RAGE, and disufide HMGB1 (ds-HMGB1) interacting with TLR4. Though it is known that dorsal root ganglia (DRG) sensory neurons exposed to HMGB1 and TLR4 agonists can influence excitation, the degree to which at-HMGB1 signaling through neuronal RAGE contributes to neuropathic pain is unknown. Here we demonstrate that at-HMGB1 activation of nociceptive neurons is dependent on RAGE and not TLR4. To distinguish the possible role of RAGE on neuropathic pain, we characterized the changes in RAGE mRNA expression up to one month after tibial nerve injury (TNI). RAGE mRNA expression in lumbar dorsal root ganglion (DRG) is substantially increased by post-injury day (PID) 28 when compared with sham injured rodents. Protein expression at PID28 confirms this injury-induced event in the DRG. Moreover, a single exposure to monoclonal antibody to RAGE (RAGE Ab) failed to abrogate pain behavior at PID 7, 14 and 21. However, RAGE Ab administration produced reversal of mechanical hyperalgesia on PID28. Thus, at-HMGB1 activation through RAGE may be responsible for sensory neuron sensitization and mechanical hyperalgesia associated with chronic neuropathic pain states.Item The role of high mobility group box 1 and toll like receptor 4 in a rodent model of neuropathic pain(2013-11-20) Feldman, Polina; Oxford, Gerry S.; White, Fletcher A.; Khanna, Rajesh; Jones, Kathryn J.; Shi, RiyiNeuropathic pain is a serious health problem that greatly impairs quality of life. The International Association for the Study of Pain (IASP) defines neuropathic pain as ‘pain arising as a direct consequence of a lesion or disease affecting the nervous system’. It is important to note that with neuropathy the chronic pain is not a symptom of injury, but rather the pain is itself a disease process. Novel interactions between the nervous system and elements of the immune system may be key facets to a chronic disease state. One of particular note is the recent finding supporting an interaction between an immune response protein high mobility group box 1 (HMGB1) and Toll like receptor 4 (TLR4). HMGB1 is an endogenous ligand for TLR4 that influences the induction of cytokines in many non-neuronal cells. After tissue damage or injury, HMGB1 may function as a neuromodulatory cytokine and influence the production of pro-nociceptive mediators altering the state of sensory neurons. Very little is known about the HMGB1-TLR4 interaction in sensory neurons and whether chronic changes in endogenous HMGB1 signaling influence the establishment of neuropathic pain. This thesis aims to determine whether a physiologically relevant neuroimmune interaction involving endogenous HMGB1 and TLR4 in the dorsal root ganglia is altered following a tibial nerve injury model of neuropathic pain. I hypothesized that sensitization of sensory neurons following a peripheral nerve injury is dependent on endogenous HMGB1 and TLR4. The studies presented here demonstrate that HMGB1 undergoes subcellular redistribution from the nucleus to the cytoplasm in primary afferent neurons following peripheral nerve injury. Further, the presence of extracellular HMGB1 may directly contribute to peripheral sensitization and injury-induced tactile hyperalgesia. Though thought to be important as a pivotal receptor for HMGB1 activation, neuronal protein expression of TLR4 does not appear to influence the effects of HMGB1-dependent behavioral changes following peripheral nerve injury. Taken together, these findings suggest that extracellular HMGB1 may serve as an important endogenous cytokine that contributes to ongoing pain hypersensitivity in a rodent model of neuropathic pain.