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Browsing by Author "Department of Anesthesia, IU School of Medicine"
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Item Acrolein involvement in sensory and behavioral hypersensitivity following spinal cord injury in the rat(Wiley, 2014-03) Due, Michael R.; Park, Jonghyuck; Zheng, Lingxing; Walls, Michael; Allette, Yohance M.; White, Fletcher A.; Shi, Riyi; Department of Anesthesia, IU School of MedicineGrowing evidence suggests that oxidative stress, as associated with spinal cord injury (SCI), may play a critical role in both neuroinflammation and neuropathic pain conditions. The production of the endogenous aldehyde acrolein, following lipid peroxidation during the inflammatory response, may contribute to peripheral sensitization and hyperreflexia following SCI via the TRPA1-dependent mechanism. Here we report that there are enhanced levels of acrolein and increased neuronal sensitivity to the aldehyde for at least 14 days after SCI. Concurrent with injury-induced increases in acrolein concentration is an increased expression of TRPA1 in the lumbar (L3-L6) sensory ganglia. As proof of the potential pronociceptive role for acrolein, intrathecal injections of acrolein revealed enhanced sensitivity to both tactile and thermal stimuli for up to 10 days, supporting the compound’s pro-nociceptive functionality. Treatment of SCI animals with the acrolein scavenger hydralazine produced moderate improvement in tactile responses as well as robust changes in thermal sensitivity for up to 49 days. Taken together, these data suggests that acrolein directly modulates SCI-associated pain behavior, making it a novel therapeutic target for preclinical and clinical SCI as an analgesic.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 Impact of Opioid and Nonopioid Drugs on Postsurgical Pain Management in the Rat(Hindawi Publishing Corporation, 2016) Wilson, Natalie M.; Ripsch, Matthew S.; White, Fletcher A.; Department of Anesthesia, IU School of MedicineAim. Nonsteroidal anti-inflammatory drugs or opioids are commonly used to control surgical pain following veterinary and clinical procedures. This study evaluated the efficacy of postoperative ketorolac or buprenorphine following abdominal surgery. Main Methods. Mean arterial pressure (MAP), heart rate, animal activity, corticosterone levels, and a nociceptive sensitivity assay were used to evaluate 18 adult male Sprague-Dawley rats which underwent aortic artery occlusion for implantation of a radiotelemetry device. The animals were treated postoperatively with intraperitoneal injections of vehicle, ketorolac (10 mg/kg), or buprenorphine (0.06 mg/kg) every 8 hours for 3 days. Key Findings. There were no consistent significant changes in any of the telemetry parameters after treatment with ketorolac compared with no saline treatment with the exception of increased MAP in the buprenorphine group during the first 48 hours when compared with other treatment groups. There was a sustained increase in fecal corticosterone levels from baseline on days 2-7 with buprenorphine compared with vehicle- or ketorolac-treated animals. All treatment conditions displayed reduced paw withdrawal thresholds (PWTs) from day 1 to day 21 following surgery. Compared with the vehicle treatment group, buprenorphine-treated animals exhibited significantly lower PWT levels from day 4 to 14 days. Significance. Given the prolonged increase in fecal corticosterone levels and pronounced changes in tactile hyperalgesia behavior in rodents subjected to buprenorphine treatment, these data suggest that ketorolac may be superior to buprenorphine for the treatment of postprocedure pain behavior in rodents.