Opioids acting at the mu (morphine) receptor represent the vast majority of clinically used opioids and remain the most effective analgesics for treating moderate to severe pain. The use of morphine and similar compounds for the management of pain is limited by adverse side effects including respiratory depression, abuse potential, motor impairment and cognitive deficits. Novel mu opioid receptor agonists developed in our laboratory are based on the structure of the endogenous ligands (endomorphins) and provide potent antinociception. Studies from our laboratory indicate that these endomorphin (EM) analogs produce fewer adverse side-effects in rodents than morphine, including reduced respiratory depression, motor impairment, tolerance, and abuse potential. Recent studies have indicated that repeated injection of morphine, for as little as a few days, can induce glial activation, an inflammatory response that can led to a “paradoxical” morphine-induced pain (Watkins et al, 2005, 2007). Morphine is recognized by glia cells similarly to a foreign antigen via toll-like receptor 4 (Hutchinson et al., 2010; Watkins et al., 2009). Since endomorphin analogs are more similar in structure to endogenous peptides, we hypothesized that they would not be recognized by the immune system as pathogenic. In support of this hypothesis, our laboratory showed activation of microglia in the spinal cord after treatment with morphine, but not endomorphin analogs (Zadina et al., 2012). This may be of particular importance in the treatment of pain in patients already vulnerable to inflammation-induced pathologies, including during older adulthood and after traumatic brain injury (TBI). The focus of this project was to evaluate the cognitive effects of morphine and endomorphin analogs using aging and TBI models. Morphine impaired cognition after both acute and chronic drug administration but EM analogs did not, despite equal or greater duration of antinociception relative to morphine. Chronic studies using young, middle-aged, and old rats revealed that middle-aged rats were more susceptible to cognitive deficits caused by morphine than younger or older rats. Likewise, morphine exacerbated cognitive deficits produced by TBI. Electrophysiology experiments revealed that morphine altered hippocampal long-term potentiation to a greater extent than an EM analog. Immunohistochemistry of the hippocampus indicated that astrocytes are activated after treatment with morphine, but not an EM analog. In TBI studies, morphine treatment led to a reduction in the number of neurons in the dentate gyrus despite an increase in volume, which may be due to increased glial activation. Thus, EM analogs may serve as safer analgesics as indicated by several models, and differential effects of morphine and EM analogs are likely mediated, in part, by alterations in glial activation. / acase@tulane.edu
| Identifer | oai:union.ndltd.org:TULANE/oai:http://digitallibrary.tulane.edu/:tulane_27751 |
| Date | January 2014 |
| Contributors | Jernberg, Jennifer N. (Author), Zadina, James (Thesis advisor) |
| Publisher | Tulane University |
| Source Sets | Tulane University |
| Language | English |
| Detected Language | English |
| Format | 110 |
| Rights | Copyright is in accordance with U.S. Copyright law |
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