Browsing by Author "Hook, Michelle"

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    Research Project
    Derivation of the Mechanisms Mediating the Adverse Effects of Morphine in a Rodent Model of SCI: Functional Recovery and Neuron Loss
    Neuroscience And Experimental Therapeuti; TAMHSC; https://hdl.handle.net/20.500.14641/443; DOD-Army-Medical Research and Materiel Command
    In the critical first few days following spinal cord injury (SCI), many patients will experience distressing pain that arises from the trauma to the cord, the spinal nerves, the spinal fracture, or from accompanying wounds and lacerations. In the battlefield arena, this pain is managed with opioids (morphine and fentanyl) and ketamine. Effective pain management in the emergency setting is essential as under-sedation may allow delirium to develop and may increase the risk of later development of affective disorders (such as post-traumatic stress disorder [PTSD]) and cognitive impairments. Moreover, early management of acute pain is paramount in minimizing the development of chronic pain. Chronic pain is cited as one of the most significant consequences of SCI and one that patients most want cured. Unfortunately, however, our studies indicate that morphine (a potent opioid) has significant adverse effects on recovery of function in a rodent model of SCI. In the rodent model, we discovered that morphine given on the day following injury undermines locomotor recovery, increases long-term pain, and increases tissue loss at the injury site. Opioids may also adversely alter the prognosis for recovery in humans. Despite similar injury severity, Soldiers injured on the battlefield have a lower level of neurological recovery than those injured outside the combat arena. Pain on the battlefield is managed with opioids (morphine, fentanyl), whereas outside of combat pain can be treated with alternative medications (non-steroidal anti-inflammatory drugs [NSAIDs]). Given these data, it is tempting to suggest that morphine should not be used for pain management after a SCI. For the significant proportion (approximately 66%) of SCI patients faced with a lifetime of intractable pain, however, simply removing morphine as a potential analgesic is not an option. Instead, we need to identify the mechanisms mediating the adverse effects of opioids and therapeutic strategies that improve their safety. In preliminary studies, we have found that a single dose of morphine, given on the day following SCI, increases the expression of immune cells (microglia) at injury site. We have shown that the microglia express kappa-opioid receptors (KORs). We hypothesize that activation of KORs on microglia underlie the morphine-induced attenuation of locomotor recovery. Indeed, we found that the adverse effects of a single dose of intrathecal morphine can be blocked with minocycline, which inhibits microglial activation, and norBNI, a KOR antagonist. These studies strongly suggest that microglia play a critical role in the adverse effects of opioids; however, both minocycline and norBNI have off-target effects that may compromise their clinical utility. We need a cell-specific targeted approach to derive the mechanisms mediating the adverse effects of opioids and to develop effective strategies for blocking these effects while preserving the analgesic efficacy of the medications. With the experiments outlined in the current proposal, we will use cutting-edge technologies to target microglia and extend these studies to a more clinically relevant model of pain management (using repeated morphine administrations to treat pain). In Aim 1, we will identify the molecular mechanism underlying morphine’s effects on the immune response and cell death after SCI. We will compare the temporal expression and the functional activity (cytokine expression, ex vivo phagocytosis) of activated microglia in morphine and vehicle-treated SCI subjects. Aim 2 will then test the efficacy of targeting microglia as a future therapeutic intervention. We will test the necessity of microglial activation in the morphine-induced attenuation of recovery (locomotor, sensory, histological) using hM4Di DREADDs to selectively inhibit microglia. We will also test the necessity of microglial KORs using a specific agonist (dynorphin) and determine whether activation of neuronal KORs alone is sufficient to reduce recovery when microglia are inactivated. Protective effects of inhibiting microglia (on recovery of function and cell survival) with opioid administration will provide a strategy that can be rapidly transitioned to the clinical setting. Identifying the critical molecular modulators of the morphine-induced attenuation of locomotor recovery, cell death, and the development of pain has the potential to change our standards of care, and enable the implementation of clinical procedures that protect recovery of function while affording effective pain management in the emergency and early hospital setting. Importantly, our data suggest that an interaction between opioids and a sensitized immune system (that would also be characteristic of traumatic brain injury, stroke and chronic pain per se) could have detrimental effects on recovery, irrespective of the injury type. We must understand the mechanisms that underlie the negative consequences of opioid (morphine) treatment to develop therapies that provide pain relief without harm.