Opioid-Immune Interactions and Their Implications for Long-Term Recovery After SCI
Abstract
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) 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 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. We recently found that high doses of opioids given in the first 24 hours post SCI increase symptoms of pain at 1-year post injury. Despite similar injury severity, soldiers injured on the battlefield also 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 (nonsteroidal anti-inflammatory drugs). Given these data, it is tempting to suggest that morphine should not be used for pain management after 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. We must identify the mechanisms mediating the adverse effects of opioids and develop therapeutic strategies that improve their safety. Our data suggest that morphine changes the immune response, and that these changes are critical to its adverse effects. We have found that morphine increases the expression of immune cells (microglia and macrophages) at the injury site. Morphine also increases the production of dynorphin (a kappa opioid receptor agonist) and pro- inflammatory cytokines by these immune cells. Notably, dynorphin and cytokines can bind to neurons to cause overexcitation, which results in cell death (increasing the amount of damaged tissue) and pain. Importantly, however, other opioids, do not activate the immune system in the same way as morphine. Fentanyl and buprenorphine, for example, do not increase dynorphin synthesis by macrophages, and buprenorphine blocks the kappa opioid receptor, acting as an antagonist. These opioids may be safer alternatives for the treatment of pain after SCI. We hypothesize that opioids that do not increase dynorphin and cytokine expression will not undermine locomotor recovery or increase chronic pain. Indeed, our preliminary studies show that blocking the kappa opioid receptor (blocking the effects of dynorphin) prevents the adverse effects of morphine on locomotor recovery. As a competitive kappa opioid receptor antagonist, buprenorphine may be an ideal alternative for pain management after SCI, but this has not been tested. With the experiments outlined in the current proposal, we will use cutting-edge technologies to test the effects of other clinically relevant opioids including oxycodone, fentanyl, and buprenorphine. Like morphine, oxycodone and fentanyl are routinely used in the clinical setting, and on the battlefield, to treat pain after SCI, but we posit that buprenorphine may be equally effective and safer for treating this pain. In Aim 1, we will test whether these opioids are equally effective at reducing pain after SCI and as
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210522
Entities
People
- Michelle Hook
Organizations
- Texas A&M Health Science Center
- United States Army