Morphine Undermines Recovery of Function After a Spinal Cord Injury: The Role of Glial and Kappa Opioid Receptor Activation

Abstract

Opioids are among the most effective analgesics for the management of pain in the acute phase of a spinal cord injury (SCI), and approximately 80% of patients are treated with morphine in the first 24 hours following SCI. Unfortunately, we have found that morphine treatment in the first 7 days after SCI increases symptoms of pain at 42 days post-injury and undermines locomotor recovery and tissue sparing in a rat model. As removing opioids from a clinicians’ pain management tool kit is not an option, we need to investigate how morphine elicits these negative outcomes to provide safe methods for the use of these powerful analgesics. Prior literature, and work from our laboratory, suggests that glial and kappa opioid receptor (KOR) activation may mediate the negative effects of morphine on recovery. To test this, the first set of experiments presented here (Chapter 3), evaluated the role of microglia/macrophage activation in the negative effects of repeated intravenous morphine. I found that morphine significantly increases glial activation and phagocytosis. However, manipulating glial activation using minocycline did not prevent the adverse effects of morphine, and minocycline independently undermined recovery. I then investigated whether blocking KOR activation with nor-binaltorphimine (norBNI) could prevent the deleterious effects of repeated, intravenous morphine (Chapter 4), and found that norBNI was sufficient. Recognizing that opioids vary in their affinity for KORs, I tested the effects of four clinically relevant opioids on SCI recovery (Chapter 5) and found that those that do not bind or actively inhibit KORs did not increase the incidence of pain, but all opioids undermined locomotor recovery. Together, these results indicate that glial and KOR activation may contribute to secondary injury mechanisms engaged by morphine, ultimately undermining recovery after SCI. Further, these studies highlight the importance of increasing the safety and utility of all opioids, not just morphine, in the clinic.