Acute to Chronic Pain Signatures
U.S. Army Medical Research and Development Command W81XWH-21-1-0870
09/01/21 – 08/31/24
Nyland, PI
Persistent and chronic pain are significant contributors to diminished quality of life following acute musculoskeletal injury. In this study, we are investigating the chronification of acute pain in patients with blunt chest trauma with multiple (>2) closed rib fractures by assessing psychological, biological, and functional neural connectivity biomarkers during the transition from acute to chronic pain. Rib fractures are commonly recognized as a significant source of acute pain following injury; however, they also have a high rate of transition to chronic pain. Published prospective data indicate the chronification of pain after multiple rib fractures observed in our institution ranges from 40 to 50%. There remains a large gap in understanding of how acute pain transitions to chronic pain and how clinical measures can predict pain chronification. At present, there are no known methods to predict which patient will develop persistent pain after injury and which patient will be resilient to persistent pain. We suspect that those presumable risk factors are related to multiple features related to both clinical factors (i.e. previous health status of the patients before injury including their medication and pain treatment during acute injury), their pain tolerance status, inherited elements (genetics) and also how the brain itself responds to injury. The objective of this research proposal is to identify and better understand all factors which can lead to chronic pain or protect from chronic pain in patients after this type of injury. It is also possible that similar factors play a role in experiencing prolonged pain in other types of trauma and injuries. It is therefore possible that these factors could be more widely applied in other areas of medicine.
Immune and neuroendocrine mediators of sex-differences in pain following traumatic burn injury
NIH/National Institute on General Medical Sciences (NIGMS) R35 GM146774
07/01/22 – 04/30/27
Nyland, PI
Pain from a traumatic burn injury is likely the most severe form of pain imaginable; these injuries generate tissue and nerve damage and induce exaggerated inflammation that results in remarkably high pain levels. There is also excruciating pain that accompanies necessary wound care procedures such as debridement, burn excision and grafting, and mobilization. Current reports suggest that burn-related pain is currently undertreated. This is partially due to a dramatic increase in pain sensitivity (hyperalgesia), as well as the accelerated development of tolerance to opioid analgesics following severe injuries. Unfortunately, the mechanisms driving increased sensitivity and tolerance are unclear. Additionally, females report more severe pain and are more likely to experience chronic pain following such injuries. Currently, the mechanisms behind these sex-specific differences are unknown. Research has primarily focused on the innate immune response to injury as a leading candidate; however, the recent inclusion of female subjects has uncovered sex-specific differences in immune-modulated pain sensitivity that has generated numerous questions regarding the influence of sex on pain processing and whether the body of male-only research is truly applicable. Hormones play a significant role in sex-specific differences in immune activity and may be vital to understanding the sex-related differences in the immune response to noxious stimuli. Further, stress-induced adaptations in neurosensory processing are believed to play an essential role in the pathogenesis of acute and chronic pain outcomes. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) and sympathoadrenal (SA) axes following traumatic injury leads to excessive glucocorticoid and catecholamine release, which has been shown to reduce the activity of descending pathways that modulate endogenous pain inhibition and opioid analgesia. We hypothesize that the immune response involved in the pathogenesis of pain is regulated in a sex-specific manner through involvement of the HPA and SA axes. Sex-specific genes, hormones, and signaling mechanisms may shed light on novel targets that have been previously overlooked, giving great hope for future sex-specific interventions. Accordingly, this project will systematically investigate the role of sex-specific immune reactivity and neuroendocrine responses in an animal model of full-thickness thermal burn injury. This program of research will lead us closer to understanding mechanisms that make pain from traumatic burn injuries so challenging to treat and identify sex-related drivers behind them. Results will identify mechanisms underlying the accelerated development of tolerance and hyperalgesia and provide insight to potential targets for sex-specific intervention in the transition to chronic pain.
Ketamine-Induced Epigenetic Changes in Traumatic Injury
PA Tobacco Settlement Fund (TSF), Commonwealth of Pennsylvania #4100095613
07/01/23 – 06/30/26
Nyland, PI
Chronic pain is the number one cause of disability and disease burden globally and is associated with diseases of despair currently plaguing the state of Pennsylvania: opioid and alcohol use, overdose, and suicide. Chronic pain often accompanies exposure to traumatic stress. We have previously shown that exposure to traumatic stress prior to injury results in a greater magnitude and longer duration of pain. We have also identified stress-related biomarkers that predict persistent pain following motor vehicle collisions or sexual assault, even in the absence of injury. Stress then, has a significant impact on the development of chronic pain. One means by which stress can affect pain is through epigenetic regulation, which is the essential link between nature (genes) and nurture (environment). Recently, the use of ketamine has grown in popularity for the treatment of various psychiatric and psychosomatic conditions including both acute and chronic pain. The mechanisms underlying the efficacy of ketamine treatment for these conditions, however, are still poorly understood. Long-term treatment with ketamine has been shown to alleviate anxiety-like behavior in a rodent model of post-traumatic stress disorder and prevent trauma-induced epigenetic changes in brain regions involved in fear conditioning. It is unclear, however, if these effects are stress dependent. Because ketamine therapy comes with serious side effects and is not effective in all patients, a major obstacle in the field is identifying patients that will most benefit from it. Therefore, the objective of this proposal is to identify epigenetic changes induced by ketamine therapy in a rodent model of traumatic injury and to determine if these changes are stress dependent.