The Influence of Pain and Analgesia in Rodent Models of Sepsis

Abstract

Sepsis is a multifaceted host response to infection that dramatically affects patient outcomes and the cost of health care. Animal models are necessary to replicate the complexity and heterogeneity of clinical sepsis. However, these models entail a high risk of pain and distress due to tissue trauma, inflammation, endotoxin-mediated hyperalgesia, and other mechanisms. Several recent studies and initiatives address the need to improve the welfare of animals through analgesics and standardize the models used in preclinical sepsis research. Ultimately, the goal is to provide high-fidelity, humane animal models that better replicate the clinical course of sepsis, to provide more effective translation and advance therapeutic discovery. The purpose of this review is to discuss the current understanding of the roles of pain and analgesia in rodent models of sepsis. The current definitions of sepsis along with an overview of pain in human sepsis are described. Finally, welfare concerns associated with animal models of sepsis and the most recent considerations for relief of pain and distress are reviewed.

Neuroimmune Regulation in Sepsis-Associated Encephalopathy: The Interaction Between the Brain and Peripheral Immunity

“…To be specific, SAE may cause long-term neurological deficits, with 10-20% of patients in septic shock showing cognitive deficits, 10-30% of them showing anxiety and stress disorders, and 31-70% of patients having chronic pain. In addition, SAE may result in epileptic seizures, delirium, mild or deep unconsciousness, and even coma (11)(12)(13).…”

Anesthesia and analgesia for common research models of adult mice

“…This has led to low consumption of analgesics in septic model studies. In fact, only 15% of studies that used the septic model reported using analgesics [ 174 , 175 ]. This concern may be truly related to NSAIDs and morphine that can elevate the level of circulating IL-6.…”

“…This concern may be truly related to NSAIDs and morphine that can elevate the level of circulating IL-6. However, other opioid analgesics such as buprenorphine have low side effects and immunosuppressive activity and should be used to control the pain [ 174 , 176 , 177 ]. Buprenorphine can be used subcutaneously, immediately before induction of the model, and then every 12 h for at least two days [ 169 , 174 ].…”

Microglia: A Potential Therapeutic Target for Sepsis-Associated Encephalopathy and Sepsis-Associated Chronic Pain

“…Chronic pain is a frequently reported consequence of critical care illnesses, with 31-70% of septic patients claiming pain 6 months after discharge from the hospital (Carpenter et al, 2019). The most likely cause of this pain can be inflammation, and microglia are believed to contribute to this pathology.…”

“…To be specific, it has been demonstrated that SAE can cause long-term neurological deficits, including cognitive deficits (10-20%) and anxiety and stress disorders (10-30%) (Iwashyna et al, 2010;Battle et al, 2013;Helbing et al, 2018). Moreover, 31-70% of sepsis survivors claim to suffer from pain 6 months after discharge from the hospital (Carpenter et al, 2019). Given that there is still a lack of specific treatment options proposed for SAE and sepsis-associated chronic pain, understanding the mechanisms of the pathological alterations in the brain is essential for developing effective treatments to avoid the potentially devasting effects of sepsis.…”