Anke Tappe-Theodor ^1,2* Thomas J Martin ³ S. Stevens Negus ⁴

• ¹ Institute of Pharmacology, Medical Faculty Heidelberg, University of Heidelberg, Heidelberg, Germany
• ² Institute of Pharmacology, University of Heidelberg, Heidelberg, Baden-Württemberg, Germany
• ³ Pain Mechanisms Laboratory, Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, United States
• ⁴ Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, United States

Accordingly, recent advances in pain research focused on more sophisticated methods and models integrating both sensory and affective dimensions of pain to address the negative impact of pain on function and quality of life, and enhance the predictive validity of animal studies for human clinical outcomes (Mogil et al., 2019;Negus 2019;Mouraux et al., 2021).A key aspect of advancing preclinical pain models involves refining behavioral endpoints that more closely mirror the affective and motivational components of human pain (Corder et al., 2019;Warncke et al., 2021;Norris et al., 2024;Zhang et al., 2022). Chronic pain in humans often leads to symptoms such as reduced physical activity, social withdrawal, and depressive-like behavior-features now being incorporated into animal models (King et al., 2009). Recognizing the limitations of traditional nociceptive measures, researchers have begun to explore novel behavioral assays that better represent pain-related disability and the broader impact of chronic pain on behavior. Such refinements are critical for improving the assessment of drug efficacy, particularly when considering treatments aimed at addressing not just the sensory, but also the emotional and cognitive consequences of pain.In this second special issue, we present four studies that explore different preclinical models and methodologies aimed at improving our understanding of pain and enhancing the predictive validity of animal models for analgesic drug development. These studies cover a range of innovative approaches, from exploring the efficacy of combined therapies for fibromyalgia, to evaluating novel behavioral assays for pain-related depression, to investigating how vascular changes in the spinal cord affect drug delivery. Each study provides valuable insights into the complex dynamics of pain and offers potential pathways for improving the translational success of new treatments.The study by Argenbreit et al. https://www.frontiersin.org/articles/10.3389/fpain.2023.1097457 investigates the efficacy of pregabalin and hyperbaric oxygen therapy (HBO2) in a rat model of fibromyalgia (FM). FM is a chronic, widespread pain disorder, characterized by both sensory abnormalities and a variety of cognitive and affective comorbidities, including anxiety and depression (Clauw, 2014). Preclinical models of FM are vital for understanding these complex interactions, as well as for testing the effectiveness of potential therapies. In this study, the authors used an acidic saline injection model, which mimics the hyperalgesia commonly seen in FM patients, and assessed both sensory (mechanical pain thresholds) and affective components (anxietylike behaviors). Interestingly, while pregabalin, a known treatment for FM, reduced avoidance behaviors, neither it nor HBO2 significantly alleviated mechanical hyperalgesia or anxiety in this model. These findings highlight the challenges of modeling the affective dimensions of FM and underscore the need for further refinements in preclinical FM models to capture the full spectrum of symptoms experienced by patients.Building on the theme of novel behavioral endpoints, Santos et al.https://www.frontiersin.org/articles/10.3389/fpain.2023.1150236 explore the use of climbing behavior in mice as a tool for assessing pain-related behavioral depression.Traditional models often focus on reflexive responses to painful stimuli, but these fail to account for the motivational deficits associated with chronic pain (Vierck et al., 2008). Santos et al. introduced a climbing assay as a way to measure motivated behavior in mice, hypothesizing that pain would lead to reduced climbing, which could then be reversed by effective analgesic treatments. Their results demonstrated that climbing behavior was depressed by intraperitoneal injections of lactic acid, a well-established model for inducing acute pain in rodents. Ketoprofen, a non-steroidal anti-inflammatory drug (NSAID), effectively reversed this depression, while opioid treatments like fentanyl disrupted climbing behavior in the absence of pain. This provides a critical tool for differentiating between analgesic and sedative effects, which is essential for developing better pain treatments.Another critical aspect of pain research is understanding how systemic factors, such as vascular health, impact the efficacy of pain treatments. Lobo et al. https://www.frontiersin.org/articles/10.3389/fpain.2023.1190440 address this issue in their study by investigating how spinal cord vascular degeneration impairs the penetration and efficacy of duloxetine, a serotonin-norepinephrine reuptake inhibitor commonly used to treat chronic pain conditions like neuropathy and fibromyalgia (Wernicke et al., 2006). Using a rodent model of spinal cord vascular degeneration, they found that reduced blood flow in the spinal cord was associated with lower concentrations of duloxetine in the tissue, leading to diminished analgesic effects. This study highlights the importance of considering vascular health when evaluating drug efficacy, particularly for conditions where spinal cord pathology may play a role. The findings suggest that enhancing vascular perfusion could be a potential strategy for improving the delivery and effectiveness of analgesic drugs in patients with spinal cord-related pain disorders.Finally, the study by Negus et al. https://www.frontiersin.org/articles/10.3389/fpain.2023.1281698 explores the role of muopioid receptor (MOR) agonist efficacy in determining the balance between analgesic effectiveness and safety. Opioids are among the most potent pain relievers available, but their use is limited by serious side effects, including respiratory depression, motor impairment, and gastrointestinal issues (Yaksh and Wallace, 2017). Negus et al. used a novel assay of pain-depressed locomotor behavior in mice to evaluate the analgesic and sideeffect profiles of opioids with varying MOR efficacies. Their results showed that intermediate-efficacy MOR agonists, such as buprenorphine, provided effective pain relief with fewer side effects compared to high-efficacy agonists like fentanyl. This suggests that intermediate-efficacy agonists may offer a promising path forward for developing safer opioid therapies, particularly in managing chronic pain conditions. Additionally, the use of pain-depressed behavior as an endpoint highlights the importance of integrating functional measures into preclinical models to assess both the efficacy and safety of analgesic drugs more holistically.In conclusion, the studies presented in this special issue provide significant advancements in preclinical pain research. By refining animal models and exploring novel behavioral endpoints, these studies contribute to improving the predictive validity of preclinical models for analgesic drug development. The findings underscore the complexity of chronic pain and the need for multidimensional approaches in both modeling pain and assessing potential treatments. As we continue to develop more sophisticated models and methodologies, these advancements will be crucial in guiding the development of more effective and safer treatments for chronic pain patients, bridging the gap between preclinical research and clinical application.