Anke Tappe-Theodor

S. Stevens Negus

Thomas J. Martin

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TYPE EditorialPUBLISHED 07 January 2025| DOI 10.3389/fpain.2024.1523938EDITED AND REVIEWED BYTony L. Yaksh,University of California, San Diego,United States*CORRESPONDENCEAnke Tappe-Theodoranke.tappe-theodor@pharma.uni-heidelberg.deRECEIVED 06 November 2024ACCEPTED 18 December 2024PUBLISHED 07 January 2025CITATIONTappe-Theodor A, Martin TJ and Negus SS(2025) Editorial: Preclinical animal models andmeasures of pain: improving predictive validityfor analgesic drug development - volume II.Front. Pain Res. 5:1523938.doi: 10.3389/fpain.2024.1523938COPYRIGHT© 2025 Tappe-Theodor, Martin and Negus.This is an open-access article distributedunder the terms of the Creative CommonsAttribution License (CC BY). The use,distribution or reproduction in other forums ispermitted, provided the original author(s) andthe copyright owner(s) are credited and thatthe original publication in this journal is cited,in accordance with accepted academicpractice. No use, distribution or reproductionis permitted which does not comply withthese terms.Frontiers in Pain ResearchEditorial: Preclinical animalmodels and measures of pain:improving predictive validity foranalgesic drug development -volume IIAnke Tappe-Theodor1*, Thomas J. Martin2 and S. Stevens Negus31Institute of Pharmacology, University of Heidelberg, Heidelberg, Germany, 2Pain MechanismsLaboratory, Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem,NC, United States, 3Department of Pharmacology and Toxicology, Virginia Commonwealth University,Richmond, VA, United StatesKEYWORDSanimal models, behavioral tests, predictive validity, analgesic drugs, pain measurementEditorial on the Research TopicPreclinical animal models and measures of pain: improving predictivevalidity for analgesic drug development - volume IIChronic pain affects millions worldwide, thereby severely impacting the quality of life, andeffective pain management still remains one of the most significant challenges in modernmedicine. Despite the urgent need for better treatments, the development of new analgesicdrugs has progressed slowly, with many promising candidates failing in clinical trials(1–4). A major reason for this high attrition rate is the disconnect between preclinicalmodels and their predictive power in clinical settings (5, 6). Nonetheless, preclinicalanimal models are crucial in the drug development process, offering mechanisticinsights and serving as an important platform for efficacy and safety testing of newtreatments. However, their limitations in accurately mimicking human pain experienceshave led to a critical bottleneck in the identification of effective analgesics.Rodent models have been used to study pain pathways and evaluate potentialtreatments, with nociceptive tests such as the hot-plate and tail-flick assays widelyemployed to assess acute pain responses. However, these reflex-based models do notadequately capture the complexity of either acute or chronic pain, which often involvesemotional, cognitive, and sensory components (7, 8). Chronic pain conditions likefibromyalgia or neuropathic pain are characterized by persistent pain along withemotional disturbances and cognitive impairments (9), aspects often overlooked inpreclinical research. This disconnect has led to a recognition that more complexmodels, which account for the multidimensional nature of pain, are necessary.01 frontiersin.orgTappe-Theodor et al. 10.3389/fpain.2024.1523938Accordingly, recent advances in pain research focused on moresophisticated methods and models integrating both sensory andaffective dimensions of pain to address the negative impact ofpain on function and quality of life, and enhance the predictivevalidity of animal studies for human clinical outcomes (10–12).A key aspect of advancing preclinical pain models involvesrefining behavioral endpoints that more closely mirror theaffective and motivational components of human pain (13–16).Chronic pain in humans often leads to symptoms such asreduced physical activity, social withdrawal, and depressive-likebehavior—features now being incorporated into animal models(17). Recognizing the limitations of traditional nociceptivemeasures, researchers have begun to explore novel behavioralassays that better represent pain-related disability and thebroader impact of chronic pain on behavior. Such refinementsare critical for improving the assessment of drug efficacy,particularly when considering treatments aimed at addressing notjust the sensory, but also the emotional and cognitiveconsequences of pain.In this second special issue, we present four studies that exploredifferent preclinical models and methodologies aimed at improvingour understanding of pain and enhancing the predictive validity ofanimal models for analgesic drug development. These studies covera range of innovative approaches, from exploring the efficacy ofcombined therapies for fibromyalgia, to evaluating novelbehavioral assays for pain-related depression, to investigatinghow vascular changes in the spinal cord affect drug delivery.Each study provides valuable insights into the complex dynamicsof pain and offers potential pathways for improving thetranslational success of new treatments.The study by Argenbright et al. investigates the efficacy ofpregabalin and hyperbaric oxygen therapy (HBO2) in a ratmodel of fibromyalgia (FM). FM is a chronic, widespread paindisorder, characterized by both sensory abnormalities and avariety of cognitive and affective comorbidities, including anxietyand depression (18). Preclinical models of FM are vital forunderstanding these complex interactions, as well as for testingthe effectiveness of potential therapies. In this study, the authorsused an acidic saline injection model, which mimics thehyperalgesia commonly seen in FM patients, and assessed bothsensory (mechanical pain thresholds) and affective components(anxiety-like behaviors). Interestingly, while pregabalin, a knowntreatment for FM, reduced avoidance behaviors, neither it norHBO2 significantly alleviated mechanical hyperalgesia or anxietyin this model. These findings highlight the challenges ofmodeling the affective dimensions of FM and underscore theneed for further refinements in preclinical FM models to capturethe full spectrum of symptoms experienced by patients.Building on the theme of novel behavioral endpoints, Santoset al. explore the use of climbing behavior in mice as a tool forassessing pain-related behavioral depression. Traditional modelsoften focus on reflexive responses to painful stimuli, but thesefail to account for the motivational deficits associated withchronic pain (19). Santos et al. introduced a climbing assay as away to measure motivated behavior in mice, hypothesizing thatFrontiers in Pain Research 02pain would lead to reduced climbing, which could then bereversed by effective analgesic treatments. Their resultsdemonstrated that climbing behavior was depressed byintraperitoneal injections of lactic acid, a well-established modelfor inducing acute pain in rodents. Ketoprofen, a non-steroidalanti-inflammatory drug (NSAID), effectively reversed thisdepression, while opioid treatments like fentanyl disruptedclimbing behavior in the absence of pain. This provides a criticaltool for differentiating between analgesic and sedative effects,which is essential for developing better pain treatments.Another critical aspect of pain research is understanding howsystemic factors, such as vascular health, impact the efficacy ofpain treatments. Lobo et al. address this issue in their study byinvestigating how spinal cord vascular degeneration impairs thepenetration and efficacy of duloxetine, a serotonin-norepinephrine reuptake inhibitor commonly used to treatchronic pain conditions like neuropathy and fibromyalgia (20).Using a rodent model of spinal cord vascular degeneration, theyfound that reduced blood flow in the spinal cord was associatedwith lower concentrations of duloxetine in the tissue, leading todiminished analgesic effects. This study highlights theimportance of considering vascular health when evaluating drugefficacy, particularly for conditions where spinal cord pathologymay play a role. The findings suggest that enhancing vascularperfusion could be a potential strategy for improving the deliveryand effectiveness of analgesic drugs in patients with spinal cord-related pain disorders.Finally, the study by Negus et al. explores the role of mu-opioidreceptor (MOR) agonist efficacy in determining the balancebetween analgesic effectiveness and safety. Opioids are amongthe most potent pain relievers available, but their use is limitedby serious side effects, including respiratory depression, motorimpairment, and gastrointestinal issues (21). Negus et al. used anovel assay of pain-depressed locomotor behavior in mice toevaluate the analgesic and side-effect profiles of opioids withvarying MOR efficacies. Their results showed that intermediate-efficacy MOR agonists, such as buprenorphine, provided effectivepain relief with fewer side effects compared to high-efficacyagonists like fentanyl. This suggests that intermediate-efficacyagonists may offer a promising path forward for developing saferopioid therapies, particularly in managing chronic painconditions. Additionally, the use of pain-depressed behavior asan endpoint highlights the importance of integrating functionalmeasures into preclinical models to assess both the efficacy andsafety of analgesic drugs more holistically.In conclusion, the studies presented in this special issueprovide significant advancements in preclinical pain research. Byrefining animal models and exploring novel behavioral endpoints,these studies contribute to improving the predictive validity ofpreclinical models for analgesic drug development. The findingsunderscore the complexity of chronic pain and the need formultidimensional approaches in both modeling pain andassessing potential treatments. As we continue to develop moresophisticated models and methodologies, these advancements willbe crucial in guiding the development of more effective and saferfrontiersin.orgTappe-Theodor et al. 10.3389/fpain.2024.1523938treatments for chronic pain patients, bridging the gap betweenpreclinical research and clinical application.Author contributionsAT-T: Writing – original draft, Writing – review & editing.TM: Writing – original draft, Writing – review & editing. SN:Writing – original draft, Writing – review & editing.FundingThe author(s) declare financial support was received for theresearch, authorship, and/or publication of this article. Theauthors acknowledge funding to AT-T from the DeutscheForschungsgemeinschaft in the form of a Collaborative ResearchCentre 1158 grant (projects A08).Frontiers in Pain Research 03Conflict of interestThe authors declare that the research was conducted in theabsence of any commercial or financial relationships that couldbe construed as a potential conflict of interest.The author(s) declared that they were an editorial boardmember of Frontiers, at the time of submission. This had noimpact on the peer review process and the final decision.Publisher’s noteAll claims expressed in this article are solely those of theauthors and do not necessarily represent those of their affiliatedorganizations, or those of the publisher, the editors and thereviewers. Any product that may be evaluated in this article, orclaim that may be made by its manufacturer, is not guaranteedor endorsed by the publisher.References1. Mogil JS. Animal models of pain: progress and challenges. 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Editorial: Preclinical animal models and measures of pain: improving predictive validity for analgesic drug development - volume II

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Editorial: Preclinical animal models and measures of pain: improving predictive validity for analgesic drug development - volume II

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