Animal models of pain: Diversity and benefits
Introduction
Pain is a vital physiological function that protects organisms against potential damage. Acute nociceptive pain is a normal function of the nervous system that provides important sensory information about the environment and reacts to harmful stimuli such as noxious heat, extreme cold, chemical irritants, and mechanical tissue damage. These noxious stimuli activate peripheral nociceptors, triggering action potentials that propagate along sensory axons to the dorsal horn of the spinal cord where nociceptive inputs are processed and relayed to the brain. In turn, the activation of specific brain areas produces a broad array of sensory, emotional, autonomic, and motor responses that shape our experience and perception of pain (Basbaum et al., 2009; Burma et al., 2017).
In contrast to acute pain, chronic pain is a maladaptive disease that heightens the sensitivity to sensory stimulation (Woolf and Salter, 2000; Costigan et al., 2009). Chronic pain results from abnormal functioning of the nervous system, with pain persisting far beyond the resolution of the primary injury. Pain hypersensitivity manifests as spontaneous pain (pain in the absence of an external stimulus), allodynia (pain resulting from an innocuous stimulus), and/or hyperalgesia (an exaggerated pain response to a noxious stimulus). Chronic pain is a major health problem that negatively impacts the quality-of-life of sufferers and exacts enormous socio-economic costs with a prevalence of around 8 % of the general population (Bouhassira et al., 2008). In the European Union, it is estimated that 20 % of the population would suffer from chronic pain during lifespan (Breivik et al., 2006; Alshami, 2014), and it is among the most significant risk factors for suicide.
Chronic pain drastically diminishes quality of life and causes enormous socio-economic costs. Besides high costs for disease management, chronic pain is associated with major impacts on daily activities and quality of life (Groenewald and Palermo, 2015) and high productivity losses due to work absences (Mayer et al., 2019) partly due to common co-morbidities such as depression (Phillips, 2006). The estimated direct and indirect healthcare costs for chronic pain disorders in European Member States vary between two and three percent of GDP across the EU (Breivik et al., 2013). For 2016, this estimate would result in up to €441 billion. In the USA, ∼100 million people suffer from pain costing ∼$600 billion/year in health care and lost productivity (Walker et al., 2014). These costs are reported to exceed those estimated for heart disease, cancer and diabetes (Breivik et al., 2013). However, chronic pain is poorly managed with treatment success rates around 30 % (Ossipov et al., 2014), mainly because chronic pain mechanisms remain poorly understood (Basbaum et al., 2009; Dolique et al., 2010; Cordero-Erausquin et al., 2016; Kuner and Flor, 2016), and patients often suffer from comorbid disorders such as anxiety and depression (Attal et al., 2011).
It is important to recognize that there is not one overarching, singular condition called chronic pain but rather, there are multiple aetiologies of pain, each resulting from different pathologies and differing in the clinical presentation of signs and symptoms (Burma et al., 2017). Pain is usually subdivided in different categories as a function of the mechanism of injury. Nociceptive pain represents the normal response to noxious insult or injury of tissues such as skin, muscles, visceral organs, joints, tendons, or bones. Inflammatory pain results of activation and sensitization (peripheral and/or central) of the nociceptive pain pathway by a variety of mediators released at a site of tissue inflammation. Neuropathic pain arises from damage to the nervous system itself, central or peripheral, either from disease, injury, or pinching. Other types of pain were characterized, e.g. cancer pain or dysfunctional pain when no biological cause is identified. To address differences in the presentation of pain symptoms across chronic pain conditions, an array of preclinical animal models has been developed to recapitulate the underlying pathology, duration, and comorbidities of pain phenotypes (Mogil, 2009). This variety of preclinical pain models is essential for understanding the molecular and cellular mechanisms that underlie distinct pain conditions. The development of novel and more efficacious therapies requires a thorough understanding of the mechanistic underpinnings of chronic pain and the design and testing of new drugs.
Rodents are employed in an large majority of preclinical pain studies (Mogil, 2009). However, the use of alternate vertebrates and invertebrates, such as zebrafish, fruit flies (Drosophila sp.) and nematodes (Caenorhabditis elegans) can also be advantageous for screening assays and for studying the genetic and molecular mechanisms of acute and chronic pain (Way and Chalfie, 1989; Gonzalez-Nunez and Rodríguez, 2009; Milinkeviciute et al., 2012). Each organism confers a distinct advantage for studying pain; the behavioral complexity of the rodents allows the analysis of the affective components of pain (Johansen et al., 2001; Panksepp and Lahvis, 2011), whereas simpler organisms, such as Drosophila, can facilitate the discovery of novel molecular players involved in the detection of noxious stimuli (Caldwell and Tracey, 2010; Mogil et al., 2010).
Another important aspect for designing animal models is to recognize that pain is a multi-dimensional experience. Indeed, pain is processed not only at the peripheral and spinal levels, but also in higher brain structures including cortical areas underlying the affective component of pain (Liu and Chen, 2014). As pain transitions from acute to chronic and becomes pathological, the associated negative emotional state not only exacerbates sensory modalities, but also worsens the comorbidities. Indeed, anxiety is a highly common comorbidity of pain where the interactions between pain and anxiety have been demonstrated in human. In addition, chronic pain and depression are complex disorders that often coexist and increase the risk of one another (Radat et al., 2013; Steel et al., 2014; Zhu et al., 2018a). Investigations of pain and psychiatric disorders are mostly conducted separately, but more knowledge of the overlap and interactions between affective and pain circuits is key to better treatments. Refined analysis of animal models of pain and depression has become mandatory to understand interactions between pain and emotional comorbidities (Kremer et al., 2020).
The present review proposes an overview of rodent and alternate models of pain. A large panel of evaluation devices used to characterize pain-like behavior in animal models has been developed over the years, and a summary description of these tools is presented here. The review focuses mainly on the broadly studied neuropathic and inflammatory types of pain. It also highlights the necessity of specific procedures dedicated to studying emotional comorbidities to pain. Finally, it summarizes the main limitations of using animal models to mimic clinical pain in humans, but also provides examples of successful translational applications of using animal models.
Section snippets
Assessment of pain
The classical pain evaluation devices aim to assess the sensory component of pain, usually by measuring a withdrawal reflex. However, more recently, specific efforts have been made to assess pain perception and to evaluate the emotional component of pain and comorbid affections. Unlike humans, animals are incapable of verbally describing pain, therefore a battery of behavioral tests has been developed in order to assess pain-like behavior in animals. These assays can be divided into
Models of inflammatory pain
Two important parameters to be considered in animal models of pain are the method of injury and the endpoint measurement. The most appropriate models, whether an injury, application of chemical agents, or other manipulations, should be based on 1) understanding the clinical disease presentation and pathology (i.e. face validity); 2) producing nociception by recapitulating the mechanisms of specific clinical conditions (i.e. construct validity). Measures of nociceptive behavior must not only
Models of migraine pain
Migraine has not classically been considered an inflammatory disease probably because it is not obviously associated with heat, redness, and swelling. Instead, a vascular aetiology was proposed and the prevailing theory of migraine for most of the twentieth century, held that pain results from an abnormal dilatation of intracranial blood vessels, leading to mechanical excitation of sensory fibers. However, in recent years, advancements in the neurobiology of migraine headache have shifted the
Models of neuropathic pain
Neuropathic pain (NP) is a painful syndrome caused by central or peripheral lesion of the nervous system. It is highly disabling, affecting 7–8 % of general population (Bouhassira et al., 2008). NP elicits sensory alteration including dysesthesia and paresthesia, spontaneous pain, increase pain sensation for innocuous stimuli (allodynia) and increase pain sensation for noxious stimuli (hyperalgesia). Animal models of NP are developed, mainly in rodents, to recapitulate one or several symptoms
Models of cancer pain
Several mammalian and non-mammalian animal models have been developed to improve our understanding of cancer biology (Schachtschneider et al., 2017). However, cancer pain, which is experienced by human patients and animals in advanced stages of cancer, has only been addressed in some of these models.
Immunocompromised and immunocompetent rodents (mouse and rat) are commonly used to study cancer pain. Because of its large size, rat model is better suited for manipulations and injections into
Models of visceral pain
Visceral pain includes pain emanating from organs localized into the thoracic, pelvic and abdominal regions. This type of pain is poorly localized, often affecting two or more visceral organs. In particular, gastrointestinal (GI) pain is common in various disorders including irritable bowel syndrome, inflammatory bowel diseases (IBD) (Crohn’s disease and ulcerative colitis), pancreatitis, kidney stones, biliary disorders or associated with cancer. Several factors have been identified as
Models of musculoskeletal pain
Similarly to cancer pain or visceral pain, muscle pain results in a diffuse, aching pain that contrasts with sharp and localized cutaneous pain. Models specific to studying muscle pain are scarce in the literature although muscle pain is a major clinical problem. Indeed, musculoskeletal pain is a chronic widespread pain manifestation that affect between one quarter and one third of the US population (Gaskin and Richard, 2012). In chronic conditions like lowback pain, myositis, myofascial pain,
The particular case of non-human primates
Although rodents are mammals, their behavior and the organization of their nervous system remains different from humans. In contrast, studying pain in non-human primates offers the opportunity to investigate mechanisms, and response to analgesic treatment, that are close to what is expected in humans. However, using non-human primates undoubtedly poses acute ethical problems and little exploration of pain-related mechanisms has been done in non-human primates as compared to rodent.
Few attempts
Pain models in simple organisms
To reduce the use of rodents in pain studies and carry out high-throughput screening studies, new models have started to appear in pain research, using lower vertebrate species such as zebrafish or Xenopus and invertebrates such as Drosophila and Caenorhabditis elegans (C. elegans).
The shared advantages of these models reside in their simplicity of use including low cost and easy maintenance, large brood and egg size and rapid external development. They are genetically similar to humans and
Limitations of animal models of pain
The study of pain always relied on preclinical animal models that attempted to explore the complex physiological and sensory implications of the condition. Various animal models of chronic pain aim to emulate different types of pain and they have been instrumental in the discovery and development of analgesic agents. While there is no doubt about the necessity of such models in chronic pain research, there are several limitations to their use. This is especially true when considering their
Translational lessons learned from animal model studies
Translation is defined by the National center for advancing translation science as “the process of turning observations in the laboratory, clinic, and community into interventions that improve the health of individuals and populations – from diagnostics and therapeutics to medical procedures and behavioral interventions” (Nakao, 2019). It is worth noting that despite the aforementioned limitations, a growing number of examples demonstrate the potential to convert new agents into widely used
Conclusion
Animal models of pain were historically viewed as reliable tools that have served to advance research in the field over the past decades. They have been instrumental in constructing a global picture of how key proteins, signalling systems, and neural circuits contribute to pain-like behaviors. However, there are limitations and caveats to these models that must be acknowledged when considering the translation of research findings from the bench to the bedside. There is not one “best model” for
CRediT authorship contribution statement
Cynthia Abboud: Writing - original draft. Alexia Duveau: Writing - original draft. Rabia Bouali-Benazzouz: Writing - original draft. Karine Massé: Writing - original draft. Joseph Mattar: Writing - original draft. Louison Brochoire: Writing - original draft, Writing - review & editing. Pascal Fossat: Writing - original draft. Eric Boué-Grabot: Writing - original draft. Walid Hleihel: Funding acquisition, Supervision, Writing - original draft. Marc Landry: Funding acquisition, Supervision,
Declaration of Competing Interest
The authors declare they have no competing interests.
Acknowledgements
This work is supported by an ANR grant (Relax, n° 193992). CA is the recipient of a scholarship from the CNRSL (Lebanon). We thank Dr. Najib NAJJAR, Adjunct Instructor at Holy Spirit University of Kaslik – USEK, Chairperson at American University of Technology – AUT, for English language editing.
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