Sensory profiling in animal models of neuropathic pain: a call for back-translation

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1. IntroductionThis Topical review considers the misalignment between outcome measures traditionally reported in animal models of neuropathic pain (For brevity, we will adhere to convention and use the shorthand “animal model of neuropathic pain.” However, we suggest that a more accurate classification is in terms of the disease they purportedly mimic [eg, traumatic nerve injury, diabetic neuropathy, etc] rather than as a model of “pain.”) and those used for estimating pain intensity and the impact/burden of pain in clinical trials. In particular, we propose that traditional methods of assessing rodent sensory thresholds could have predictive utility for the sensory profiling approaches being explored for patient stratification in clinical trials. To initiate this process, we propose a “research agenda” to develop and validate a protocol and normative values for sensory profiling in rodents, which reflects the best established clinical methods. This could then be used to establish definitive sensory profiles of new and existing rodent neuropathic pain models.In general, animal modelling of neuropathic pain has 2 main goals: First, to identify pain mechanisms and thus potential targets for drug development. However, it is difficult to identify clear examples of the success of this approach in delivering new drugs for neuropathic pain, with the exception of high concentration topical capsaicin.22 Second, animal models are used in an attempt to predict the clinical efficacy of a novel therapeutic and thus justify the initiation of clinical trials. We concentrate on the latter aspect and ask whether the drug response associated with specific sensory profiles in animal models might predict the most appropriate patients to examine in exploratory clinical trials?2. The problem of homogeneity in current animal models of neuropathic painTo date, animal modelling of neuropathic pain has been dominated by homogeneity in both the models created and outcomes (behavioural constructs) measured in those models. The predominant animal model reported is of traumatic injury to a rodent sciatic nerve. The predominant “pain” outcome measure is limb withdrawal evoked by applied sensory stimuli (in passing, we note that experiments are usually conducted in genetically similar animals, although we do recognise that such homogeneity may be of relevance in the specific context of animal genetic studies. There has also been a tradition of homogeneity of sex and age,36 with the use of young male animals predominating). In contrast to the homogeneity of animal modelling, there is emerging evidence of the importance of clinical heterogeneity in neuropathic pain in terms of underlying disease, clinical presentations, pain mechanisms, and treatment responses at the individual patient level. Recognising such heterogeneity is fundamental to developing the concept of precision (personalised) medicine for neuropathic pain.7 Therefore, we argue that refinement of preclinical methods is required to achieve alignment with emerging concepts of clinical heterogeneity.3. Potential biomarkers to reveal clinical heterogeneity in neuropathic painThere are multiple potential biomarkers that might be hypothesised to predict efficacy of analgesic interventions in neuropathic pain at the individual patient level.58 One example is the prediction of duloxetine efficacy in diabetic neuropathy by measuring endogenous pain modulation.76 Others include symptom and epidermal innervation profiling,3 testing nociceptor function with capsaicin,13 and even ascertaining the characteristics of patient-derived stem cells.14 However, here, we focus on aligning sensory measurements made in animal models with current methods of clinical sensory assessment.4,18,19,27 In this context, we argue that the traditional evoked limb withdrawal outcome measures used in animal models of neuropathic pain should be redeployed as sensory profiling tools.

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