Human surrogate models of central sensitization: A critical review and practical guide

Abstract

Background: As in other fields of medicine, development of new medications for management of neuropathic pain has been difficult since preclinical rodent models do not necessarily translate to the clinics. Aside from ongoing pain with burning or shock-like qualities, neuropathic pain is often characterized by pain hypersensitivity (hyperalgesia and allodynia), most often towards mechanical stimuli, reflecting sensitization of neural transmission. Data treatment: We therefore performed a systematic literature review (PubMed-Medline, Cochrane, WoS, ClinicalTrials) and semi-quantitative meta-analysis of human pain models that aim to induce central sensitization, and generate hyperalgesia surrounding a real or simulated injury. Results: From an initial set of 1569 reports, we identified and analysed 269 studies using more than a dozen human models of sensitization. Five of these models (intradermal or topical capsaicin, low-or high-frequency electrical stimulation, thermode-induced heat-injury) were found to reliably induce secondary hyperalgesia to pinprick and have been implemented in multiple laboratories. The ability of these models to induce dynamic mechanical allodynia was however substantially lower.The proportion of subjects who developed hypersensitivity was rarely provided, giving rise to significant reporting bias. In four of these models pharmacological profiles allowed to verify similarity to some clinical conditions, and therefore may inform basic research for new drug development. Conclusions: While there is no single "optimal" model of central sensitization, the range of validated and easy-to-use procedures in humans should be able to inform preclinical researchers on helpful potential biomarkers, thereby narrowing the translation gap between basic and clinical data. Significance: Being able to mimic aspects of pathological pain directly in humans has a huge potential to understand pathophysiology and provide animal research with translatable biomarkers for drug development. One group of human surrogateThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

During capsaicin‐induced central sensitization, brush allodynia is associated with baseline warmth sensitivity, whereas mechanical hyperalgesia is associated with painful mechanical sensibility, anxiety and somatization

“…Finally, there was no correlation of area of hyperalgesia and area of allodynia within individual after 15 min of capsaicin removal. The development of mechanical hyperalgesia in 63 of the 66 subjects tested and allodynia in 30 of 61 subjects tested corresponds with the previously reported smaller proportion of subjects developing allodynia in experimental pain models (for a comprehensive review; see Quesada et al, 2021). However, information on proportion of healthy subjects developing mechanical hyperalgesia and allodynia in response to human surrogate models of neuropathic pain or capsaicinbased tonic pain models is limited due to reporting inconsistencies and the variety of models used.…”

Chiropractic Spinal Manipulation Prevents Secondary Hyperalgesia Induced by Topical Capsaicin in Healthy Individuals

“…Although central sensitization cannot be measured directly in humans (21), its perceptual correlates have been examined in healthy individuals using experimental pain and in patients with clinical pain (18,22,23). A topical application of capsaicin can evoke secondary hyperalgesia, one of the features of central sensitization that is characterized by hypersensitivity to mechanical pain stimuli beyond the area of capsaicin application (24)(25)(26)(27)(28). Further, capsaicin-induced pain and ongoing clinical back pain induce changes in prefrontal cortex activity (29)(30)(31).…”

Prolonged tonic pain in healthy humans enhances functional connectivity of descending pain modulation networks involving the amygdala, periaqueductal gray and parabrachial nucleus to cortical sensory-discriminative areas

“…Resting state FC of subcortical DPMN-associated structures such the PAG, AMYG and PBN with their cortical targets, as described in this and other recent work, may allow development of novel invasive and non-invasive neuromodulation methods and tracking of objective brain-derived biomarkers in future novel analgesic interventions. It is especially relevant to observe these findings in a large sample size of participants in a pathologically relevant human model of nociceptive central sensitization (Lotsch et al, 2014;Meeker et al, 2019;Meeker et al, 2021;Quesada et al, 2021;Simone et al, 1991). with seed-driven functional connectivity maps of right amygdala complex seed during pain-free state.…”