JMIR Publications

ABSTRACT

Background:

Visceral diseases often lead to referred pain, but clinical management and treatment development are challenging due to a poor understanding of its underlying mechanisms. Prior preclinical studies have shown that experimental induction of visceral diseases in animal models can cause cutaneous neurogenic inflammation, as assessed by Evans Blue dye extravasation. Neurogenic inflammation is associated with increased pain sensitivity. Thus, these preclinical findings may provide important mechanistic insights into the relationship between visceral diseases and referred somatic pain.

Objective:

The objective of this systematic review is to synthesize evidence on cutaneous neurogenic inflammation and corresponding somatic pain sensitivity in preclinical animal models of visceral diseases, to lay out the current state of knowledge and identify any gaps or limitations to be addressed in future research on this topic.

Methods:

This systematic review will be conducted, following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocol (PRISMA-P) guideline. The literature search will be conducted in MEDLINE (Ovid), Embase, and Web of Science, using search terms related to cutaneous neurogenic inflammation and animal models of visceral diseases. Two investigators will independently screen and select studies meeting the eligibility criteria. For each included study, a predefined template will be used to extract relevant information, including the details of animal species and strains, visceral disease models, outcomes related to the distribution and extent of Evans Blue dye extravasation, and other pertinent findings and methodologies. Quality assessment will be independently performed by two investigators using the Risk of Bias tool from the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE). A summary of the findings will be provided for outcomes related to the distribution of Evans Blue dye extravasation. For outcomes related to the extent of Evans Blue dye extravasation in the control vs. disease animal model and associated pain sensitivity, data will be combined to provide a quantitative synthesis.

Results:

Literature search and screening have been completed. Data extraction and quality assessment are ongoing, and the manuscript is expected to be completed by December 2025.

Conclusions:

Prior preclinical animal studies have investigated cutaneous neurogenic inflammation as a potential mechanistic outcome of referred visceral pain. The proposed review will be the first to summarize research findings and study quality on this topic. This will be an important step towards gaining insights into one of the potential mechanisms underlying referred visceral pain and informing future research in this area. Clinical Trial: This protocol was registered in PROSPERO on February 14, 2024.