Exploring the roles of neuropeptides in trigeminal neuropathic pain: A systematic review and narrative synthesis of animal studies

•Neuropeptides have a role in the pathophysiology of trigeminal neuropathic pain.•Animal models that better mirror clinical phenomena are needed.•Nociception assays exclusive to neuropathic pain should be considered.•Future studies should comply with reporting guidelines to improve research quality. This systematic review aims to explore the changes in expression of neuropeptides and/or their receptors following experimental trigeminal neuropathic pain in animals. MEDLINE, Embase, and Scopus were searched for publications up to 31st March 2021. Study selection and data extraction were completed by two independent reviewers based on the eligibility criteria. The quality of articles was judged based on the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) risk-of-bias tool. A total of 19 studies satisfied the eligibility criteria and were included for narrative synthesis. Methods of trigeminal neuropathic pain induction were nerve ligation, nerve compression/crush, nerve transection and dental pulp injury. Animal behaviours used for pain verification were evoked responses to mechanical and thermal stimuli. Non-evoked behaviours, including vertical exploration, grooming and food consumption, were also employed in some studies. Calcitonin gene-related peptide (CGRP) and substance P were the most frequently reported neuropeptides. Overall, unclear to high risk of bias was identified in the included studies. Limited evidence has suggested the pro-nociceptive role of CGRP in trigeminal neuropathic pain. In order to further translational pain research, animal models of trigeminal neuropathic pain and pain validation methods need to be optimised. Complete reporting of future studies based on available guidelines to improve confidence in research is encouraged.