Microglial activation is increasingly recognized as a critical contributor to both the initiation and chronification of migraine. Recent advances have highlighted the importance of receptor-mediated signaling pathways in regulating microglial responses; however, their integrated role in central inflammation remains insufficiently characterized. This review aimed to evaluate the mechanistic involvement and therapeutic relevance of microglial receptors in chronic migraine. A comprehensive systematic search was conducted in PubMed, Web of Science, and Scopus to identify studies investigating the mechanisms or effects of microglial receptors in chronic migraine models. Methodological quality and risk of bias were assessed using the CAMARADES checklist and the SYRCLE risk-of-bias tool. Quantitative outcomes, including calcitonin gene-related peptide (CGRP) relative density, Iba-1 immunoreactive cells, paw withdrawal latency, periorbital mechanical threshold, and paw mechanical threshold, were analyzed using Review Manager 5.4. Meta-analyses were performed using fixed-effects or random-effects models based on the degree of heterogeneity. A total of twelve studies met the inclusion criteria. Among these, five studies investigated purinergic P2 receptors, two focused on GLP-1R, and one study each examined TREM1, TREM2, S1PR1, TLR2, and CB2R, encompassing ten distinct microglial receptors. Compared with the nitroglycerin (NTG) control group, receptor-targeted interventions significantly attenuated acute thermal and mechanical hyperalgesia (all p < 0.00001). In addition, these interventions were associated with reduced CGRP expression and a decreased number of Iba-1-positive microglial cells, indicating suppression of neuroinflammatory activation. Notably, substantial heterogeneity was observed in the analysis of Iba-1 immunoreactive cells (I² = 87%), and its source could not be clearly identified despite sensitivity analyses. Overall, the included studies demonstrated moderate-to-high methodological quality; however, the limited number of studies precluded a formal assessment of publication bias. Despite the limited number of available studies, the present findings support the hypothesis that microglial receptors represent promising therapeutic targets in chronic migraine. The data further suggest that modulation of a single receptor pathway may be insufficient, given the complexity and interconnectivity of microglial signaling networks. Future investigations should focus on elucidating receptor-specific mechanisms and the interactions among downstream signaling pathways to inform the development of more effective, multi-target therapeutic strategies. This study was prospectively registered in PROSPERO (CRD420251112473). Not applicable.
Lin et al. (Mon,) studied this question.