Pain is an aversive sensory and emotional experience typically caused by, or resembling, an actual or potential tissue injury (Raja et al., 2020). It often manifests as a comorbidity with various clinical complaints, including sensory discomfort, emotional disorders, cognitive impairment, and even social or family problems, causing significant distress to patients and their families (Raja et al., 2020; Zhang X. et al., 2023). Pain generation, progression, and management mechanisms have been extensively studied both macroscopically and microscopically.

MicroRNAs (miRNAs) are a class of small non-coding RNAs that can target numerous protein-coding genes and are involved in the evolutionary and pathological progression of animals and humans. By controlling post-transcriptional gene expression, miRNAs are involved in various diseases (Saliminejad et al., 2019). Many studies have revealed that miRNAs can modulate pain, with many miRNAs being upregulated or downregulated in response to tissue or nerve injury (Morchio et al., 2023; Tao et al., 2023; Vali et al., 2023). This modulation affects target miRNAs, either suppressing or promoting pain generation. These findings demonstrate that targeting miRNAs could be an essential pathway in pain pathophysiology and therapeutics (Zhang X. et al., 2023; Saliminejad et al., 2019; Lopez-Gonzalez et al., 2017; Vali et al., 2023; Sakai and Suzuki, 2015; Tao et al., 2018). Nevertheless, the articles or reviews rarely present an intuitive and visual mapping of the research trends and highlights in this specific field.

Visualized bibliometric analysis is a novel and efficient method for providing an understandable review of prominent publications over a specific period (Chen et al., 2014). A recently published bibliometric analysis of the global study trends on neuropathic pain and epigenetics focused on the extensive function of genetics. It revealed some information and frontiers in epigenetics and neuropathic pain, especially DNA methylation, circular RNA, acetylation, and long non-coding RNA. However, a minuscule portion was associated with miRNA and the retrieve keyword mainly centered on all types of neuropathic pain (Zhu et al., 2023). The literature on pain and miRNA has been rapidly increasing, but no systematic review of these publications has yet been conducted. Therefore, this study systematically reviewed publications to explore the development of this field, reviewed key publications, assessed current research focus, forecasted future trends, and provided an overview for researchers.

We conducted a bibliometric analysis of scientific publications on the relationship between miRNA and neuropathic pain globally since 2000. Numerous articles have been published, and literature production kept a yearly growth, reflecting notable advances that have been made in understanding the relationship between miRNA and pain over the past two decades. Also, the establishment of extensive collaboration among different countries, and worldwide authors indicated an increase in global scientific concerns on the exploration of pain mechanisms.

The top three most frequently occurring keywords were “expression,” “neuropathic pain,” and “micro RNA,” which indicated that neuropathic pain was the most widely used disease model for the research of micro RNA and pain. The expression level of some microRNAs might be involved in the development and persistence of neuropathic pain. It’s widely known that miRNA plays a crucial role in post-transcriptional gene regulation and has demonstrated its potential value in pain progression and prognosis, including chronic, inflammatory, and neuropathic pain (Lopez-Gonzalez et al., 2017; Sakai and Suzuki, 2015).

Indeed, the revealed pain mechanisms have suggested a close relationship between miRNAs and the proteins or genes they regulate (Tao et al., 2018; Sakai and Suzuki, 2015; Jiangpan et al., 2016; Zhang et al., 2021; Hao et al., 2022; Zhang et al., 2020; Pan et al., 2018; Phạm et al., 2020; Favereaux et al., 2011; Tan et al., 2015). For instance, Zhang et al. (2021) discovered that miRNA-107 contributes to inflammatory pain by downregulating GLT-1 expression. Hao et al. (2022) discovered that the miRNA-22-Mtf1 signaling axis in the dorsal horn is critical for inflammatory pain progression. In neuropathic pain, which was the second most frequently occurring keyword, several novel miRNAs have been identified in recent years (Morchio et al., 2023). miRNA-103 was the first well-characterized miRNA in this field (Favereaux et al., 2011). Researchers discovered that subunits with Ca V 1.2 L-type calcium channels directly targeted miRNA-103. Calcium transient modulation was also observed in cultured spinal neurons, and altering the level of miRNA-103 expression altered pain behaviors (Favereaux et al., 2011). miRNA-128-3p was demonstrated to alleviate neuropathic pain by targeting ZEB1 through neuroinflammation inhibition (Zhang et al., 2020). MiRNA-155, which regulates inflammation-associated diseases, was upregulated, with its inhibition suppressing proinflammatory cytokines expression in the spinal cord of a CCI neuropathic pain rats model (Tan et al., 2015). miRNA-23a was identified to regulate neuropathic pain via TXNIP/NLRP3 inflammasome axis by directly targeting CXCR4 in a partial sciatic nerve ligation mouse model (Pan et al., 2018). Phạm et al. (2020) discovered that miRNA 146a-5p-encapsulated nanoparticles alleviate pain behaviors by inhibiting various inflammatory pathways in spinal microglia and reducing proinflammatory cytokine release. In the animal pain model, some experiments demonstrated that functional manipulation of miRNAs can suppress pain-related behavior in various pain diseases. Although these findings presented an extensive and dynamic change in microRNA expression in different pain models or animal studies, the strong relationship between pain development and miRNA changes was highlighted. This makes some promising miRNAs potential therapeutic molecular targets for pain medication for the high conservation of miRNAs and their target sequences among species (Sakai and Suzuki, 2015).

Similarly, researches were also conducted on humans suffering from pain disease and uncovered the biomarker potential of miRNA. Mari et al. (2019) found that miRNA-320 and miRNA-98 derived from circulating plasma were proven to successfully classify the pain type patients suffering in 70% of the cases. The circulating miRNA-320 was demonstrated to be responsible for post-traumatic pain by Linnstaedt et al. (2018). In our current visualized bibliometric study, further analysis of the most cited papers was performed, and we found that microRNA-21, miRNA-146a, miRNA-155, and miRNA-939 from peripheral were extensively studied in pain research for the critical role of inflammatory pain and neuropathic pain (Sommer et al., 2017; Ramanathan et al., 2019). Besides, spinal microglia-derived miRNA-124 and miRNA-155 were identified to serve critical roles in neuropathic pain (Tang et al., 2021). These promising microRNAs share the role of biomarkers in chronic pain in basic research. However, as for the application of miRNAs in clinical trials or pain management, it must be acknowledged that there is still a long way to go and some major obstacles and barriers remain before miRNA or its targeted gene is used as a medication, which the drug delivery strategy and the specificity of microRNA are the greatest barriers (Lopez-Gonzalez et al., 2017). To do so, the employment of viral vectors, as well as the incorporation of cholesterol molecules into a miRNA depressant or the sense strand of a miRNA mimic has been demonstrated to be efficacious strategies (Lopez-Gonzalez et al., 2017). Recently, packaging miRNA into extracellular vesicles, such as exosomes, proved to be a novel maneuver and could be potentially used as a candidate analgesic method (Zhang L. et al., 2023; Ramanathan et al., 2019; DaCunza et al., 2024; Kumar et al., 2024). Besides, more highly specified miRNAs and human tissue-derived miRNA data are warranted among the numerous candidates. Whatever, these studies, together with our current visualized analysis highlight the significance of miRNA in pain and show the direction of pain research in the future.

Our bibliometric analysis generated another interesting finding, which revealed that Chinese researchers contributed the most productions to the publications about pain and miRNA. Our study uncovered that 80% of the top 10 productive organizations and the top 3 most prolific scientists were from China. These findings were consistent with the comment in Nature, which noted that China has surpassed the United States in the total number of scientific publications, becoming the largest global producer of scientific articles (Tollefson, 2018). According to the recently announced Global Research Pulse report from Springer Nature (Springer Nature. 2024, August. China Impact Report), China is now the largest contributor to global research output. The production of scientific research is tightly related to the economic level of a country. China is world’s second-largest economy. In 2015, the Chinese government allocated about $400 billion to research and development, with this investment continuing to grow (Tollefson, 2018), among which, Natural Science Foundation of China (NSFC) provided great funding and basic research assistance from the national level. Significant national funding and support have encouraged a growing number of researchers to explore basic medicine and promote the achievement of international cooperation. A deep-going retrieve of the most productive author’s publications revealed that the top 1 ranked author Y. Zhang and his team established extensive collaboration with several internationally renowned hospitals or institutes, such as the East Tennessee State University, Henry Ford Hospital, and the Department of Physics Oakland University (Jia et al., 2018; Qiu et al., 2015). Extensive international exchanges and cooperations and the collaborative and open research environment would promote the launch of more innovative and comprehensive global research.

Our bibliometric study utilizes multiple visualized tools, including R language, bibliometric website, VOS viewer, and CiteSpace software, and fully uncovered the global tendency of research on the relationship between miRNA and pain by analyzing the number of publications, keywords, author data, countries, institutions, collaborations, citations, etc. The number of publications kept a steady growth, reflecting an increasing interest in and exploring the relationship between miRNAs and pain. Keywords analysis indicates that “expression,” “neuropathic pain,” and “microRNA” were the most frequently occurring words in this research field. Authors from China contributed to most publications. Among them, Yi Zhang was the most productive researcher. However, papers from prestigious journals were sparsely searched. More robust and globally recognized basic studies and clinical trials from renowned journals are demanded.