Postherpetic neuralgia (PHN) is the most common sequela of herpes zoster (HZ), which can be diagnosed if the neuralgia lasts more than 3 months after HZ healing (2019). PHN is a typical neuropathic pain (NP) (Lee et al., 2020), and effective medicine is still lacking (Snedecor et al., 2014; Wen et al., 2021). Previous studies reported that PHN may be related to skin abnormality during and after herpes zoster. For example, postherpetic scar is correlated with PHN severity (El Hayderi et al., 2018). Reduction of intradermal nerve fiber endings in patients with PHN has been widely reported (Truini et al., 2015). Therefore, some scholars think that PHN may be a “phantom-skin” pain associated with loss of nociceptors (Oaklander, 2001). Besides, Abdo et al. find that subcutaneous sensory nerve endings (unmyelinated nerve fibers) and skin glial cells (Schwann cells) can form a unique pain sensing organ of the skin (Abdo and Calvo-Enrique, 2019), which is affected by singles breakout in the epidermis. This is maybe the reason of PHN. Some researchers believe that the mechanism of PHN may be related to the increase of spontaneous discharge of peripheral nerves in the skin (Devor, 2018). Therefore, the pathological changes of nerve endings in the epidermis may be involved in PHN. It has been reported that GluA4 in keratinocytes may be related to PHN (Cabanero et al., 2016). By using cytokine array, we detected 21/40 cytokines in PHN skin. However, only interleukin-1α showed differential expression between PHN skin and normal mirror skin (Cao et al., 2020).

MicroRNA (miRNA) is a non-coding RNA with regulatory function, which inhibits the function of the target genes mainly by binding to them. Currently, a number of therapies based on miRNA have been applied to clinical trials (Esrick et al., 2021; Hong et al., 2020). Bai et al. (2007) first reported the differential expression of miRNA in mice with inflammatory pain in 2007. Chronic compression injury (CCI) causes abnormal expression of miRNA in spinal cord of rats (Cao et al., 2019b; Tan et al., 2015). Besides, different expression profiles of serum miRNAs between HZ and PHN patients have been reported, five different miRNAs of which may be involved in the transformation of HZ to PHN (Huang et al., 2017). In one of the PHN-mimic models, i.e, the resiniferatoxin (RTX) induced rat with PHN-mimic symptoms, electroacupuncture treatment affected the miRNA expression in the spinal cord, which could be the reason of its analgesic effect (Zou et al., 2019). These data suggest that miRNAs are essential for the pathology of neuropathic pain, including PHN.

It is feasible and effective to intervene miRNAs in skin (Jiang et al., 2022; Singhvi et al., 2018). Animal studies have shown that interfering the expression of miRNAs in skin affects the prognosis of diseases (Ban et al., 2020; Yu et al., 2020). For example, intradermal injection of lentivirus encoding miRNA reduced the inflammatory pain in rats (Liu et al., 2017). Injecting agomir of miR-129 and/or miR-335 into the wound edge of diabetic rats accelerated wound healing (Wang et al., 2018). In mouse trauma model, the expression of miR-21 was up-regulated, while local injection of antagomir-21 weakened the collagen deposition and reduced wound-healing effects of miR-21 (Wang et al., 2012). In summary, interfering the expression of miRNAs in the affected skin of PHN patients is a potential therapeutic strategy.

In this study, we found that compared with normal mirror skin, 317 differential miRNAs were found in the PHN skin in patients with PHN more than one month (Cao et al., 2019c). To further investigate the effects of differential miRNAs on PHN, we selected 19 candidate miRNAs and verified in PHN patients with PCR. Later, the expressions of differential miRNAs were verified in RTX mice, and the expression trends of miR-16–5p and let-7a-5p were consistent with those in the skin of PHN patients. Plantar injection of miR-16–5p agomir (agomir-16–5p) alleviated PHN-mimic symptoms in mice. Meanwhile, local injection of agomir-16–5p down-regulated the expression of Akt3 mRNA and protein. This study indicates that interfering the expression of miRNA in the plantar is effective in RTX mice, which provides a new clue for the clinical treatment of PHN.