Spexin, first discovered in 2007, is also known as the neuropeptide Q . In the CNS of rodents, Spexin was detected in the brainstem, trigeminal ganglia, and brain cortex , which is closely related to nociceptive transmission. This study provided evidence of a negative correlation between serum Spexin levels and painful DPN after adjusting for age, sex, BMI, diabetes duration, HbA1c, 2hPBG, hypertension and smoking or drinking status.
Multiple studies have shown that Spexin plays a role in central pain syndrome. Intraventricular injection of Spexin produced antiinjury effects in a warm water tail withdrawal test in mice . Intra hippocampal CA3 (IHCA3) injection of Spexin reduced pain sensitivity in both the early and late phases of the formalin test in rats . Centrally administered Spexin also produced antinociceptive effects against acute inflammatory pain in the formalin test and visceral pain in the writhing test . All these results indicate the central analgesic effect of Spexin. Mechanically, Spexin activated dynorphin/KOR by Fos pathway . As mentioned before, the pathogenesis of painful DPN is still largely unknown. For the first time, our study suggests that Spexin might play a role in modulating painful DPN, and further research is needed to explore these mechanisms.
Pain as a sensory experience includes nociceptive, inflammatory, and neuropathic pain. Harmful stimuli such as cold, heat, and mechanical stimuli through specific receptors or ion channels, or the release of chemical mediators from locally damaged tissues and inflammatory immune cells, can be converted into electrical activity at the terminals of nerve fiber nociceptors. This electrical activity is transmitted to the dorsal root ganglion and spinal cord, and finally transmitted to the cortex after passing through the central path, and produces the sensation of pain . Functional defects or damage of the peripheral or central nervous system can cause neuropathic pain . M1 macrophages are significantly increased in patients with T2DM and DPN . Macrophages in peripheral or central nerve injury sites or dorsal root ganglia have been shown to be involved in the initiation and maintenance of pain after nerve injury [26,27༌28] through releasing mass proinflammatory mediators and sensitizing sensory neurons. A recent study reported that Spexin reduced M1 macrophage polarization in adipose tissue . It can be postulated that reduced serum Spexin in painful DPN might facilitate the accumulation of M1 macrophages around injury nerve sites.
Although the specific Spexin receptor has not been identified, it is suggested that Spexin could bind and activate galanin receptors . The effects of Spexin on bowel mobility and food intake can be partially blocked by Galanin receptor antagonists [9, 13]. Macrophages express Galanin receptors [31༌32༌33], which participate in the inflammatory response mediated by galanin and its related family members (GALP) [34༌35༌36]. We speculate that Spexin may directly act on nervous system macrophages via binding Galanin receptors to reduce the polarization of macrophages, thereby improving nervous system inflammation and reducing pain sensitivity in patients with DPN, which needs to be further explored.
One of the limitations of this study is the lack of more comprehensive neurophysiological examinations in the diagnosis of DPN, such as quantitative sensory tests and skin biopsy, both of which can be used to diagnose and evaluate small fiber neuropathy. Painful symptoms were assessed applying only NSS, because it well displays the symptoms of specific for painful DPN. Therefore, we believe that NSS is more appropriate in our study. Another limitation is the relatively small cohort size and cross-sectional design. To minimize the impacts of other factors, we had well matched the age and BMI of the three groups of patients. Although the duration of diabetes in the three groups was not matched and was shorter in the group of painful DPN when compared with the group of painless DPN, it should be pointed out that the duration of diabetes is rather long in the subgroup of DPN (P༞0.05), and Spexin indeed reduced in the group of painful DPN. In summary, we accurately stratified the presence of DPN and painful DPN through detailed clinical and neurophysiological assessments of all participants. Further long-term prospective cohort studies or intervention studies are needed to clarify the specific relationship.