ZNRD1‐AS and RP11‐819C21.1 long non‐coding RNA changes following painful laser stimulation correlate with laser‐evoked potential amplitude and habituation in healthy subjects: A pilot study

Abstract

Background Non‐coding RNAs (lncRNAs) are a group of non‐coding RNAs that act as regulators of gene expression; they are implicated in various human diseases and have been reported to be involved in the modulation of pain. We aimed to study whether: (a) lncRNAs modifications could be found in an experimental model of pain; (b) there was a correlation between lncRNA changes and laser evoked potential (LEP) amplitude/laser‐pain rating. Methods Laser evoked potentials were recorded from 11 healthy subjects to both left hand and perioral region stimulation. Three consecutive averages were calculated for each stimulation site in order to investigate the LEP amplitude habituation. Blood samples were obtained immediately before LEP recording (pre‐pain) and 30‐min after the recording of the last LEP average (post‐pain). Eighty‐four lncRNAs, involved in autoimmunity and human inflammatory response, were screened. The criteria used for lncRNAs analysis were fold change >2 and p < .05. By Real‐Time PCR, we identified two lncRNAs up‐regulated at the post‐pain time, as compared to the pre‐pain time: RP11‐819C21.1 (fold change = 8.2; p = .038) and ZNRD1 antisense RNA 1 non‐protein coding (ZNRD1‐AS; fold change = 6.3; p = .037). Results The ZNRD1‐AS up‐regulation was directly correlated with the N1 amplitude, while the RP11‐819C21.1 increase after pain showed a correlation with the reduced N2/P2 amplitude and laser‐pain habituation. Conclusion IncRNA changes in a human experimental phasic pain model. The correlation between lncRNA changes and LEP amplitude and habituation suggests that RP11‐819C21.1 and ZNRD1‐AS could be involved in the pathophysiology of painful diseases characterized by abnormal excitability of the cerebral cortex. Significance Long non‐coding RNAs are upregulated after experimental pain. RP11‐819C21.1 and ZNRD1 could be involved in the pathophysiology of diseases characterized by reduced habituation to pain.

The temporal expression of circulating microRNAs after acute experimental pain in humans

“…It is currently unclear whether the changes caused by experimental muscle pain can be identified only in the alteration in a short time (30 minutes) or the effect could include the changes continuing to develop up to 24 hours after the insult. Even though the alteration of miRNA has not been thoroughly investigated in relation to acute pain, a study has evaluated changes in other circulating non‐coding RNA after laser stimulation showing an alteration of these molecules in the serum of healthy participants (Santoro et al, 2020). A recent study has highlighted how alteration of circulating miR‐1 in acute chest pain improves the diagnosis of acute myocardial infarction (AMI) when evaluated at 3 hours from chest pain onset (Su et al, 2020).…”

“…Blood samples were collected at baseline for every participant at 09:00 to avoid normal fluctuations of blood composition molecules. Additional blood samples were collected 30 minutes, 3 hours and 24 hours after the injections, to make sure to avoid a “plateau” effect of the miRNA expressions (Santoro et al, 2020). Samples were not obtained directly after saline injection, to avoid alteration of the pain perception derived from the intervention.…”

Habituation to pain: self-report, electroencephalography, and functional magnetic resonance imaging in healthy individuals. A scoping review and future recommendations

“…Habituation of the N2-P2 amplitude was shown to be affected by a genotype involved in monoaminergic activity and regulators of gene expression. 19,84 Age effects on the N2-P2 amplitude showed an increase in habituation over several groups between 18 and 72, although there were no differences between the groups after a Bonferroni correction. 17 Another study reported a decrease in the N2-P2 amplitude in participants between 50 and 70 compared with young subjects (mean age 5 24.9 years).…”

Circulating long non-coding RNA signature in knee osteoarthritis patients with postoperative pain one-year after total knee replacement

“…Studies show how lncRNA are involved in several physiological and pathological processes acting in different pathways on several genes at transcriptional, post-transcriptional, and epigenetic levels [31,32]. Moreover, LncRNA have been associated with responses to experimental pain [20,22,[33][34][35] and has been suggested as a new target for future pain therapies [36,37]. Previous studies have been looking deeply at the expression of different RNA and ncRNA in relation to the pathophysiology of OA [38,39].…”

“…Moreover, Fu and colleagues showed variable expression of lncRNA in the cartilage of OA patients, demonstrating upregulation of a specific lncRNA, uc.343, that acts on genes implicated in the development of cartilage, leading to a cartilage disruption and faster progression of OA [21]. In a human experimental phasic pain model two lncRNA, such as ZNRD1-AS and RP11-819C21.1, were up-regulated and directly correlated with features of the laser evoked potential suggesting that lncRNA could be involved in abnormal excitability of the cerebral cortex in relation to pain [22].…”