Effect of spirocyclopiperazinium salt compound LXM‐15 on spinal nerve injury in rats

Abstract Background Currently available therapies for neuropathic pain show limited efficacy. This study aimed to investigate the anti‐nociceptive effect of the spirocyclopiperazinium salt compound LXM‐15 in spinal nerve ligation (SNL) rats and to explore the potential mechanisms. Methods Mechanical allodynia and thermal hyperalgesia tests were used to evaluate the effects of LXM‐15 in SNL rats. The expression of CaMKIIα, CREB, JAK2, STAT3, c‐fos and TNF‐α was detected by western blotting, ELISA or qRT‐PCR analysis. Receptor blocking test was performed to explore possible target. Results Administration of LXM‐15 (1, 0.5, 0.25 mg/kg, i.g.) dose‐dependently attenuated mechanical allodynia and thermal hyperalgesia in rats subjected to SNL ( p < 0.01, p < 0.05), and the effects were completely blocked by peripheral α7 nicotinic or M4 muscarinic receptor antagonist ( p > 0.05). LXM‐15 significantly decreased the overexpression of phosphorylated CaMKIIα, CREB, JAK2 and STAT3 proteins and the mRNA levels of TNF‐α and c‐fos ( p < 0.01, p < 05). All of the effects could be blocked by α7 or M4 receptor antagonist. Furthermore, LXM‐15 reduced the protein expression of TNF‐α and c‐fos ( p < 0.01, p < 0.05). No significant acute toxicity or abnormal hepatorenal function was observed. Conclusions This is the first study to report that LXM‐15 exerts significant anti‐nociceptive effect on SNL rats. This effect may occur by activating peripheral α7 nicotinic and M4 muscarinic receptors, further inhibiting the CaMKIIα/CREB and JAK2/STAT3 signalling pathways, and finally inhibiting the expression of TNF‐α and c‐fos. Significance Existing treatments for neuropathic pain show limited efficacy with severe adverse reactions. This paper is the first to report that LXM‐15, a new spirocyclopiperazinium salt compound, exerts a significant anti‐nociception in SNL rats without obvious toxicity. The underlying mechanisms include activating peripheral α7 nicotinic and M4 muscarinic receptors, then inhibiting the signalling pathways of CaMKIIα/CREB and JAK2/STAT3 and the expressions of TNF‐α and c‐fos. This study sheds new light on the development of novel analgesic drugs with fewer side effects.