Abstract
Translocator protein 18 kDa (TSPO) is an evolutionarily conserved 5-transmembrane domain protein, and has been considered as an important therapeutic target for the treatment of pain. We have recently reported the in vitro and in vivo pharmacological characterization of koumine as a TSPO positive allosteric modulator (PAM), more precisely ago-PAM. However, the probe dependence in the allostery of koumine is an important question to resolve, and the possible analgesic mechanism of koumine remains to be clarified. Here, we report the in vivo evaluation of the allostery of koumine when orthosteric ligand PK11195 was used and preliminarily explore the possible analgesic mechanism of koumine associated with neurosteroids. We find that koumine is an ago-PAM of the PK11195-mediated analgesic effect at TSPO, and the analgesic mechanism of this TSPO ago-PAM may be associated with neurosteroids as the analgesic effects of koumine in the formalin-induced inflammatory pain model and chronic constriction injury-induced neuropathic pain model can be antagonized by neurosteroid synthesis inhibitor aminoglutethimide. Although our results cannot fully clarify the allosteric modulatory effect of koumine, it further prove the allostery in TSPO and provide a solid foundation for koumine to be used as a new clinical candidate drug to treat pain.
Highlights
Gelsemium elegans Benth. is indigenous to Southeast Asia, China (Jin et al, 2014), and was first recorded in the earliest extant pharmaceutical monograph Divine Farmer’s Classic of Materia Medica (Shen Nong Ben Cao Jing) in China
We report the in vivo evaluation of the allostery of koumine when orthosteric ligand PK11195 was used and preliminarily explore the possible analgesic mechanism of koumine
We recently studied the allostery of koumine with Translocator protein kDa (TSPO) in a formalininduced inflammatory pain model, collagen-induced arthritis model and constriction injury (CCI) model in which Ro5-4864 was used (Xiong et al, 2021)
Summary
Gelsemium elegans Benth. is indigenous to Southeast Asia, China (Jin et al, 2014), and was first recorded in the earliest extant pharmaceutical monograph Divine Farmer’s Classic of Materia Medica (Shen Nong Ben Cao Jing) in China. In view of its obvious analgesic effect, the roots and leaves of G. elegans Benth. Alkaloids are the main active ingredients of G. elegans Benth. Clinical studies showed that the parenteral solution of crude alkaloid extraction has a significant analgesic effects on cancerous pain and colic caused by visceral smooth muscle. Koumine is the most abundant alkaloid in G. elegans Benth. With low toxicity (Jin et al, 2014), our previous series of studies showed that koumine has potent analgesic effect and no morphine-like tolerance or dependence. It is of great value to develop koumine as a new candidate drug for pain treatment (Xu et al, 2012; Ling et al, 2014; Qiu et al, 2015; Xiong et al, 2017; Jin et al, 2018a; Jin et al, 2018b; Jin et al, 2021)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
