[Application of three artemisinin derivatives in neuropathic pain: evaluating co-curation of nociceptive and emotional syndromes in spinal cord ligation mice].

In this study, on aspects of the nociceptive, anxiety and depressive syndromes in neuropathic pain (NP), the effects of dihydroartemisinine (DHA), artesunate (ART) and artemether (ARTN) (40 mg·kg⁻¹) were analyzed in the spinal cord ligation (SNL) mice. Clinical equivalent dose of the first-line drug for NP, pregabalin (PGB, 25 mg·kg⁻¹) and amitriptyline (ARP, 20 mg·kg⁻¹), were used as positive controls. General, from day 7 to 14, significant remissions of the nociceptive, anxiety and depressive behaviors were achieved by DHA, ART and ARTN separately. Moreover, on day 14, on aspects of the nociceptive behaviors, analyzed 1.5 h after the gavage administration, no significant difference between the shamed mice and mice administrated with DHA, ART and ARTN was detected; analyzed 3 h after the gavage, significant decreases of pain thresholds in ARTN, but not in DHA nor ART group, were detected as compared with thresholds measured 1.5 h; analyzed 24 h after gavage, pain thresholds in DHA, ART and ARTN were still higher than PGB, in spite of the significant decreases as compared to Sham group. On aspects of the anxiety and depressive behaviors, no significant difference was detected between the shamed mice and mice administrated with DHA nor ART. However, differences still remained between the shamed ones and ones administrated with ARTN. Preliminarily, the effects of DHA, ART and ARTN were consolidated in SNL mice. On aspects of the duration of analgesic effects and the control of negative emotion, ART and ARTN were proven more favorable than ARTN.

The Chinese Medicine Wu-Tou Decoction Relieves Neuropathic Pain by Inhibiting Hippocampal Microglia Activation.

The comorbidity between the nociceptive and mental syndromes adds to the refractoriness of neuropathic pain (NP). Wu-Tou decoction (WTD) has been prescribed for chronic pain for thousands of years in China. Recently, we reported that WTD was helpful for hippocampus and co-curative for the nociceptive, depressive and anxiety behaviors in the spinal cord ligation (SNL) mice. However, the mechanism underlying the rescue of hippocampus, as well as the roles hippocampus assumed in co-curation remain unexplored. In this study, we validated that in SNL mice, the long-lasting damages to limbic system were mainly limited to hippocampus. In addition, hippocampal neurons were proven sensitive to harms induced by microglia and rescued by WTD, which in sum indicated hippocampal microglia as the critical modulator of co-curation. To validate this hypothesis the hippocampal microglia were mal-activated in shamed mice, in which the atrophy of hippocampus and the development of NP syndromes were consolidated and proven rescued by WTD. On the contrary, in the SNL mice, the failure to control hippocampal microglia was sufficient to void all the rescues mediated by WTD. In sum, our study points out that the effective modulation of microglia in hippocampus is of pivotal importance for the co-curation by WTD.

Wu-tou decoction attenuates neuropathic pain via suppressing spinal astrocytic IL-1R1/TRAF6/JNK signaling.

Neuropathic pain (NP) caused by nerve injuries continues to be an intractable challenge due to inadequate therapeutic strategies. Recent study demonstrated glia-induced neuro-inflammation in the spinal cord, especially the activation of astrocytes, plays an essential role in the development of NP, which opens new avenues for NP treatment. In this study, we explored the anti-hyperalgesia properties of Wu-tou decoction (WTD) and showed that WTD potently attenuates mechanical allodynia and heat hyperalgesia in lumbar 5 (L5) spinal nerve ligation (SNL)-induced NP without noticeable side effect or affecting basal pain perception of mice. Mechanistically, initial targets screening tests indicated WTD's analgesic action may be centrally mediated within the spinal cord, which further verified by its inhibitory actions on glia-releasing factors of IL-1ß, CCL2 and CXCL1. Meanwhile, WTD significantly reduced spinal IL-1R1, TRAF6 expressions, p-JNK levels, and number of GFAP/IL-1R1, GFAP/TRAF6, GFAP/p-JNK positive astrocytes in the superficial lamina of spinal cord. Additionally, co-administration of IL-1Ra increased the anti-hyperalgesia effects of WTD and further decreased CCL2 and CXCL1 expressions, while no synergistic effects were detected when TRAF6 or JNK inhibitors were co-administrated with WTD. Thus, our data suggested that the effective inhibition of spinal astrocytic IL-1R1/TRAF6/JNK signaling (especially IL-1R1) contributes, at least in part, to WTD's anti-hyperalgesia action. It also indicates that WTD might be a promising candidate for the treatments of chronic pain, especially under NP-related neurological disorders.

Evidence that CA3 is Underling the Comorbidity Between Pain and Depression and the Co-curation by Wu-Tou decoction in Neuropathic Pain.

In neuropathic pain (NP), the atrophy of hippocampus contributes to the comorbidity between pain, depression and the cognitive deficits. However, the exact mechanism underling the comorbidity, the effective control of the degenerations in hippocampus and the remission of the accompanied depressive symptoms are still lacking. Wu-Tou decoction (WTD) has been prescribed for inflammatory pain for thousands of years. In this study, we manifested the effects of WTD on the pain, depression and anxiety co-curative symptoms of NP. Moreover, we reported that WTD rescued the mal-regulated BDNF and TNF-α in hippocampal CA3 alone, which is proven contributing to the pain and induced psychiatric symptoms. Finally, analysis of biochemistry, morphology and electrophysiology exhibited the potential mechanism of WTD in CA3. We found that, in the late stage of SNL condition, WTD mediated the rescue of the down-regulated glutamate as well as its pre-synaptic vesicular glutamate transporters (VGLuT1) and the post-synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in CA3. In sum, the targeted mediation of glutamatergic system in CA3 suggest that WTD may be responsible for the remission of the hypo-functioned CA3 glutamatergic neurons and further contribute to the co-curative effects of WTD.