Levo-Tetrahydropalmatine Retards the Growth of Ectopic Endometrial Implants and Alleviates Generalized Hyperalgesia in Experimentally Induced Endometriosis in Rats

Abstract

One primary goal of medical treatment of endometriosis is to alleviate pain and there is a pressing need for new therapeutics for endometriosis with better efficacy and side-effect profiles. Levo-tetrahydropalmatine (l-THP) has been used as a sedative or analgesic for chronic pains in China since 1970s. In this study, we sought to evaluate the efficacy of l-THP, with or without valproic acid (VPA), in a rat model of endometriosis. We surgically induced endometriosis in 55 adult female rats. Two weeks after, all rats were further divided into 5 groups randomly: untreated, low- and high-dose of l-THP, VPA, and l-THP + VPA. Response latency in hotplate test was measured before the surgery, before and after 3-week treatment of respective drugs. All rats were then sacrificed for analysis. The average lesion size and the immunoreactivity to N-methyl-d-asparate receptor 1 (NMDAR1), acid-sensing ion channel 3 (ASIC3), calcitonin gene-related peptide (CGRP), c-Fos, tyrosine kinase receptor A (TrkA), and histone deacetylase 2 (HDAC2) in dorsal root ganglia (DRG), to phorphorylated p65, HDAC2, TrkA, and CGRP in ectopic endometrium and to phorphorylated p65 and CGRP in eutopic endometrium were evaluated. We found that rats receiving l-THP, with or without VPA, had significantly reduced lesion size and exhibited significantly improved response to noxious thermal stimulus. The treatment also significantly lowered immunoreactivity to all mediators involved in central sensitization and to HDAC2 in DRG, to TrkA and CGRP in ectopic endometrium, and to CGRP in eutopic endometrium. In summary, l-THP reduces lesion growth and generalized hyperalgesia. Thus, l-THP may be a promising therapeutics for endometriosis.