Effects of tramadol via a -opioid receptor on pancreatic ductal adenocarcinoma in vitro and in vivo

IntroductionTramadol, a weak opioid anesthetic, is used for pain management in patients with cancer, but the effects of tramadol on cancer via & mu;-opioid receptor are still unknown. We assessed the effects of tramadol on pancreatic ductal adenocarcinoma using transgenic mice (LSL-Kras(G12D/+); Trp53(flox/flox); Pdx-1(cre/+)). MethodsSix-week-old transgenic mice were orally administered 10 mg/kg/day tramadol (n=12), 10 mg/kg/day tramadol and 1 mg/kg/day naltrexone (n=9), or vehicle water (n=14) until the humane endpoint. Cancer-related pain and plasma cytokine levels were assessed by the mouse grimace scale and cytokine array, respectively. Tumor status was determined histopathologically. Tramadol's effects on proliferation and invasion in pancreatic ductal adenocarcinoma cell lines were studied in vitro. ResultsTramadol with/without naltrexone improved mouse grimace scale scores while decreasing inflammatory cytokines such as tumor necrosis factor-& alpha; and interleukin-6. Proliferative Ki-67 and cyclins decreased by tramadol, while local M1-like tumor-associated macrophages increased by tramadol, which was blocked by naltrexone. Meanwhile, tramadol with/without naltrexone reduced juxta-tumoral cancer-associated fibroblasts and M2-like tumor-associated macrophages. Tumor-associated neutrophils, natural killers, and cytotoxic T cells were not altered. Tramadol decreased the proliferative and invasive potentials of pancreatic ductal adenocarcinoma cell lines via decreasing cyclins/cyclin-dependent kinases, which was partially reversed by naltrexone. ConclusionsThese findings imply that tramadol might be a useful anesthetic for pancreatic ductal adenocarcinoma: inhibiting the proliferation and invasion along with increasing antitumor M1-like tumor-associated macrophages via the & mu;-opioid receptor, while improving cancer-associated pain possibly through the antitumor effects with the decrease of inflammatory cytokines.