ABSTRACT
G (1-5)-NH2, G (1-7)-NH2, and G (1-9) are the active fragments of ghrelin. The aim of this study was to investigate the antinociceptive effects, their ability to cross the blood-brain barrier, and the receptor mechanism(s) of these fragments using the tail withdrawal test in male Kunming mice. The antinociceptive effects of these fragments (2, 6, 20, and 60 nmol/mouse) were tested at 5, 10, 20, 30, 40, 50, and 60 min after intravenous (i.v.) injection. These fragments induced dose- and time-related antinociceptive effects relative to saline. Using the near infrared fluorescence imaging experiments, our results showed that these fragments could cross the brain-blood barrier and enter the brain. The antinociceptive effects of these fragments were completely antagonized by naloxone (intracerebroventricular, i.c.v.); however, naloxone methiodide (intraperitoneal, i.p.), which is the peripheral restricted opioid receptor antagonist, did not antagonize these antinociceptive effects. Furthermore, the GHS-R1α antagonist [D-Lys3]-GHRP-6 (i.c.v.) completely antagonized these antinociceptive effects, too. These results suggested that these fragments induced antinociceptive effects through central opioid receptors and GHS-R1α. In conclusion, our studies indicated that these active fragments of ghrelin could cross the brain-blood barrier and enter the brain and induce antinociceptive effects through central opioid receptors and GHS-R1α after intravenous injection.
Subject(s)
Acute Pain/drug therapy , Analgesics/pharmacology , Blood-Brain Barrier/metabolism , Brain/metabolism , Ghrelin/administration & dosage , Ghrelin/pharmacokinetics , Hot Temperature/adverse effects , Acute Pain/etiology , Acute Pain/metabolism , Acute Pain/pathology , Animals , Animals, Outbred Strains , Blood-Brain Barrier/drug effects , Brain/drug effects , Ghrelin/pharmacology , Male , Mice , Narcotic Antagonists/pharmacology , Receptors, Ghrelin/antagonists & inhibitors , Receptors, Ghrelin/metabolism , Receptors, Opioid/chemistry , Receptors, Opioid/metabolismABSTRACT
Colorectal cancer (CRC) is the third most common malignant tumor in humans. Chemotherapy is used for the treatment of CRC. However, the effect of chemotherapy remains unsatisfactory due to drug resistance. Growing evidence has shown that the presence of highly metastatic tumor stem cells, regulation of noncoding RNAs and the tumor microenvironment contributes to drug resistance mechanisms in CRC. Wnt/ßcatenin signaling mediates the chemoresistance of CRC in these three aspects. Therefore, the present study analyzed the abundant evidence of the contribution of Wnt/ßcatenin signaling to the development of drug resistance in CRC and discussed its possible role in improving the chemosensitivity of CRC, which may provide guidelines for its clinical treatment.
