A low pKa ligand inhibits cancer-associated pain in mice by activating peripheral mu-opioid receptors
Autor: | Halina Machelska, Ana Lastra, Sara González-Rodríguez, Luis Menéndez, Ana Baamonde, Christoph Stein, Viola Seitz |
---|---|
Rok vydání: | 2020 |
Předmět: |
Male
medicine.drug_class Narcotic Antagonists Melanoma Experimental Receptors Opioid mu lcsh:Medicine Bone Neoplasms Chronic pain (+)-Naloxone Pharmacology Ligands Article Mice Piperidines Naltrindole Opioid receptor Cell Line Tumor Bone cancer medicine Animals lcsh:Science Receptor Mice Inbred C3H Multidisciplinary Cyprodime Naloxone Chemistry lcsh:R Cancer Pain Hydrogen-Ion Concentration Naltrexone Analgesics Opioid Fentanyl Mice Inbred C57BL Morphinans Opioid Hyperalgesia lcsh:Q medicine.symptom μ-opioid receptor medicine.drug |
Zdroj: | Scientific Reports Scientific Reports, Vol 10, Iss 1, Pp 1-10 (2020) Scopus RUO. Repositorio Institucional de la Universidad de Oviedo instname |
ISSN: | 2045-2322 |
Popis: | The newly designed fentanyl derivative [( ±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide] (NFEPP) was recently shown to produce analgesia selectively via peripheral mu-opioid receptors (MOR) at acidic pH in rat inflamed tissues. Here, we examined the pH-dependency of NFEPP binding to brain MOR and its effects on bone cancer-induced pain in mice. The IC50 of NFEPP to displace bound [3H]-DAMGO was significantly higher compared to fentanyl at pH 7.4, but no differences were observed at pH 5.5 or 6.5. Intravenous NFEPP (30–100 nmol/kg) or fentanyl (17–30 nmol/kg) inhibited heat hyperalgesia in mice inoculated with B16-F10 melanoma cells. The peripherally-restricted opioid receptor antagonist naloxone-methiodide reversed the effect of NFEPP (100 nmol/kg), but not of fentanyl (30 nmol/kg). The antihyperalgesic effect of NFEPP was abolished by a selective MOR- (cyprodime), but not delta- (naltrindole) or kappa- (nor-binaltorphimine) receptor antagonists. Ten-fold higher doses of NFEPP than fentanyl induced maximal antinociception in mice without tumors, which was reversed by the non-restricted antagonist naloxone, but not by naloxone-methiodide. NFEPP also reduced heat hyperalgesia produced by fibrosarcoma- (NCTC 2472) or prostate cancer-derived (RM1) cells. These data demonstrate the increased affinity of NFEPP for murine MOR at low pH, and its ability to inhibit bone cancer-induced hyperalgesia through peripheral MOR. In mice, central opioid receptors may be activated by ten-fold higher doses of NFEPP. |
Databáze: | OpenAIRE |
Externí odkaz: |