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Dimerization of ETARs and μ opioid receptors was confirmed by Western blot and total internal reflection fluorescence microscopy in live cells. In vivo, Compound-E potentiated and prolonged the analgesic effects of morphine, enhanced hypothermia, and increased locomotor activity compared to morphine alone. The results suggest that attenuation by endothelin-1 of morphine analgesia may be caused by dimerization of Endothelin A/μ opioid receptors. The novel ETAR antagonist Compound-E could be an effective adjunct to reduce opioid use. The re

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