Unlike Morphine, Long-Term Exposure to Analgesic Mitragynine, 7-Hydroxymitragynine, Paynantheine, and Speciociliatine Alkaloids Does Not Contribute to Antinociceptive Tolerance of μ-Opioid Receptors

Abstract

<jats:title>Abstract</jats:title> <jats:p><jats:bold>Background</jats:bold>: Opioids are the most well known antinociceptive alkaloids all over the world, but tolerance and physical dependence are their dominant concerns in clinical applications. In contrast, monoterpene alkaloids are newly considered for their roles in pain management.<jats:bold>Methods</jats:bold>: In this regard, the clinical safety of mitragynine, 7-hydroxymitragynine, speciociliatine, and paynantheine was determined by cytotoxicity, antioxidant, and antigenotoxicity assays. In parallel alkaloids were studied on β-arrestin-2, ERK1/2, and p-ERK1/2 transcription and translation levels during three days on SH-SY5Y cells. <jats:bold>Results</jats:bold>: Results confirmed alkaloid- and concentration- dependency of the cytotoxicity, antigenotoxicity, and antioxidant activity. Although morphine was recorded as the safest alkaloid here, speciociliatine and mitragynine represented around 1200- and 20- fold higher DNA protection capacity than morphine, respectively. Monoterpene alkaloids transiently made the transcript ocean turbulent, but western blot analyses have proved significant down-regulation of targeted proteins in SH-SY5Y cells during the experiment days. <jats:bold>Conclusion</jats:bold>s: Data indicated that monoterpene alkaloid derivatives are putative analgesic agents that do not stimulate opioid receptor tolerance and suggesting that patients may benefit from their antinociceptive activities without physical dependence or tolerance concerns in future clinics.</jats:p>