Selective blockade of spinal D2DR by levo-corydalmine attenuates morphine tolerance via suppressing PI3K/Akt-MAPK signaling in a MOR-dependent manner

Morphine tolerance remains a challenge in the management of chronic pain in the clinic. As shown in our previous study, the dopamine D2 receptor (D2DR) expressed in spinal cord neurons might be involved in morphine tolerance, but the underlying mechanisms remain to be elucidated. In the present study, selective spinal D2DR blockade attenuated morphine tolerance in mice by inhibiting phosphatidylinositol 3 kinase (PI3K)/serine–threonine kinase (Akt)-mitogen activated protein kinase (MAPK) signaling in a μ opioid receptor (MOR)-dependent manner. Levo -corydalmine ( l -CDL), which exhibited micromolar affinity for D2DR in D2/CHO-K1 cell lines in this report and effectively alleviated bone cancer pain in our previous study, attenuated morphine tolerance in rats with chronic bone cancer pain at nonanalgesic doses. Furthermore, the intrathecal administration of l -CDL obviously attenuated morphine tolerance, and the effect was reversed by a D2DR agonist in mice. Spinal D2DR inhibition and l -CDL also inhibited tolerance induced by the MOR agonist DAMGO. l -CDL and a D2DR small interfering RNA (siRNA) decreased the increase in levels of phosphorylated Akt and MAPK in the spinal cord; these changes were abolished by a PI3K inhibitor. In addition, the activated Akt and MAPK proteins in mice exhibiting morphine tolerance were inhibited by a MOR antagonist. Intrathecal administration of a PI3K inhibitor also attenuated DAMGO-induced tolerance. Based on these results, l -CDL antagonized spinal D2DR to attenuate morphine tolerance by inhibiting PI3K/Akt-dependent MAPK phosphorylation through MOR. These findings provide insights into a more versatile treatment for morphine tolerance. Pain medicine: why blocking dopamine receptors alleviates morphine tolerance By blocking dopamine receptors located in the spinal cord, a compound found in a traditional Chinese herbal medicine may help mitigate tolerance to morphine, a common problem among cancer patients who regularly take the opioid painkiller. A team led by Ji-Hua Liu and Bo-Yang Yu from China Pharmaceutical University in Nanjing had previously showed that inhibiting dopamine D2 receptors in spinal neurons prevented mice from developing morphine tolerance, but it wasn’t clear why. They have now demonstrated that blocking D2 receptors prevents the relay of cellular signals from morphine-binding “μ-opioid” receptors to mediators of drug tolerance. Levo -corydalmine, a compound isolated from the Asian Corydalis plant, bind