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

Abstract

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.

Morphine Addiction and Oxidative Stress: The Potential Effects of Thioredoxin-1

“…Although mechanisms underlying morphine-mediated processes remain the subject of much debate, morphine stimulation activates G protein-coupled opioid receptors and then induces significant molecular changes inside the cell, such as an inhibition of adenylate cyclase activity, and activation of potassium channels (Qu et al, 2017;Yang et al, 2019). In addition, other signalling pathways, including mitogenactivated kinases (MAPK), b-arrestin, phospholipase C, protein kinase, PI3K, and extracellular signal-regulated kinase (ERK) pathways, are also involved in morphine activity (Bianchi et al, 2010;Zhang and Pan, 2010;Dai et al, 2018;Shen et al, 2018;de Freitas et al, 2019;Dekan et al, 2019;Listos et al, 2019). Recently, the role of oxidative stress in morphine action has been paid more attention.…”

The dopamine D1–D2DR complex in the rat spinal cord promotes neuropathic pain by increasing neuronal excitability after chronic constriction injury

“…In our previous study, levo -corydalmine ( l -CDL) was found to significantly attenuate neuropathic pain in CCI rats 31 , 32 . Moreover, our previous research showed that l -CDL exhibits micromolar affinity for both D1DR and D2DR with half maximal inhibitory concentrations (IC50) of 0.20 μM and 0.86 μM, respectively 33 . D1DR, D2DR, and D1–D2DR heterodimer agonists were used to investigate whether the l -CDL-induced analgesic effect is mediated by the D1–D2DR complex in the spinal cord.…”

Heterodimerization of Mu Opioid Receptor Protomer with Dopamine D2 Receptor Modulates Agonist-Induced Internalization of Mu Opioid Receptor

“…In a recent study by Dai et al [21], it was demonstrated that l -CDL could attenuate morphine tolerance in rats with chronic bone cancer pain. This compound proved to be an antagonist of D 2 R as it inhibited dopamine-induced calcium release in CHO-K1 cells expressing D 2 R. A similar effect, as observed in their previous study [35], was noticed upon coadministration of l -CDL with morphine, and the effect was reversed upon addition of quinpirole, a D 2 R agonist in mice.…”

“…Although these studies clearly suggest an interplay between D 2 R and MOR, the link between D 2 R and opioid analgesia, as well as tolerance, still remains unclear as there are reports for both D 2 R antagonists and D 2 R agonists to attenuate morphine tolerance [21,35].…”

“…Importantly, the analgesic properties of morphine remained unaltered [20]. A recent study by Dai et al [21], demonstrated that levo -corydalmine ( l -CDL), a traditional herb used in China to alleviate pain, when coadministered with morphine, attenuated morphine tolerance in mice. l -CDL acted as an antagonist of D 2 R and the inhibition of tolerance demonstrated by this compound was reversed upon addition of quinpirole, a D 2 R agonist.…”