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.
Highlights
Opioids are still extremely potent analgesics in the clinic, for chronic severe pain, such as chronic bone cancer pain and other types of pain
Data are presented as means ± SE. n = 12, *P < 0.05, **P < 0.01, compared with the morphine group. c, d Intrathecal administration of the D2DR agonist quinpirole (1 μg/10 μl) abolished l-CDL (3.3 μg/10 μl)-induced inhibition of morphine tolerance in mice
The analgesia was further reported as area under the curve (AUC) units
Summary
Opioids are still extremely potent analgesics in the clinic, for chronic severe pain, such as chronic bone cancer pain and other types of pain. Repeated morphine treatments induce tolerance that contributes to the risk of developing drug dependence, addiction and tolerance, as dose escalation is required to maintain adequate analgesia.[1,2] Despite the extensive research into the mechanism of morphine tolerance in the past few decades,[3,4] morphine tolerance is still a substantial clinical challenge. Considerable progress has been made in determining the mechanisms underlying opioid tolerance. The desensitization, internalization and downregulation of MOR,[4] or heterodimerization with other receptors[5] causes opioid receptor-mediated adaptive changes in the spinal cord to participate in the development of morphine tolerance.[4,6].
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