Simultaneous inhibition of NMDA and mGlu1/5 receptors by levo‐corydalmine in rat spinal cord attenuates bone cancer pain

Abstract

Bone cancer pain is a challenge for its not completely clarified mechanism and broad clinical morbidity. Therefore, novel and more effective drugs are urgent needed for improvement of patients' quality of life. Glutamate receptors have been associated with the development of the central sensitization of chronic pain. Inhibition of N-methyl-d-aspartate (NMDA) and metabotropic glutamate (mGlu) receptors can effectively attenuate bone cancer pain, respectively. Herein, our results indicated that levo-Corydalmine (l-CDL), a compound from Corydalis yanhusuo W.T. Wang, which has been used in traditional Chinese medicine for pain relief could effectively attenuate bone cancer pain induced by tibia bone cavity tumor cell implantation (TCI) through simultaneously inhibiting the NMDA and mGlu1/5 receptors in rat spinal cord without notable side effects. Both intragastric and intrathecal administration of l-CDL significantly alleviated the mechanical hypersensitivity induced by TCI in rats, and the analgesic effect of l-CDL could be reversed by intrathecal administration of NMDA receptor agonist NMDA and mGlu1/5 receptor agonist DHPG but not AMPA receptor agonist AMPA. l-CDL could also selectively suppress NMDA and DHPG induced rapid rise in Ca oscillations in primary cultures neurons of spinal cord in vitro. The antinociception of l-CDL were partially mediated by the reduced phosphorylation of PKC γ and ERK1/2 in spinal cord of TCI rats in a NMDA and mGlu1/5 dependent manner. In conclusion, these results suggested that l-CDL attenuates TCI induced bone cancer pain through simultaneously inhibiting the NMDA and mGlu1/5 receptors and the downstream PKC γ, ERK1/2 signaling pathways in the spinal cord.

Suppression of peripheral NGF attenuates neuropathic pain induced by chronic constriction injury through the TAK1-MAPK/NF-κB signaling pathways

“…7c, g). The NF-κB inhibitor PDTC (25,50, and 100 μM) and the CREB inhibitor KG-501 (10,25, and 50 μM) did not inhibit LPS induced upregulation of NGF mRNA in RAW264.7 cells ( Fig. 7d, e), while the AP-1 inhibitor SR11302 (1, 10, and 50 μM) obviously decreased the upregulation of NGF mRNA in RAW264.7 cells (Fig.…”

“…Von Frey hairs (Woodland Hills, Los Angeles) were used as previously described [10]. A series of Von Frey hairs with logarithmically incremental stiffness (1.4~15.0 g) were used to stimulate the hind paws of rats, and each hair was held for approximately 6 s. A positive response was defined as quick withdrawal or licking of the hind paw upon the stimulus.…”

“…In brief, the rats were anesthetized with pentobarbital (50 mg/kg, i.p.) 2 h after drug administration, and the ipsilateral L4-L6 DRGs, and sciatic nerves were collected and extracted using RIPA buffer [10]. The proteins in the cell culture supernatants were extracted by methanolchloroform precipitation [13].…”

“…7k). In RSC96 cells, the NF-κB inhibitor PDTC (25,50, and 100 μM), CREB inhibitor KG-501 (10,25, and 50 μM) and AP-1 inhibitor SR11302 (1, 10, and 50 μM) all inhibited IL-1β-induced upregulation of NGF mRNA (Fig. 7h-j), while only the CREB agonist rolipram (20 μM) but not the NF-κB agonist prostrain (5 μM) or AP-1 activator anisomycin (30 μM) abolished the l-CDL (10 μM)-induced decease in NGF mRNA (Fig.…”

“…l-CDL is a trace alkaloid found in Corydalis yanhusuo W.T. Wang, which was found to have favorable antinociceptive effects in acute and chronic pain in our previous work, and the mechanism of l-CDL in the spinal cord has also been clarified [9][10][11]. However, the underlying mechanism of l-CDL in attenuating neuropathic pain in the periphery has still not been fully elucidated.…”