期刊
NEUROPHARMACOLOGY
卷 128, 期 -, 页码 255-268出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2017.10.014
关键词
Calcium channel; Neurokinin 1 receptor; Mu-opioid receptor; NMDA receptor; Primary afferent; Protein kinase A
资金
- Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research & Development Service [1I01RX000378, 1I01RX001646A]
- National Institutes of Health [R01-DA033059]
The interaction between NMDA receptors and-opioid receptors in primary afferent terminals was studied by using NMDA to induce substance P release, measured as neurokinin 1 receptor internalization. In rat spinal cord slices, the mu-opioid receptor agonists morphine, DAMGO and endomorphin-2 inhibited NMDA-induced substance P release, whereas the antagonist CTAP right-shifted the concentration response of DAMGO. In vivo, substance P release induced by intrathecal NMDA after priming with BDNF was inhibited by DAMGO. (D-Conotoxins MVIIC and GVIA inhibited about half of the NMDA-induced substance P release, showing that it was partially mediated by the opening of voltage-gated calcium (Cav) channels. In contrast, DAMGO or w-conotoxins did not inhibit capsaicin-induced substance P release. In cultured DRG neurons, DAMGO but not w-conotoxin inhibited NMDA-induced increases in intracellular calcium, indicating that jt-opioid receptors can inhibit NMDA receptor function by mechanisms other than inactivation of Cav channels. Moreover, DAMGO decreased the omega-conotoxin-insensitive component of the substance P release. Potent inhibition by ifenprodil showed that these NMDA receptors have the NR2B subunit. Activators of adenylyl cyclase and protein kinase A (PICA) induced substance P release and this was decreased by the NMDA receptor blocker MK-801 and by DAMGO. Conversely, inhibitors of adenylyl cyclase and PICA, but not of protein kinase C, decreased NMDA-induced substance P release. Hence, these NMDA receptors are positively modulated by the adenylyl cyclase-PICA pathway, which is inhibited by mu-opioid receptors. In conclusion, mu-opioid receptors inhibit NMDA receptor-induced substance P release through Cav channel inactivation and adenylyl cyclase inhibition. Published by Elsevier Ltd.
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