Mechanisms of μ-opioid receptor inhibition of NMDA receptor-induced substance P release in the rat spinal cord

NEUROPHARMACOLOGY

卷:128

Article

Chen, Wenling^1,2  Ennes, Helena S.²  McRoberts, James A.²  Marvizon, Juan Carlos^1,2 

[1] Vet Affairs Greater Los Angeles Healthcare Syst, 11310 Wilshire Blvd,Bldg 115, Los Angeles, CA 90073 USA

[2] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Vatche & Tamar Manoukian Div Digest Dis, 900 Vet Ave,Warren Hall Bldg, Los Angeles, CA 90095 USA

关键词: Calcium channel;    Neurokinin 1 receptor;    Mu-opioid receptor;    NMDA receptor;    Primary afferent;    Protein kinase A;   

DOI  :  10.1016/j.neuropharm.2017.10.014

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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