| First Author | Rodríguez-Muñoz M | Year | 2015 |
| Journal | Antioxid Redox Signal | Volume | 22 |
| Issue | 10 | Pages | 799-818 |
| PubMed ID | 25557043 | Mgi Jnum | J:301581 |
| Mgi Id | MGI:6506274 | Doi | 10.1089/ars.2014.5993 |
| Citation | Rodriguez-Munoz M, et al. (2015) The sigma1 receptor engages the redox-regulated HINT1 protein to bring opioid analgesia under NMDA receptor negative control. Antioxid Redox Signal 22(10):799-818 |
| abstractText | AIMS: The in vivo pharmacology of the sigma 1 receptor (sigma1R) is certainly complex; however, sigma1R antagonists are of therapeutic interest, because they enhance mu-opioid receptor (MOR)-mediated antinociception and reduce neuropathic pain. Thus, we investigated whether the sigma1R is involved in the negative control that glutamate N-methyl-d-aspartate acid receptors (NMDARs) exert on opioid antinociception. RESULTS: The MOR C terminus carries the histidine triad nucleotide-binding protein 1 (HINT1) coupled to the regulator of G-protein signaling RGSZ2-neural nitric oxide synthase assembly. Activated MORs stimulate the production of nitric oxide (NO), and the redox zinc switch RGSZ2 converts this signal into free zinc ions that are required to recruit the redox sensor PKCgamma to HINT1 proteins. Then, PKCgamma impairs HINT1-RGSZ2 association and enables sigma1R-NR1 interaction with MOR-HINT1 complexes to restrain opioid signaling. The inhibition of NOS or the absence of sigma1Rs prevents HINT1-PKCgamma interaction, and MOR-NMDAR cross-regulation fails. The sigma1R antagonists transitorily remove the binding of sigma1Rs to NR1 subunits, facilitate the entrance of negative regulators of NMDARs, likely Ca(2+)-CaM, and prevent NR1 interaction with HINT1, thereby impairing the negative feedback of glutamate on opioid analgesia. INNOVATION: A redox-regulated process situates MOR signaling under NMDAR control, and in this context, the sigma1R binds to the cytosolic C terminal region of the NMDAR NR1 subunit. CONCLUSION: The sigma1R antagonists enhance opioid analgesia in naive mice by releasing MORs from the negative influence of NMDARs, and they also reset antinociception in morphine tolerant animals. Moreover, sigma1R antagonists alleviate neuropathic pain, probably by driving the inhibition of up-regulated NMDARs. |
