title: The σ1 receptor engages the redox-regulated HINT1 protein to bring opioid analgesia under NMDA receptor negative control.
abstract: OBJECTIVE
  The in vivo pharmacology of the sigma 1 receptor (σ1R) is certainly complex; however, σ1R antagonists are of therapeutic interest, because they enhance mu-opioid receptor (MOR)-mediated antinociception and reduce neuropathic pain. Thus, we investigated whether the σ1R 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 PKCγ to HINT1 proteins. Then, PKCγ impairs HINT1-RGSZ2 association and enables σ1R-NR1 interaction with MOR-HINT1 complexes to restrain opioid signaling. The inhibition of NOS or the absence of σ1Rs prevents HINT1-PKCγ interaction, and MOR-NMDAR cross-regulation fails. The σ1R antagonists transitorily remove the binding of σ1Rs 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.
  
  
  METHODS
  A redox-regulated process situates MOR signaling under NMDAR control, and in this context, the σ1R binds to the cytosolic C terminal region of the NMDAR NR1 subunit.
  
  
  CONCLUSIONS
  The σ1R antagonists enhance opioid analgesia in naïve mice by releasing MORs from the negative influence of NMDARs, and they also reset antinociception in morphine tolerant animals. Moreover, σ1R antagonists alleviate neuropathic pain, probably by driving the inhibition of up-regulated NMDARs.
authors.affiliation: 1 Neurofarmacología, Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC) , Madrid, Spain .
authors.forename: María
authors.initials: M
authors.lastname: Rodríguez-Muñoz
authors.forename: Pilar
authors.initials: P
authors.lastname: Sánchez-Blázquez
authors.forename: Raquel
authors.initials: R
authors.lastname: Herrero-Labrador
authors.forename: Ricardo
authors.initials: R
authors.lastname: Martínez-Murillo
authors.forename: Manuel
authors.initials: M
authors.lastname: Merlos
authors.forename: José Miguel
authors.initials: JM
authors.lastname: Vela
authors.forename: Javier
authors.initials: J
authors.lastname: Garzón
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction; D011493:Protein Kinase C / Q000378:metabolism; D020710:RGS Proteins / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism; D000097605:Sigma-1 Receptor
chemical_list: D000701:Analgesics, Opioid; D009020:Morphine; D009419:Nerve Tissue Proteins; D009569:Nitric Oxide; D011493:Protein Kinase C; D020710:RGS Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; D015032:Zinc; D000097605:Sigma-1 Receptor; C489275:Hint1 protein, mouse; C532880:RGS17 protein, mouse; C087857:protein kinase C gamma