Aims: 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 Ca2+-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 σ1R binds to the cytosolic C terminal region of the NMDAR NR1 subunit. Conclusion: 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. Antioxid. Redox Signal. 22, 799–818.

Through the cannabinoid receptor 1 (CB1), the endocannabinoid system plays a physiological role in maintaining the activity of glutamate N-methyl-D-aspartate (NMDA) receptor within harmless limits. The influence of cannabinoids must be proportional to the stimulus in order to prevent NMDAR overactivation or exaggerated hypofunction that may precipitate symptoms of psychosis. In this framework, the recently reported association of CB1s with NMDARs, which mediates the reduction of cannabinoid analgesia promoted by NMDAR antagonism, could also support the precipitation of schizophrenia brought about by the abuse of smoked cannabis, mostly among vulnerable individuals. Accordingly, we have investigated this possibility using neuroprotection and analgesia as reporters of the CB1-NMDAR connection. We found that the Sigma 1 receptor (σ1R) acts as a safety switch, releasing NMDARs from the influence of CB1s and thereby avoiding glutamate hypofunction. In σ1R(-/-) mice the activity of NMDARs increases and cannot be regulated by cannabinoids, and NMDAR antagonism produces no effect on cannabinoid analgesia. In wild-type mice, ligands of the σ1R did not affect the CB1-NMDAR regulatory association, however, experimental NMDAR hypofunction enabled σ1R antagonists to release NMDARs from the negative control of CB1s. Of the σ1R antagonists tested, their order of activity was: S1RA > BD1047 ≫ NE100 = BD1063, although SKF10047, PRE-084 and (+)pentazocine were inactive yet able to abolish the effect of S1RA in this paradigm. Thus, the σ1R controls the extent of CB1-NMDAR interaction and its failure might constitute a vulnerability factor for cannabis abuse, potentially precipitating schizophrenia that might otherwise be induced later in time by the endogenous system.

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