The International Journal of Neuropsychopharmacology

The calcium-sensitive Sigma-1 receptor prevents cannabinoids from provoking glutamate NMDA receptor hypofunction: implications in antinociception and psychotic diseases

Pilar Sánchez-Blázqueza1, María Rodríguez-Muñoza1, Raquel Herrero-Labradora1, Javier Burgueñoa2, Daniel Zamanilloa2 and Javier Garzóna1 c1

a1 Neuropharmacology, Cajal Institute, CSIC, Avenida Doctor Arce, 37. 28002 Madrid, Spain

a2 Drug Discovery & Preclinical Development, Esteve. Scientific Park of Barcelona, Bardiri y Reixac 4-8, 08028, Barcelona, Spain


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.

(Received October 22 2013)

(Reviewed November 13 2013)

(Revised December 17 2013)

(Accepted January 06 2014)

(Online publication January 31 2014)

Key words

  • Antinociception;
  • cannabinoid receptor type 1;
  • HINT1 protein;
  • NMDA receptor hypofunction;
  • schizophrenia;
  • Sigma-1 receptor


c1 Address for correspondence: J. Garzón, Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Doctor Arce 37, 28002 Madrid, Spain. Tel.: 34 915854733 Fax: 34 915854754 Email: