Sigma-1 receptor blockade enhances opioid-induced analgesia

JM Baeyens. University of Granada, Department of Pharmacology, Avenida de Madrid 11, 18012 Granada, Spain

The sigma-1 (σ1) receptor was firstly cloned in 1996. It is highly homologous among different species (including humans), but it shows no significant homology with other mammalian proteins. The σ1 receptor is widely distributed in peripheral organs and different areas of the central nervous system, including areas of great importance in pain control. This receptor is a ligand-regulated molecular chaperone that modulates the activity of several receptors and ion channels. In particular, σ1 receptors physically associate with µ-opioid receptors and modulate opioid transduction without influencing opioid receptor binding. Thus, blockade of σ1 receptors in vitro potentiates DAMGO-induced stimulation of [35S]GTP-É£-S binding to G proteins (without modifying [3H]DAMGO binding to the opioid receptor). This enhancement of opioid-induced G-protein activation appears to have behavioral consequences, because blockade of σ1 receptor function in vivo with σ1 receptor antagonists (BD-1063, BD-1047, NE-100 or S1RA) enhances morphine-induced analgesia against thermal (tail flick test) and mechanical (paw pressure test) nociceptive stimuli in rodents. The enhancement by σ1 antagonists of morphine analgesia was specifically mediated by σ1 receptor blockade because it was not produced in σ1 receptor knockout (σ1-KO) mice and it was reversed by σ1 receptor agonists in wild-type (WT) animals. Interestingly, the analgesia induced by other agonists of µ-opioid receptors (fentanyl, oxicodone, tramadol and buprenorphine) in the paw pressure test is also markedly enhanced in σ1-KO mice in comparison to that produced in WT mice. Altogether, these results suggest that σ1 receptors are tonically inhibiting the antinociceptive effect of µ-opioid receptor agonists. This tonic inhibition is produced at the central nervous system, because intracerebroventricular administration of σ1 receptor antisense oligodeoxynucleotides enhances morphine-induced antinociception in the tail flick test. Nevertheless, the tonic inhibition also happens at peripheral level and it is particularly important when mechanical nociceptive stimuli are applied. Thus, intraplantar (i.pl.) administration of low doses (µg) of morphine did not produce any analgesia in the paw pressure test in WT mice, but produced a marked analgesia in σ1-KO mice or if they were i.pl. coadministered with µg of σ1 receptor antagonists to WT mice. In both cases the analgesia induced by i.pl. morphine was observed in the injected paw but not in the contralateral paw, which indicates that the antinociceptive effect of the opioid and the potentiation of its effect by the pharmacological or genetic inactivation of σ1 receptors were produced locally in the paw.

In conclusion, the pharmacological blockade of σ1 receptors enhances the analgesia induced by µ-opioid receptor agonists and may have therapeutic interest for pain treatment.

Supported by Ministerio de Ciencia e Investigación (project SAF2010-15343) and Junta de Andalucía (CTS-109 group)