Sigma-1 receptor expression in the dorsal root ganglion: Reexamination using a highly specific antibody

Abstract

Sigma-1 receptor (S1R) is a unique pluripotent modulator of living systems and has been reported to be associated with a number of neurological diseases including pathological pain. Intrathecal administration of S1R antagonists attenuate the pain behavior of rodents in both inflammatory and neuropathic pain models. However, the S1R localization in the spinal cord shows a selective ventral horn motor neuron distribution, suggesting the high likelihood of S1R in the dorsal root ganglion (DRG) mediating the pain relief by intrathecally administered drugs. Since primary afferents are the major component in the pain pathway, we examined the mouse and rat DRGs for the presence of the S1R. At both mRNA and protein levels, qRT-PCR and Western confirmed that the DRG contains greater S1R expression in comparison to spinal cord, cortex, or lung but less than liver. Using a custom-made highly specific antibody, we demonstrated the presence of a strong S1R immuno-fluorescence in all rat and mouse DRG neurons co-localizing with the NSE marker, but not in neural processes or GFAP-positive glial satellite cells. In addition, S1R was absent in afferent terminals in the skin and in the dorsal horn of the spinal cord. Using immuno-electron microscopy, we showed that S1R is detected in the nuclear envelope and endoplasmic reticulum of DRG cells. In contrast to other cells, S1R is also located directly at the plasma membrane of the DRG neurons. The presence of S1R in the nuclear envelope of all DRG neurons suggests an exciting potential role of S1R as a regulator of neuronal nuclear activities and/or gene expression, which may provide insight towards new molecular targets for modulating nociception at the level of primary afferent neurons.

Sigma-1 receptors control immune-driven peripheral opioid analgesia during inflammation in mice

“…The marked potentiation of opioid antinociception by peripheral sigma-1 antagonism is consistent with its higher density in the dorsal root ganglion than in several central areas (10). Moreover, these receptors in the dorsal root ganglion are selectively located in sensory neurons and not in glial cells (11). It is now known that sigma-1 receptors can form a macromolecular complex with opioid receptors, tonically inhibiting receptor functioning, and that sigma-1 antagonism can protect opioid receptors from the tonic inhibitory effects of sigma-1 receptors, thus enhancing opioid analgesia (12,13).…”

The sigma‐1 receptor behaves as an atypical auxiliary subunit to modulate the functional characteristics of Kv1.2 channels expressed in HEK293 cells

“…Previous work has shown that the Sig‐1R resides in the ER membrane where it is clustered at ER specializations juxtaposed to mitochondria (Hayashi and Su ), and the plasma membrane (Mavlyutov et al. , , ; Wong et al. ).…”

“…Previous work has shown that the Sig-1R resides in the ER membrane where it is clustered at ER specializations juxtaposed to mitochondria (Hayashi and Su 2007), and the plasma membrane (Mavlyutov et al , 2016Wong et al 2016). Additionally, it has been shown that the Sig-1R can translocate to the nuclear envelope upon activation with cocaine, and it has also been reported that the Sig-1R may reside in the PM in dorsal root ganglion (DRG) neurons Tsai et al 2015).…”

Sigma 2 Receptor/Tmem97 Agonists Produce Long Lasting Antineuropathic Pain Effects in Mice

“…Another possibility is that while the mechanism of action of σ 1R antagonists in pain was first thought to involve a spinal mechanism of action, 21–23 more recent studies suggest an action of DRG neurons where σ 1R is also expressed. 44 It is therefore probable that the time to onset of effects is due to the time that is needed for the drug to diffuse to sites of action that are more distant from the injection site in the intrathecal space. Because σ 1Rs are found on the nuclear envelop of DRG neurons, 44 yet another possibility is that the effect of these compounds is transcriptional.…”

“…44 It is therefore probable that the time to onset of effects is due to the time that is needed for the drug to diffuse to sites of action that are more distant from the injection site in the intrathecal space. Because σ 1Rs are found on the nuclear envelop of DRG neurons, 44 yet another possibility is that the effect of these compounds is transcriptional. If this were the case, this would also potentially take longer to manifest as a behavioral change.…”