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Interferon alpha inhibits spinal cord synaptic and nociceptive transmission via neuronal-glial interactions

View Article: PubMed Central - PubMed

ABSTRACT

It is well known that interferons (IFNs), such as type-I IFN (IFN-α) and type-II IFN (IFN-γ) are produced by immune cells to elicit antiviral effects. IFNs are also produced by glial cells in the CNS to regulate brain functions. As a proinflammatory cytokine, IFN-γ drives neuropathic pain by inducing microglial activation in the spinal cord. However, little is known about the role of IFN-α in regulating pain sensitivity and synaptic transmission. Strikingly, we found that IFN-α/β receptor (type-I IFN receptor) was expressed by primary afferent terminals in the superficial dorsal horn that co-expressed the neuropeptide CGRP. In the spinal cord IFN-α was primarily expressed by astrocytes. Perfusion of spinal cord slices with IFN-α suppressed excitatory synaptic transmission by reducing the frequency of spontaneous excitatory postsynaptic current (sEPSCs). IFN-α also inhibited nociceptive transmission by reducing capsaicin-induced internalization of NK-1 and phosphorylation of extracellular signal-regulated kinase (ERK) in superficial dorsal horn neurons. Finally, spinal (intrathecal) administration of IFN-α reduced inflammatory pain and increased pain threshold in naïve rats, whereas removal of endogenous IFN-α by a neutralizing antibody induced hyperalgesia. Our findings suggest a new form of neuronal-glial interaction by which IFN-α, produced by astrocytes, inhibits nociceptive transmission in the spinal cord.

No MeSH data available.


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Expression of IFN-α receptors in primary sensory neurons in the DRG.(A) Double staining showing colocalization of IFN-α/βR with substance P and IB4 but not with NF200 in the DRG. Arrows indicate double-labeled neurons. Scale, 50 μm. (B) Size frequency distribution of IFN-α/βR-positive neurons in the DRG. Twelve DRG sections from 4 animals were included for quantification. Note that 26% DRG neurons express IFN-α/βR in normal conditions. Most IFN-α/βR-positive neurons have cross-sectional areas of 200–600 μm2.
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f2: Expression of IFN-α receptors in primary sensory neurons in the DRG.(A) Double staining showing colocalization of IFN-α/βR with substance P and IB4 but not with NF200 in the DRG. Arrows indicate double-labeled neurons. Scale, 50 μm. (B) Size frequency distribution of IFN-α/βR-positive neurons in the DRG. Twelve DRG sections from 4 animals were included for quantification. Note that 26% DRG neurons express IFN-α/βR in normal conditions. Most IFN-α/βR-positive neurons have cross-sectional areas of 200–600 μm2.

Mentions: To define whether IFN-α/βR in the spinal cord is originated from primary afferent neurons, we examined IFN-α/βR expression the dorsal root ganglion (DRG). In DRG sections, IFN-α/βR was expressed by small-sized neurons that are negative for NF-200, a marker for myelinated large-sized A fiber neurons. Thus, IFN-α/βR is mainly present in C-fiber neurons (Fig. 2A). Size frequency analysis revealed that most IFN-α/βR-positive neurons had the size of small neurons, with a cross section area of 200–600 μm2 (Fig. 2B). Further analysis showed that 26% of DRG neurons were positive for IFN-α/βR. In parallel with spinal cord staining, IFN-α/βR-positive neurons co-expressed the neuropeptide substance P (Fig. 2A). In addition, non-peptidergic neurons (IB4+) expressed IFN-α/βR (Fig. 2A). The unique distribution patterns of type-I receptors in the DRG and spinal cord strongly suggest a role of the receptors in nociception.


Interferon alpha inhibits spinal cord synaptic and nociceptive transmission via neuronal-glial interactions
Expression of IFN-α receptors in primary sensory neurons in the DRG.(A) Double staining showing colocalization of IFN-α/βR with substance P and IB4 but not with NF200 in the DRG. Arrows indicate double-labeled neurons. Scale, 50 μm. (B) Size frequency distribution of IFN-α/βR-positive neurons in the DRG. Twelve DRG sections from 4 animals were included for quantification. Note that 26% DRG neurons express IFN-α/βR in normal conditions. Most IFN-α/βR-positive neurons have cross-sectional areas of 200–600 μm2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037469&req=5

f2: Expression of IFN-α receptors in primary sensory neurons in the DRG.(A) Double staining showing colocalization of IFN-α/βR with substance P and IB4 but not with NF200 in the DRG. Arrows indicate double-labeled neurons. Scale, 50 μm. (B) Size frequency distribution of IFN-α/βR-positive neurons in the DRG. Twelve DRG sections from 4 animals were included for quantification. Note that 26% DRG neurons express IFN-α/βR in normal conditions. Most IFN-α/βR-positive neurons have cross-sectional areas of 200–600 μm2.
Mentions: To define whether IFN-α/βR in the spinal cord is originated from primary afferent neurons, we examined IFN-α/βR expression the dorsal root ganglion (DRG). In DRG sections, IFN-α/βR was expressed by small-sized neurons that are negative for NF-200, a marker for myelinated large-sized A fiber neurons. Thus, IFN-α/βR is mainly present in C-fiber neurons (Fig. 2A). Size frequency analysis revealed that most IFN-α/βR-positive neurons had the size of small neurons, with a cross section area of 200–600 μm2 (Fig. 2B). Further analysis showed that 26% of DRG neurons were positive for IFN-α/βR. In parallel with spinal cord staining, IFN-α/βR-positive neurons co-expressed the neuropeptide substance P (Fig. 2A). In addition, non-peptidergic neurons (IB4+) expressed IFN-α/βR (Fig. 2A). The unique distribution patterns of type-I receptors in the DRG and spinal cord strongly suggest a role of the receptors in nociception.

View Article: PubMed Central - PubMed

ABSTRACT

It is well known that interferons (IFNs), such as type-I IFN (IFN-α) and type-II IFN (IFN-γ) are produced by immune cells to elicit antiviral effects. IFNs are also produced by glial cells in the CNS to regulate brain functions. As a proinflammatory cytokine, IFN-γ drives neuropathic pain by inducing microglial activation in the spinal cord. However, little is known about the role of IFN-α in regulating pain sensitivity and synaptic transmission. Strikingly, we found that IFN-α/β receptor (type-I IFN receptor) was expressed by primary afferent terminals in the superficial dorsal horn that co-expressed the neuropeptide CGRP. In the spinal cord IFN-α was primarily expressed by astrocytes. Perfusion of spinal cord slices with IFN-α suppressed excitatory synaptic transmission by reducing the frequency of spontaneous excitatory postsynaptic current (sEPSCs). IFN-α also inhibited nociceptive transmission by reducing capsaicin-induced internalization of NK-1 and phosphorylation of extracellular signal-regulated kinase (ERK) in superficial dorsal horn neurons. Finally, spinal (intrathecal) administration of IFN-α reduced inflammatory pain and increased pain threshold in naïve rats, whereas removal of endogenous IFN-α by a neutralizing antibody induced hyperalgesia. Our findings suggest a new form of neuronal-glial interaction by which IFN-α, produced by astrocytes, inhibits nociceptive transmission in the spinal cord.

No MeSH data available.


Related in: MedlinePlus