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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.

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Expression of IFN-α receptors in the spinal cord dorsal horn.(A–C) Double staining of Type I-IFN receptor (IFN-α/βR) and CGRP in the superficial dorsal horn. Scale, 100 μm. (D,E) High magnification images showing colocalization of IFN-α/βR and CGRP in primary afferent terminals in the superficial dorsal horn (laminae I-IIo). Arrows in (D) indicate double-labeled terminals. Arrows in E show IFN-α/βR labeling in inner lamina II (IIi). Scales, 3 μm (D) and 100 μm (E).
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f1: Expression of IFN-α receptors in the spinal cord dorsal horn.(A–C) Double staining of Type I-IFN receptor (IFN-α/βR) and CGRP in the superficial dorsal horn. Scale, 100 μm. (D,E) High magnification images showing colocalization of IFN-α/βR and CGRP in primary afferent terminals in the superficial dorsal horn (laminae I-IIo). Arrows in (D) indicate double-labeled terminals. Arrows in E show IFN-α/βR labeling in inner lamina II (IIi). Scales, 3 μm (D) and 100 μm (E).

Mentions: To determine the role of spinal IFN-α in pain modulation, we first investigated the expression of type-I IFN receptor (IFN-α/βR) in the spinal cord. Remarkably, IFN-α/βR expression was restricted to the superficial dorsal horn (laminae I-II) in the spinal cord, where nociceptive primary afferents (C/Aδ) terminate Fig. 1A). Double staining further demonstrated that IFN-α/βR was co-localized with the neuropeptide calcitonin gene-related peptide (CGRP) (Fig. 1B–D) in axonal terminals in the lamina I-IIo. Further analysis in higher magnification image showed additional IFN-α/βR staining in axonal terminals in the inner lamina II (IIi, Fig. 1E), suggesting that non-peptidergic fibers may also express IFN-α/βR. Together, these results imply that IFN-α/βR is predominantly expressed on C-fibers on the superficial dorsal horn.


Interferon alpha inhibits spinal cord synaptic and nociceptive transmission via neuronal-glial interactions
Expression of IFN-α receptors in the spinal cord dorsal horn.(A–C) Double staining of Type I-IFN receptor (IFN-α/βR) and CGRP in the superficial dorsal horn. Scale, 100 μm. (D,E) High magnification images showing colocalization of IFN-α/βR and CGRP in primary afferent terminals in the superficial dorsal horn (laminae I-IIo). Arrows in (D) indicate double-labeled terminals. Arrows in E show IFN-α/βR labeling in inner lamina II (IIi). Scales, 3 μm (D) and 100 μm (E).
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5037469&req=5

f1: Expression of IFN-α receptors in the spinal cord dorsal horn.(A–C) Double staining of Type I-IFN receptor (IFN-α/βR) and CGRP in the superficial dorsal horn. Scale, 100 μm. (D,E) High magnification images showing colocalization of IFN-α/βR and CGRP in primary afferent terminals in the superficial dorsal horn (laminae I-IIo). Arrows in (D) indicate double-labeled terminals. Arrows in E show IFN-α/βR labeling in inner lamina II (IIi). Scales, 3 μm (D) and 100 μm (E).
Mentions: To determine the role of spinal IFN-α in pain modulation, we first investigated the expression of type-I IFN receptor (IFN-α/βR) in the spinal cord. Remarkably, IFN-α/βR expression was restricted to the superficial dorsal horn (laminae I-II) in the spinal cord, where nociceptive primary afferents (C/Aδ) terminate Fig. 1A). Double staining further demonstrated that IFN-α/βR was co-localized with the neuropeptide calcitonin gene-related peptide (CGRP) (Fig. 1B–D) in axonal terminals in the lamina I-IIo. Further analysis in higher magnification image showed additional IFN-α/βR staining in axonal terminals in the inner lamina II (IIi, Fig. 1E), suggesting that non-peptidergic fibers may also express IFN-α/βR. Together, these results imply that IFN-α/βR is predominantly expressed on C-fibers on the superficial dorsal horn.

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