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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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IFN-α inhibits nociceptive signal transduction in the spinal cord.(A) Intraplantar capsaicin (75 μg, 5 min) induces NK-1 internalization in superficial dorsal horn neurons, which is suppressed by IFN-α (i.t., 100 ng). Green and white arrows indicate surface-expressed and internalized NK-1 receptors, respectively. Scales, 10 μm. Low panel, Percentage of NK-1-positive neurons with receptor internalization in laminae I-II. **P < 0.01, one-way ANOVA, n = 4 rats/group. Scale, 10 μm. (B) Bath application of capsaicin (3 mM, 5 min) to spinal cord slices induces robust ERK phosphorylation (pERK), which is abolished by IFN-α (2.5 ng/ml). Scale, 100 μm. Low panel, number of pERK (+) neurons in superficial dorsal horn. **P < 0.01, one-way ANOVA, n = 4 slices from separate rats. (C) Double staining of NK-1 and pERK shows co-localization in a lamina I neuron following intraplantar capsaicin (75 μg, 5 min). Scale, 100 μm. All data were mean ± S.E.M.
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f4: IFN-α inhibits nociceptive signal transduction in the spinal cord.(A) Intraplantar capsaicin (75 μg, 5 min) induces NK-1 internalization in superficial dorsal horn neurons, which is suppressed by IFN-α (i.t., 100 ng). Green and white arrows indicate surface-expressed and internalized NK-1 receptors, respectively. Scales, 10 μm. Low panel, Percentage of NK-1-positive neurons with receptor internalization in laminae I-II. **P < 0.01, one-way ANOVA, n = 4 rats/group. Scale, 10 μm. (B) Bath application of capsaicin (3 mM, 5 min) to spinal cord slices induces robust ERK phosphorylation (pERK), which is abolished by IFN-α (2.5 ng/ml). Scale, 100 μm. Low panel, number of pERK (+) neurons in superficial dorsal horn. **P < 0.01, one-way ANOVA, n = 4 slices from separate rats. (C) Double staining of NK-1 and pERK shows co-localization in a lamina I neuron following intraplantar capsaicin (75 μg, 5 min). Scale, 100 μm. All data were mean ± S.E.M.

Mentions: To further support the idea that IFN-α inhibits nociceptive transmission in the spinal cord, we examined the release of the neuropeptide substance P, an important neurotransmitter for pain. Noxious stimulation-induced substance P release is measured by internalization of its NK-1 receptors in dorsal horn neurons2930. NK-1 was normally expressed on cell surface in the superficial dorsal horn especially in lamina I, and only 10% NK-1-positive neurons showed notable NK-1 expression in endosomes (Fig. 4A). Intraplantar injection of capsaicin elicited marked NK-1 internalization: more than 80% NK-1-positve neurons exhibited NK-1 labeling in endosome-like structures after 5 min (Fig. 4A). Notably, intrathecal administration of IFN-α (100 ng), 30 min prior to capsaicin injection, significantly suppressed capsaicin-induced NK-1 internalization (Fig. 4A, P < 0.01, n = 4).


Interferon alpha inhibits spinal cord synaptic and nociceptive transmission via neuronal-glial interactions
IFN-α inhibits nociceptive signal transduction in the spinal cord.(A) Intraplantar capsaicin (75 μg, 5 min) induces NK-1 internalization in superficial dorsal horn neurons, which is suppressed by IFN-α (i.t., 100 ng). Green and white arrows indicate surface-expressed and internalized NK-1 receptors, respectively. Scales, 10 μm. Low panel, Percentage of NK-1-positive neurons with receptor internalization in laminae I-II. **P < 0.01, one-way ANOVA, n = 4 rats/group. Scale, 10 μm. (B) Bath application of capsaicin (3 mM, 5 min) to spinal cord slices induces robust ERK phosphorylation (pERK), which is abolished by IFN-α (2.5 ng/ml). Scale, 100 μm. Low panel, number of pERK (+) neurons in superficial dorsal horn. **P < 0.01, one-way ANOVA, n = 4 slices from separate rats. (C) Double staining of NK-1 and pERK shows co-localization in a lamina I neuron following intraplantar capsaicin (75 μg, 5 min). Scale, 100 μm. All data were mean ± S.E.M.
© Copyright Policy - open-access
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getmorefigures.php?uid=PMC5037469&req=5

f4: IFN-α inhibits nociceptive signal transduction in the spinal cord.(A) Intraplantar capsaicin (75 μg, 5 min) induces NK-1 internalization in superficial dorsal horn neurons, which is suppressed by IFN-α (i.t., 100 ng). Green and white arrows indicate surface-expressed and internalized NK-1 receptors, respectively. Scales, 10 μm. Low panel, Percentage of NK-1-positive neurons with receptor internalization in laminae I-II. **P < 0.01, one-way ANOVA, n = 4 rats/group. Scale, 10 μm. (B) Bath application of capsaicin (3 mM, 5 min) to spinal cord slices induces robust ERK phosphorylation (pERK), which is abolished by IFN-α (2.5 ng/ml). Scale, 100 μm. Low panel, number of pERK (+) neurons in superficial dorsal horn. **P < 0.01, one-way ANOVA, n = 4 slices from separate rats. (C) Double staining of NK-1 and pERK shows co-localization in a lamina I neuron following intraplantar capsaicin (75 μg, 5 min). Scale, 100 μm. All data were mean ± S.E.M.
Mentions: To further support the idea that IFN-α inhibits nociceptive transmission in the spinal cord, we examined the release of the neuropeptide substance P, an important neurotransmitter for pain. Noxious stimulation-induced substance P release is measured by internalization of its NK-1 receptors in dorsal horn neurons2930. NK-1 was normally expressed on cell surface in the superficial dorsal horn especially in lamina I, and only 10% NK-1-positive neurons showed notable NK-1 expression in endosomes (Fig. 4A). Intraplantar injection of capsaicin elicited marked NK-1 internalization: more than 80% NK-1-positve neurons exhibited NK-1 labeling in endosome-like structures after 5 min (Fig. 4A). Notably, intrathecal administration of IFN-α (100 ng), 30 min prior to capsaicin injection, significantly suppressed capsaicin-induced NK-1 internalization (Fig. 4A, P < 0.01, n = 4).

View Article: PubMed Central - PubMed

ABSTRACT

It is well known that interferons (IFNs), such as type-I IFN (IFN-&alpha;) and type-II IFN (IFN-&gamma;) 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-&gamma; drives neuropathic pain by inducing microglial activation in the spinal cord. However, little is known about the role of IFN-&alpha; in regulating pain sensitivity and synaptic transmission. Strikingly, we found that IFN-&alpha;/&beta; 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-&alpha; was primarily expressed by astrocytes. Perfusion of spinal cord slices with IFN-&alpha; suppressed excitatory synaptic transmission by reducing the frequency of spontaneous excitatory postsynaptic current (sEPSCs). IFN-&alpha; 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-&alpha; reduced inflammatory pain and increased pain threshold in na&iuml;ve rats, whereas removal of endogenous IFN-&alpha; by a neutralizing antibody induced hyperalgesia. Our findings suggest a new form of neuronal-glial interaction by which IFN-&alpha;, produced by astrocytes, inhibits nociceptive transmission in the spinal cord.

No MeSH data available.


Related in: MedlinePlus