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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 excitatory synaptic transmission in IIo neurons of rat and mouse spinal cord.(A) Patch clamp recording in spinal cord slice (ex vivo) shows an inhibition of the frequency but not the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in lamina II neurons after superfusion of IFN-α (rat, 25 ng/ml, 2 min). i and ii are enlarged recordings before and after IFN-α application. iii and iv are further enlargements of i and ii, respectively. (B) Frequency and amplitude of sEPSCs, expressed as ratio of baseline. 7 out of 9 recorded neurons respond to IFN-α. *P < 0.05, n = 7 neurons/group. The comparison was made between pre-treatment baseline and post-treatment in the same neurons using two-tailed paired student’s t-test. (C) Mouse spinal cord slice image showing a recording electrode (white arrow) in a SOM+ neuron (black arrow). Scale, 20 μm. (D) Traces of sEPSCs in mouse spinal cord slice before and after the IFN-α treatment (mouse, 50 Units/ml). (E) Frequency and amplitude of sEPSCs in mouse spinal cord slice. *P < 0.05, two-tailed paired student’s test, n = 6 neurons/group. ns, not significant. All the data were mean ± S.E.M.
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f3: IFN-α inhibits excitatory synaptic transmission in IIo neurons of rat and mouse spinal cord.(A) Patch clamp recording in spinal cord slice (ex vivo) shows an inhibition of the frequency but not the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in lamina II neurons after superfusion of IFN-α (rat, 25 ng/ml, 2 min). i and ii are enlarged recordings before and after IFN-α application. iii and iv are further enlargements of i and ii, respectively. (B) Frequency and amplitude of sEPSCs, expressed as ratio of baseline. 7 out of 9 recorded neurons respond to IFN-α. *P < 0.05, n = 7 neurons/group. The comparison was made between pre-treatment baseline and post-treatment in the same neurons using two-tailed paired student’s t-test. (C) Mouse spinal cord slice image showing a recording electrode (white arrow) in a SOM+ neuron (black arrow). Scale, 20 μm. (D) Traces of sEPSCs in mouse spinal cord slice before and after the IFN-α treatment (mouse, 50 Units/ml). (E) Frequency and amplitude of sEPSCs in mouse spinal cord slice. *P < 0.05, two-tailed paired student’s test, n = 6 neurons/group. ns, not significant. All the data were mean ± S.E.M.

Mentions: Since IFN-α/βR is localized in axonal terminals in the spinal cord, we hypothesized that IFN-α modulates neurotransmitter release and synaptic transmission in the spinal cord. To test this hypothesis, we used patch clamp technique to record spontaneous excitatory synaptic currents (sEPSCs) in lamina IIo nociceptive neurons in isolated spinal cord slices from rats. Application of IFN-α to spinal cord slices (25 ng/ml) significantly reduced the frequency of sEPSCs without changing the amplitude of sEPSCs (P < 0.05, paired two-tailed t-test) (Fig. 3A,B). Since 1) sEPSC is mediated by glutamate receptors (AMPA/Kainate receptors) and 2) frequency change of sEPSC is caused by presynaptic mechanism222324, our results suggest that IFN-α inhibits excitatory synaptic transmission by suppressing glutamate release from presynaptic terminals.


Interferon alpha inhibits spinal cord synaptic and nociceptive transmission via neuronal-glial interactions
IFN-α inhibits excitatory synaptic transmission in IIo neurons of rat and mouse spinal cord.(A) Patch clamp recording in spinal cord slice (ex vivo) shows an inhibition of the frequency but not the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in lamina II neurons after superfusion of IFN-α (rat, 25 ng/ml, 2 min). i and ii are enlarged recordings before and after IFN-α application. iii and iv are further enlargements of i and ii, respectively. (B) Frequency and amplitude of sEPSCs, expressed as ratio of baseline. 7 out of 9 recorded neurons respond to IFN-α. *P < 0.05, n = 7 neurons/group. The comparison was made between pre-treatment baseline and post-treatment in the same neurons using two-tailed paired student’s t-test. (C) Mouse spinal cord slice image showing a recording electrode (white arrow) in a SOM+ neuron (black arrow). Scale, 20 μm. (D) Traces of sEPSCs in mouse spinal cord slice before and after the IFN-α treatment (mouse, 50 Units/ml). (E) Frequency and amplitude of sEPSCs in mouse spinal cord slice. *P < 0.05, two-tailed paired student’s test, n = 6 neurons/group. ns, not significant. All the data were mean ± S.E.M.
© Copyright Policy - open-access
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getmorefigures.php?uid=PMC5037469&req=5

f3: IFN-α inhibits excitatory synaptic transmission in IIo neurons of rat and mouse spinal cord.(A) Patch clamp recording in spinal cord slice (ex vivo) shows an inhibition of the frequency but not the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in lamina II neurons after superfusion of IFN-α (rat, 25 ng/ml, 2 min). i and ii are enlarged recordings before and after IFN-α application. iii and iv are further enlargements of i and ii, respectively. (B) Frequency and amplitude of sEPSCs, expressed as ratio of baseline. 7 out of 9 recorded neurons respond to IFN-α. *P < 0.05, n = 7 neurons/group. The comparison was made between pre-treatment baseline and post-treatment in the same neurons using two-tailed paired student’s t-test. (C) Mouse spinal cord slice image showing a recording electrode (white arrow) in a SOM+ neuron (black arrow). Scale, 20 μm. (D) Traces of sEPSCs in mouse spinal cord slice before and after the IFN-α treatment (mouse, 50 Units/ml). (E) Frequency and amplitude of sEPSCs in mouse spinal cord slice. *P < 0.05, two-tailed paired student’s test, n = 6 neurons/group. ns, not significant. All the data were mean ± S.E.M.
Mentions: Since IFN-α/βR is localized in axonal terminals in the spinal cord, we hypothesized that IFN-α modulates neurotransmitter release and synaptic transmission in the spinal cord. To test this hypothesis, we used patch clamp technique to record spontaneous excitatory synaptic currents (sEPSCs) in lamina IIo nociceptive neurons in isolated spinal cord slices from rats. Application of IFN-α to spinal cord slices (25 ng/ml) significantly reduced the frequency of sEPSCs without changing the amplitude of sEPSCs (P < 0.05, paired two-tailed t-test) (Fig. 3A,B). Since 1) sEPSC is mediated by glutamate receptors (AMPA/Kainate receptors) and 2) frequency change of sEPSC is caused by presynaptic mechanism222324, our results suggest that IFN-α inhibits excitatory synaptic transmission by suppressing glutamate release from presynaptic terminals.

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