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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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IFN-α is an endogenous pain inhibitor.(A,B) Intrathecal injection of IFN-α (100 ng) on CFA day 4 reduces CFA-induced heat hyperalgesia (A) and mechanical allodynia. *P < 0.05; ***P < 0.001, compared to corresponding saline control, n = 5 rats/group. (C) Intrathecal IFN-α raises paw withdrawal latency in naive rats. *P < 0.05, compared to saline control, n = 6 rats/group. (D) Intrathecal IFN-α neutralizing antibody (30 ng) decreases paw withdrawal latency in naive rats. *P < 0.05, compared to control serum (30 ng), n = 8 rats/group. (E) Intrathecal IFN-α decreases paw withdrawal threshold and induces heat hyperalgesia in naive rats. *P < 0.05, compared to control serum (30 ng), n = 5 rats/group. (F) Intrathecal IFN-α neutralizing antibody (30 ng) decreases paw withdrawal threshold and induces mechanical allodynia in naive rats. *P < 0.05, compared to control serum (30 ng), n = 5 rats/group. The data were compared by student’s t-test. All data were mean ± S.E.M.
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f7: IFN-α is an endogenous pain inhibitor.(A,B) Intrathecal injection of IFN-α (100 ng) on CFA day 4 reduces CFA-induced heat hyperalgesia (A) and mechanical allodynia. *P < 0.05; ***P < 0.001, compared to corresponding saline control, n = 5 rats/group. (C) Intrathecal IFN-α raises paw withdrawal latency in naive rats. *P < 0.05, compared to saline control, n = 6 rats/group. (D) Intrathecal IFN-α neutralizing antibody (30 ng) decreases paw withdrawal latency in naive rats. *P < 0.05, compared to control serum (30 ng), n = 8 rats/group. (E) Intrathecal IFN-α decreases paw withdrawal threshold and induces heat hyperalgesia in naive rats. *P < 0.05, compared to control serum (30 ng), n = 5 rats/group. (F) Intrathecal IFN-α neutralizing antibody (30 ng) decreases paw withdrawal threshold and induces mechanical allodynia in naive rats. *P < 0.05, compared to control serum (30 ng), n = 5 rats/group. The data were compared by student’s t-test. All data were mean ± S.E.M.

Mentions: To determine whether spinal IFN-α would regulate pain sensitivity, we induced inflammatory pain by intraplantar injection of complete Freund’s adjuvant (CFA). Four days after CFA injection, inflamed rats exhibited robust heat hyperalgesia, a reduction in paw withdrawal latency (Fig. 7A), and mechanical allodynia, a reduction in paw withdrawal threshold (Fig. 7B). Intrathecal (i.t.) administration of IFN-α (100 ng) significantly reduced CFA-induced heat hyperalgesia (Fig. 7A) and mechanical allodynia (Fig. 7B) one and two hours after the injection (P < 0.01, n = 5). Intrathecal IFN-α (100 ng) also increased paw withdrawal latency and paw withdrawal threshold in naïve animals (Fig. 7C,E), indicating an analgesic action of IFN-α.


Interferon alpha inhibits spinal cord synaptic and nociceptive transmission via neuronal-glial interactions
IFN-α is an endogenous pain inhibitor.(A,B) Intrathecal injection of IFN-α (100 ng) on CFA day 4 reduces CFA-induced heat hyperalgesia (A) and mechanical allodynia. *P < 0.05; ***P < 0.001, compared to corresponding saline control, n = 5 rats/group. (C) Intrathecal IFN-α raises paw withdrawal latency in naive rats. *P < 0.05, compared to saline control, n = 6 rats/group. (D) Intrathecal IFN-α neutralizing antibody (30 ng) decreases paw withdrawal latency in naive rats. *P < 0.05, compared to control serum (30 ng), n = 8 rats/group. (E) Intrathecal IFN-α decreases paw withdrawal threshold and induces heat hyperalgesia in naive rats. *P < 0.05, compared to control serum (30 ng), n = 5 rats/group. (F) Intrathecal IFN-α neutralizing antibody (30 ng) decreases paw withdrawal threshold and induces mechanical allodynia in naive rats. *P < 0.05, compared to control serum (30 ng), n = 5 rats/group. The data were compared by student’s t-test. All data were mean ± S.E.M.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7: IFN-α is an endogenous pain inhibitor.(A,B) Intrathecal injection of IFN-α (100 ng) on CFA day 4 reduces CFA-induced heat hyperalgesia (A) and mechanical allodynia. *P < 0.05; ***P < 0.001, compared to corresponding saline control, n = 5 rats/group. (C) Intrathecal IFN-α raises paw withdrawal latency in naive rats. *P < 0.05, compared to saline control, n = 6 rats/group. (D) Intrathecal IFN-α neutralizing antibody (30 ng) decreases paw withdrawal latency in naive rats. *P < 0.05, compared to control serum (30 ng), n = 8 rats/group. (E) Intrathecal IFN-α decreases paw withdrawal threshold and induces heat hyperalgesia in naive rats. *P < 0.05, compared to control serum (30 ng), n = 5 rats/group. (F) Intrathecal IFN-α neutralizing antibody (30 ng) decreases paw withdrawal threshold and induces mechanical allodynia in naive rats. *P < 0.05, compared to control serum (30 ng), n = 5 rats/group. The data were compared by student’s t-test. All data were mean ± S.E.M.
Mentions: To determine whether spinal IFN-α would regulate pain sensitivity, we induced inflammatory pain by intraplantar injection of complete Freund’s adjuvant (CFA). Four days after CFA injection, inflamed rats exhibited robust heat hyperalgesia, a reduction in paw withdrawal latency (Fig. 7A), and mechanical allodynia, a reduction in paw withdrawal threshold (Fig. 7B). Intrathecal (i.t.) administration of IFN-α (100 ng) significantly reduced CFA-induced heat hyperalgesia (Fig. 7A) and mechanical allodynia (Fig. 7B) one and two hours after the injection (P < 0.01, n = 5). Intrathecal IFN-α (100 ng) also increased paw withdrawal latency and paw withdrawal threshold in naïve animals (Fig. 7C,E), indicating an analgesic action of IFN-α.

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