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Distinctive response of CNS glial cells in oro-facial pain associated with injury, infection and inflammation.

Lee S, Zhao YQ, Ribeiro-da-Silva A, Zhang J - Mol Pain (2010)

Bottom Line: However, LPS induced microglial activation did not specifically occur along the pain signaling pathway.In contrast, CFA injection led to minor microglial morphological changes and an induction of IκB-α mRNA in the CVO regions; a significant increase in IL-1β and IL-6 mRNA started only at 48 hours post-injection, when the induced pain-related behavior started to resolve.Our detailed analysis of CNS glial response clearly revealed that both nerve injury and oro-facial infection/inflammation induced CNS glial activation, but in a completely different pattern, which suggests a remarkable plasticity of glial cells in response to dynamic changes in their microenvironment and different potential involvement of this non-neuronal cell population in pathological pain development.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Alan Edwards Centre for Research on Pain, McGill University, 740, Dr, Penfield Ave, Montreal, Quebec, H3A 2B2, Canada.

ABSTRACT
Oro-facial pain following injury and infection is frequently observed in dental clinics. While neuropathic pain evoked by injury associated with nerve lesion has an involvement of glia/immune cells, inflammatory hyperalgesia has an exaggerated sensitization mediated by local and circulating immune mediators. To better understand the contribution of central nervous system (CNS) glial cells in these different pathological conditions, in this study we sought to characterize functional phenotypes of glial cells in response to trigeminal nerve injury (loose ligation of the mental branch), infection (subcutaneous injection of lipopolysaccharide--LPS) and to sterile inflammation (subcutaneous injection of complete Freund's adjuvant--CFA) on the lower lip. Each of the three insults triggered a specific pattern of mechanical allodynia. In parallel with changes in sensory response, CNS glial cells reacted distinctively to the challenges. Following ligation of the mental nerve, both microglia and astrocytes in the trigeminal nuclear complex were highly activated, more prominent in the principal sensory nucleus (Pr5) and subnucleus caudalis (Sp5C) area. Microglial response was initiated early (days 3-14), followed by delayed astrocytes activation (days 7-28). Although the temporal profile of microglial and astrocyte reaction corresponded respectively to the initiation and chronic stage of neuropathic pain, these activated glial cells exhibited a low profile of cytokine expression. Local injection of LPS in the lower lip skin also triggered a microglial reaction in the brain, which started in the circumventricular organs (CVOs) at 5 hours post-injection and diffused progressively into the brain parenchyma at 48 hours. This LPS-induced microglial reaction was accompanied by a robust induction of IκB-α mRNA and pro-inflammatory cytokines within the CVOs. However, LPS induced microglial activation did not specifically occur along the pain signaling pathway. In contrast, CFA injection led to minor microglial morphological changes and an induction of IκB-α mRNA in the CVO regions; a significant increase in IL-1β and IL-6 mRNA started only at 48 hours post-injection, when the induced pain-related behavior started to resolve. Our detailed analysis of CNS glial response clearly revealed that both nerve injury and oro-facial infection/inflammation induced CNS glial activation, but in a completely different pattern, which suggests a remarkable plasticity of glial cells in response to dynamic changes in their microenvironment and different potential involvement of this non-neuronal cell population in pathological pain development.

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Subcutaneous injection of LPS in the lower lip induced microglial activation in the brain. In response to local LPS administration, microglial activation was first observed in the CVOs, such as the area postrema (AP) and at the edge of the grey matter at 5 hours post-injection. At 48 hours, activated microglia were dispersed throughout the parenchyma. Activated microglia exhibited remarkable changes in microglial morphology (inserts). Diagrams were adapted and modified from [59]. Orange shadowed area indicated where the pictures were taken. Scale bar: 50 μm.
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Figure 5: Subcutaneous injection of LPS in the lower lip induced microglial activation in the brain. In response to local LPS administration, microglial activation was first observed in the CVOs, such as the area postrema (AP) and at the edge of the grey matter at 5 hours post-injection. At 48 hours, activated microglia were dispersed throughout the parenchyma. Activated microglia exhibited remarkable changes in microglial morphology (inserts). Diagrams were adapted and modified from [59]. Orange shadowed area indicated where the pictures were taken. Scale bar: 50 μm.

Mentions: To analyze the glial response to local oro-facial infection/inflammation, in addition to the trigeminal complex in the brainstem, we have paid special attention to regions where the capillaries in these structures are fenestrated and the blood brain barrier (BBB) is not complete, including circumventricular organs (CVOs), ventricles and choroid plexus. Five hours following LPS injection, at a time where an acute mechanical allodynia was detected in the lower lip, we found some morphological changes of Iba-1+ microglia in the CVOs, such as area postrema (AP) where the soma of these Iba-1+ cells started to enlarge, and displayed thick and rigid processes (Figure 5, mid-column). Some enlarged Iba-1+ cells also appeared at the edge of the grey matter (Figure 5, mid-column), but we did not observe any evidence of microglial activation restricted to the trigeminal complex. However, 48 hours later, when the mechanical hypersensitivity in the lower lips was completely resolved, scattered, enlarged, Iba-1 intensely labeled microglia were found across the entire parenchyma (Figure 5, right-column). No significant changes on GFAP labeled astrocytes were detected at any time, in any regions of the brain (data not shown).


Distinctive response of CNS glial cells in oro-facial pain associated with injury, infection and inflammation.

Lee S, Zhao YQ, Ribeiro-da-Silva A, Zhang J - Mol Pain (2010)

Subcutaneous injection of LPS in the lower lip induced microglial activation in the brain. In response to local LPS administration, microglial activation was first observed in the CVOs, such as the area postrema (AP) and at the edge of the grey matter at 5 hours post-injection. At 48 hours, activated microglia were dispersed throughout the parenchyma. Activated microglia exhibited remarkable changes in microglial morphology (inserts). Diagrams were adapted and modified from [59]. Orange shadowed area indicated where the pictures were taken. Scale bar: 50 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2992508&req=5

Figure 5: Subcutaneous injection of LPS in the lower lip induced microglial activation in the brain. In response to local LPS administration, microglial activation was first observed in the CVOs, such as the area postrema (AP) and at the edge of the grey matter at 5 hours post-injection. At 48 hours, activated microglia were dispersed throughout the parenchyma. Activated microglia exhibited remarkable changes in microglial morphology (inserts). Diagrams were adapted and modified from [59]. Orange shadowed area indicated where the pictures were taken. Scale bar: 50 μm.
Mentions: To analyze the glial response to local oro-facial infection/inflammation, in addition to the trigeminal complex in the brainstem, we have paid special attention to regions where the capillaries in these structures are fenestrated and the blood brain barrier (BBB) is not complete, including circumventricular organs (CVOs), ventricles and choroid plexus. Five hours following LPS injection, at a time where an acute mechanical allodynia was detected in the lower lip, we found some morphological changes of Iba-1+ microglia in the CVOs, such as area postrema (AP) where the soma of these Iba-1+ cells started to enlarge, and displayed thick and rigid processes (Figure 5, mid-column). Some enlarged Iba-1+ cells also appeared at the edge of the grey matter (Figure 5, mid-column), but we did not observe any evidence of microglial activation restricted to the trigeminal complex. However, 48 hours later, when the mechanical hypersensitivity in the lower lips was completely resolved, scattered, enlarged, Iba-1 intensely labeled microglia were found across the entire parenchyma (Figure 5, right-column). No significant changes on GFAP labeled astrocytes were detected at any time, in any regions of the brain (data not shown).

Bottom Line: However, LPS induced microglial activation did not specifically occur along the pain signaling pathway.In contrast, CFA injection led to minor microglial morphological changes and an induction of IκB-α mRNA in the CVO regions; a significant increase in IL-1β and IL-6 mRNA started only at 48 hours post-injection, when the induced pain-related behavior started to resolve.Our detailed analysis of CNS glial response clearly revealed that both nerve injury and oro-facial infection/inflammation induced CNS glial activation, but in a completely different pattern, which suggests a remarkable plasticity of glial cells in response to dynamic changes in their microenvironment and different potential involvement of this non-neuronal cell population in pathological pain development.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Alan Edwards Centre for Research on Pain, McGill University, 740, Dr, Penfield Ave, Montreal, Quebec, H3A 2B2, Canada.

ABSTRACT
Oro-facial pain following injury and infection is frequently observed in dental clinics. While neuropathic pain evoked by injury associated with nerve lesion has an involvement of glia/immune cells, inflammatory hyperalgesia has an exaggerated sensitization mediated by local and circulating immune mediators. To better understand the contribution of central nervous system (CNS) glial cells in these different pathological conditions, in this study we sought to characterize functional phenotypes of glial cells in response to trigeminal nerve injury (loose ligation of the mental branch), infection (subcutaneous injection of lipopolysaccharide--LPS) and to sterile inflammation (subcutaneous injection of complete Freund's adjuvant--CFA) on the lower lip. Each of the three insults triggered a specific pattern of mechanical allodynia. In parallel with changes in sensory response, CNS glial cells reacted distinctively to the challenges. Following ligation of the mental nerve, both microglia and astrocytes in the trigeminal nuclear complex were highly activated, more prominent in the principal sensory nucleus (Pr5) and subnucleus caudalis (Sp5C) area. Microglial response was initiated early (days 3-14), followed by delayed astrocytes activation (days 7-28). Although the temporal profile of microglial and astrocyte reaction corresponded respectively to the initiation and chronic stage of neuropathic pain, these activated glial cells exhibited a low profile of cytokine expression. Local injection of LPS in the lower lip skin also triggered a microglial reaction in the brain, which started in the circumventricular organs (CVOs) at 5 hours post-injection and diffused progressively into the brain parenchyma at 48 hours. This LPS-induced microglial reaction was accompanied by a robust induction of IκB-α mRNA and pro-inflammatory cytokines within the CVOs. However, LPS induced microglial activation did not specifically occur along the pain signaling pathway. In contrast, CFA injection led to minor microglial morphological changes and an induction of IκB-α mRNA in the CVO regions; a significant increase in IL-1β and IL-6 mRNA started only at 48 hours post-injection, when the induced pain-related behavior started to resolve. Our detailed analysis of CNS glial response clearly revealed that both nerve injury and oro-facial infection/inflammation induced CNS glial activation, but in a completely different pattern, which suggests a remarkable plasticity of glial cells in response to dynamic changes in their microenvironment and different potential involvement of this non-neuronal cell population in pathological pain development.

Show MeSH
Related in: MedlinePlus