Acute morphine activates satellite glial cells and up-regulates IL-1β in dorsal root ganglia in mice via matrix metalloprotease-9

Sensory Plasticity Laboratory, Pain Research Center, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Molecular Pain (Impact Factor: 3.65). 03/2012; 8(1):18. DOI: 10.1186/1744-8069-8-18
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Activation of spinal cord glial cells such as microglia and astrocytes has been shown to regulate chronic opioid-induced antinociceptive tolerance and hyperalgesia, due to spinal up-regulation of the proinflammatory cytokines such as interleukin-1 beta (IL-1β). Matrix metalloprotease-9 (MMP-9) has been implicated in IL-1β activation in neuropathic pain. However, it is unclear whether acute opioid treatment can activate glial cells in the peripheral nervous system. We examined acute morphine-induced activation of satellite glial cells (SGCs) and up-regulation of IL-1β in dorsal root ganglia (DRGs), and further investigated the involvement of MMP-9 in these opioid-induced peripheral changes.
Subcutaneous morphine injection (10 mg/kg) induced robust peripheral glial responses, as evidenced by increased GFAP expression in DRGs but not in spinal cords. The acute morphine-induced GFAP expression is transient, peaking at 2 h and declining after 3 h. Acute morphine treatment also increased IL-1β immunoreactivity in SGCs and IL-1β activation in DRGs. MMP-9 and GFAP are expressed in DRG neurons and SGCs, respectively. Confocal analysis revealed a close proximity of MMP-9 and GFAP immunostaining. Importantly, morphine-induced DRG up-regulation of GFAP expression and IL-1β activation was abolished after Mmp9 deletion or naloxone pre-treatment. Finally, intrathecal injections of IL-1β-selective siRNA not only reduced DRG IL-1β expression but also prolonged acute morphine-induced analgesia.
Acute morphine induces opioid receptors- and MMP-9-dependent up-regulation of GFAP expression and IL-1β activation in SGCs of DRGs. MMP-9 could mask and shorten morphine analgesia via peripheral neuron-glial interactions. Targeting peripheral glial activation might prolong acute opioid analgesia.

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    • "Indeed, neutrophil-and macrophage-derived serine proteases such as PR3, elastase, and cathepsin-G have been identified as alternative enzymes implicated in processing pro-IL-1b into 21-kDa active fragments (Dinarello, 1996; Coeshott et al., 1999; Greten et al., 2007; Joosten et al., 2009; Netea et al., 2010; van de Veerdonk et al., 2011). Moreover, the gelatinases, MMP2 and MMP9, have been suggested to process pro-IL-1b into bioactive IL-1b in vitro (Scho¨nbeck et al., 1998) and in vivo (Amantea et al., 2007; Berta et al., 2012). We have previously observed that early brain elevation of IL-1b after transient MCAo in rats is associated with increased gelatinolytic activity and cytokine production is prevented by GM6001, a broad spectrum inhibitor of MMPs (Amantea et al., 2007). "
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    • "Additionally, IL-1β induces MMP-9 secretion and activation via NF-κB signaling pathways, which conferred a barrier-damage effect [33], [34]. In turn, active MMP-9 could further drive IL-1β activation [35]. Moreover, MMP-9 alters the localization of tight junction components, such as claudin-1, occludin, and ZO-1, adversely affecting barrier function and eventually directly damaging respiratory epithelium in asthma [36], [37]. "
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    • "In fact, among the variety of substances released by activated immune and glial cells, proinflammatory cytokines (TNF-α, IL-1, IL-6) appear to be of particular importance in neuronal hyperexcitability (29). The satellite glial cells in DRG and TG have gained attention in recent years, particularly for their involvement in pain facilitation (30,31). These SGCs act as a mechanical barrier to neurons of the DRG and TG (15), participate in neurotransmitter reuptake mechanisms and can exert fine control of the neuronal microenvironment (32). "
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