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
Source: PubMed


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.

Download full-text


Available from: Tong Liu
  • Source
    • "The MMP-3- mediated activation of microglia is a characteristic response to neuronal apoptosis for inflammatory reactions, which subsequently exacerbate neuronal apoptosis[15,87]. MMP-2 and MMP-9 have been suggested to process pro-IL-1í µí»½ into bioactive IL-1í µí»½ in vitro[88]and in vivo[34,89]. Studies have proposed that MMPs may mediate neuronal death by proapoptotic signaling upstream of caspases , potentiating neuroinflammation through processing of IL-1í µí»½ in ischemic cortex[87,90,91]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Evidence of the pathological roles of matrix metalloproteinases (MMPs) in various neurological disorders has made them attractive therapeutic targets. MMPs disrupt the blood-brain barrier and cause neuronal death and neuroinflammation in acute cerebral ischemia and are critical for angiogenesis during recovery. However, some challenges have to be overcome before MMPs can be further validated as drug targets in stroke injury. Identifying in vivo substrates of MMPs should greatly improve our understanding of the mechanisms of ischemic injury and is critical for providing more precise drug targets. Recent works have uncovered nontraditional roles for MMPs in the cytosol and nucleus. These have shed light on intracellular targets and biological actions of MMPs, adding additional layers of complexity for therapeutic MMP inhibition. In this review, we discussed the recent advances made in understanding nuclear location of MMPs, their regulation of intranuclear sorting, and their intranuclear proteolytic activity and substrates. In particular, we highlighted the roles of intranuclear MMPs in oxidative DNA damage, neuronal apoptosis, and neuroinflammation at an early stage of stroke insult. These novel data point to new putative MMP-mediated intranuclear actions in stroke-induced pathological processes and may lead to novel approaches to treatment of stroke and other neurological diseases.
    Full-text · Article · Jan 2016 · Oxidative medicine and cellular longevity
  • Source
    • "The prevailing evidence shows that acute and chronic morphine treatment increases the expression of TNF-α, IL-1β, and IL-6 in activated glia in the DRG and spinal cord, which ultimately results in the decreased analgesic efficacy of morphine. The development and maintenance of morphine tolerance are effectively prevented by inhibition of the synthesis of these cytokines or by their neutralization with specific antibodies in the spinal cord [15] [17] [18] [19] [20] . NF-κB activation plays an important role in regulating the expression of TNF-α, IL-1β, IL-6, and other cytokines in immune cells [4] . "
    [Show abstract] [Hide abstract]
    ABSTRACT: Nuclear factor kappa B (NF-κB) in the spinal cord is involved in pro-inflammatory cytokine-mediated pain facilitation. However, the role of NF-κB activation in chronic morphine-induced analgesic tolerance and the underlying mechanisms remain unclear. In the present study, we found that the level of phosphorylated NF-κB p65 (p-p65) was increased in the dorsal horn of the lumbar 4-6 segments after intrathecal administration of morphine for 7 consecutive days, and the p-p65 was co-localized with neurons and astrocytes. The expression of TNF-α and IL-1β was also increased in the same area. In addition, pretreatment with pyrrolidinedithiocarbamate (PDTC) or SN50, inhibitors of NF-κB, prevented the development of morphine analgesic tolerance and alleviated morphine withdrawal-induced allodynia and hyperalgesia. The increase in TNF-α and IL-1β expression induced by chronic morphine exposure was also partially blocked by PDTC pretreatment. In another experiment, rats receiving PDTC or SN50 beginning on day 7 of morphine injection showed partial recovery of the anti-nociceptive effects of morphine and attenuation of the withdrawal-induced abnormal pain. Meanwhile, intrathecal pretreatment with lipopolysaccharide from Rhodobacter sphaeroides, an antagonist of toll-like receptor 4 (TLR4), blocked the activation of NF-κB, and prevented the development of morphine tolerance and withdrawal-induced abnormal pain. These data indicated that TLR4-mediated NF-κB activation in the spinal cord is involved in the development and maintenance of morphine analgesic tolerance and withdrawal-induced pain hypersensitivity.
    Full-text · Article · Dec 2014 · Neuroscience Bulletin
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The pathophysiological processes implicated in ischemic brain damage are strongly affected by an inflammatory reaction characterised by activation of immune cells and release of soluble mediators, including cytokines and chemokines. The pro-inflammatory cytokine interleukin (IL)-1β has been implicated in ischemic brain injury, however, to date, the mechanisms involved in the maturation of this cytokine in the ischemic brain have not been completely elucidated. We have previously suggested that matrix metalloproteases (MMPs) may be implicated in cytokine production under pathological conditions. Here, we demonstrate that significant elevation of IL-1β occurs in the cortex as early as 1h after the beginning of reperfusion in rats subjected to 2h middle cerebral artery occlusion (MCAo). At this early stage, we observe increased expression of IL-1β in pericallosal astroglial cells and in cortical neurons and this latter signal colocalizes with elevated gelatinolytic activity. By gel zymography, we demonstrate that the increased gelatinolytic signal at 1h reperfusion is mainly ascribed to MMP2. Thus, MMP2 seems to contribute to early brain elevation of IL-β after transient ischemia and this mechanism may promote damage since pharmacological inhibition of gelatinases by the selective MMP2/MMP9 inhibitor V provides neuroprotection in rats subjected to transient MCAo.
    Full-text · Article · Aug 2014 · Neuroscience
Show more