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

ABSTRACT

BACKGROUND: 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-1ß). Matrix metalloprotease-9 (MMP-9) has been implicated in IL-1ß 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-1ß in dorsal root ganglia (DRGs), and further investigated the involvement of MMP-9 in these opioid-induced peripheral changes. RESULTS: 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-1ß immunoreactivity in SGCs and IL-1ß 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-1ß activation was abolished after Mmp9 deletion or naloxone pre-treatment. Finally, intrathecal injections of IL-1ß-selective siRNA not only reduced DRG IL-1ß expression but also prolonged acute morphine-induced analgesia. CONCLUSIONS: Acute morphine induces opioid receptors- and MMP-9-dependent up-regulation of GFAP expression and IL-1ß 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.