Astroglial Glutamate–Glutamine Shuttle Is Involved in Central Sensitization of Nociceptive Neurons in Rat Medullary Dorsal Horn

Blockade of spinal glutamate recycling produces paradoxical antinociception in rats with orofacial inflammatory pain

“…Chronic constriction of the sciatic nerve (Garrison et al, 1991), spinal nerve ligation (Colburn et al, 1999;Zhuang et al, 2006), and infraorbital nerve ligation (Wei et al, 2008) have all been shown to result in the activation of astroglia and cell hypertrophy. Moreover, a recent report has indicated that the astroglial glutamate-glutamine shuttle is essential for the initiation of inflammation-induced central sensitization (Chiang et al, 2007). These results were further supported by our present immunohistochemical analysis.…”

“…The intrathecal administration of methionine sulfoximine (MSO), an astroglial glutamine synthetase inhibitor, attenuates nociceptive behavior (Tsuboi et al, 2011) and central sensitization in medullary dorsal horn neurons in models of trigeminal neuropathic pain (Chiang et al, 2007) and chronic pulpitis (Tsuboi et al, 2011). These findings suggest that the astroglial glutamate-glutamine shuttle is essential for maintaining glutamate homeostasis in the synapse.…”

SNO-ing at the Nociceptive Synapse?

“…Although neurons themselves are able to release D-serine upon depolarization (Rosenberg et al, 2010) development of long-term potentiation (LTP) depends on the release of D-serine from astrocytes (Henneberger et al, 2010), which thereby control NMDA-receptor-dependent plasticity in nearby excitatory synapses. NMDA receptordependent LTP at the nociceptive synapse in the spinal cord presumably depends on neuron-to-glia and glia-toneuron communication via nitric oxide (Chiang et al, 2007) (Fig. 4).…”

Cyclotraxin-B, a New TrkB Antagonist, and Glial Blockade by Propentofylline, Equally Prevent and Reverse Cold Allodynia Induced by BDNF or Partial Infraorbital Nerve Constriction in Mice

“…Signaling systems involving cytokines, adenosine triphosphate (ATP), and brainderived neurotrophic factor (BDNF) could contribute to the progressive, long-term increases in excitability of second-order neurons following nerve injury. 3,22 Recent studies have shown that activation of microglia and astrocytes also contributes to the so-called central sensitization phenomenon in the spinal cord dorsal horn and trigeminal nucleus caudalis by releasing a number of substances, 7,8,17,37,46 again including BDNF. 11 BDNF could play a key role as a central pronociceptive modulator of pain, acting through postsynaptic TrkB receptors whose activation triggers intracellular signaling cascades leading to central sensitization.…”