Metabotropic glutamate receptors are expressed abundantly in the spinal cord and have been shown to play important roles in the modulation of nociceptive transmission and plasticity. Most previous studies have focused on the group I metabotropic glutamate receptors (mGluR1 and mGluR5) and activation of phospholipase C signaling by these receptors in modulating nociception. Recently, it was shown that the extracellular signal-regulated kinases (ERKs)/mitogen-activated protein kinases are activated in spinal cord dorsal horn neurons in response to stimulation of nociceptors and that ERK signaling is involved in nociceptive plasticity. In the present studies, we sought to test the hypothesis that group I mGluRs modulate nociceptive transmission or plasticity via modulation of ERK signaling in dorsal horn neurons. We show that activation of mGluR1 and mGluR5 leads to activation of ERK1 and ERK2 in the spinal cord. Furthermore, we find that inflammation-evoked ERK activation, which is required for nociceptive plasticity, is downstream of mGluR1 and mGluR5. Finally, we show colocalization of group I mGluRs with activated ERK in dorsal horn neurons. These results show that mGluR1 and mGluR5 are activated in dorsal horn neurons in response to peripheral inflammation and that activation of these group I mGluRs leads to activation of ERK1 and ERK2, resulting in enhanced pain sensitivity.

Plantar incision-induced mechanical allodynia can be prevented by the p38 inhibitor. Our results suggest that p38 activation in spinal microglia play a role in incision-induced mechanical allodynia in rats. Therefore, p38 inhibition may be useful in treating postsurgical pain.

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A midline dorsal column lesion has been shown to be an effective surgical treatment for the relief of pelvic visceral pain in patients. The aim of this study was to examine the effectiveness of a dorsal column lesion upon: (i) increased electrophysiological responses of neurons in the ventral posterolateral thalamic nucleus in anesthetized rats evoked by the application of bradykinin to the surface of the pancreas, and (ii) pain-related behaviors observed after pancreatic infusion with bradykinin. In rats anesthetized with pentobarbital, recordings from individual thalamic neurons were made using tungsten electrodes. Brief application of bradykinin (10 microg/ml) to the surface of the pancreas resulted in an increased firing rate in approximately 20% of neurons recorded. A dorsal column lesion or intrathecal administration of morphine greatly reduced the excitatory effects of pancreatic bradykinin application on thalamic neurons. In a separate group of rats, bradykinin was infused into the pancreas through a previously implanted catheter resulting in a decrease in exploratory behavior and an increase in other pain-related behaviors, e.g. licking of the abdomen. A dorsal column lesion made prior (1 week) to the bradykinin infusion reduced the decrease in exploratory behavior but did not return exploratory behavior to control levels. In conclusion, nociceptive information relayed to the thalamus about the pancreas is transmitted from the spinal cord through the dorsal columns, possibly by the post-synaptic dorsal column pathway. However, the dorsal column pathway may not be the sole route for relaying information about noxious stimulation of the pancreas, particularly that impacting complex behavioral responses.

Although nerve injury-induced long-term postsynaptic changes have been investigated, less is known regarding the molecular mechanisms within presynaptic axonal terminals. We investigated the molecular changes in presynaptic nerve terminals underlying chronic pain-induced plastic changes in the medial prefrontal cortex (mPFC). After neuropathic pain was induced by spared nerve injury (SNI) in rats, we assessed the release of the excitatory neurotransmitter glutamate by using in vitro synaptosomal preparations from the mPFC. We also measured the levels of synaptic proteins and protein kinases in synaptosomes using Western blotting. The results showed that unilateral long-term SNI augmented depolarization-evoked glutamate release from synaptosomes of the bilateral mPFC. This result was confirmed by a rapid destaining rate of FM1-43 dye in SNI-operated rats. Unilateral long-term nerve injury also significantly increased synaptic proteins (including synaptophysin, synaptotagmin, synaptobrevin, syntaxin, and 25-kDa synaptosome-associated protein) in synaptosomal fractions from the bilateral mPFC, and ultrastructure images demonstrated increased synaptic vesicular profiles in synaptosomes from SNI animals. Chronic pain upregulated the phosphorylation of endogenous protein kinases, including extracellular signal-regulated kinases 1 and 2 (ERK1/2) and Ca(2+)/calmodulin-dependent kinase II (CaMKII), and synapsin I, the primary presynaptic target of ERK1/2 and CaMKII. Both presynaptic proteins and protein kinases were upregulated after SNI in a time-dependent manner. These results indicate that the long-term neuropathic pain-induced enhancement of glutamate release in the mPFC is linked to increased synaptic vesicle proteins and the activation of the ERK1/2- and CaMKII-synapsin signaling cascade in presynaptic axonal terminals.

In this study, we have examined the role of corticosterone (CORT) in the regulation of neuronal glutamate release using nerve terminals (synaptosomes) isolated from the rat hippocampus. Adult male Sprague-Dawley rats received either a chronic systemic administration of CORT (daily 25 mg/kg in sesame oil, subcutaneously) or long-term bilateral adrenalectomy (ADX) (3-4 weeks), and then the release of 4-aminopyridine (4AP)-evoked endogenous glutamate and the levels of glucocorticoid receptor (GR) expression from hippocampal nerve terminals were studied. Chronic administration of CORT resulted in a significant increase of 4AP-evoked glutamate release from hippocampal nerve terminals, whereas ADX reduced 4AP-evoked glutamate release. In addition, chronic administration of CORT and ADX induced a significant reduction and increase in GR expression in hippocampal synaptosomes, respectively, as detected by Western blots. Furthermore, acute treatment of CORT or dexamethasone facilitated 4AP-evoked glutamate release from synaptosomes freshly isolated from naïve rat hippocampus and this effect can be significantly prevented by pretreatment of GR antagonist mifepristone, but not by mineralocorticoid receptor (MR) antagonist RU28318. Together, our results strongly support the presence of GRs on presynaptic nerve terminals in the rat hippocampus acting to facilitate the release of neuronal glutamate.