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.

POSTOPERATIVE pain results from surgical injuries in skin, fascia, muscle, and small nerves innervating these tissues and is a common form of acute pain in clinics. Despite increased basic and clinical research and improved understanding of pathologic mechanisms, optimal postsurgical pain therapy remains a challenge for physicians. To investigate the underlying mechanisms of postsurgical pain, Brennan et al. 1 have developed a rat model of incisional pain that is characterized by increased mechanical sensitivity after a surgical incision made in the plantar aspect of rat hind paw. This model has been shown to possess a battery of nociceptive responses that parallel the time course of postoperative pain in humans.1,2

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.