Group I metabotropic glutamate receptor plasticity after peripheral inflammation alters nociceptive transmission in the dorsal horn of the spinal cord in adult rats

Abstract

The dorsal horn of the spinal cord is a crucial site for pain transmission and modulation. Dorsal horn neurons of the spinal cord express group I metabotropic glutamate receptors (group I mGluRs) that exert a complex role in nociceptive transmission. In particular, group I mGluRs promote the activation of L-type calcium channels, voltage-gated channels involved in short- and long-term sensitization to pain. In this study, we analyzed the role of group I mGluRs in spinal nociceptive transmission and the possible cooperation between these receptors and L-type calcium channels in the pathophysiology of pain transmission in the dorsal horn of the spinal cord. We demonstrate that the activation of group I mGluRs induces allodynia and L-type calcium channel-dependent increase in nociceptive field potentials following sciatic nerve stimulation. Surprisingly, in a model of persistent inflammation induced by complete Freund’s adjuvant, the activation of group I mGluRs induced an analgesia and a decrease in nociceptive field potentials. Among the group I mGluRs, mGluR1 promotes the activation of L-type calcium channels and increased nociceptive transmission while mGluR5 induces the opposite through the inhibitory network. These results suggest a functional switch exists in pathological conditions that can change the action of group I mGluR agonists into possible analgesic molecules, thereby suggesting new therapeutic perspectives to treat persistent pain in inflammatory settings.

Alteration of nociceptive integration in the spinal cord of a rat model of Parkinson's disease

“…Mechanical allodynia was assessed by the electronic von Frey test (Bioseb, Vitrolles, France), in order to measure the mechanical threshold of the hindpaw withdrawal reflex, as previously described . A progressive pressure was applied, with pipette tip connected to a force sensor, under the paw of the hindlimb until the animals withdraw the limb.…”

Recent Advances in the Modulation of Pain by the Metabotropic Glutamate Receptors

“…Spinal cord. Intrathecal administration of a group I mGluR agonist (DHPG or 1S,3R-ACPD) induced nociceptive behaviors [ 54 , 55 , 59 , 60 , 61 ], cold hypersensitivity [ 56 ], mechanical allodynia and thermal hyperalgesia [ 57 , 58 , 62 ] in normal animals; these effects were blocked by pretreatment with mGluR1 NAM (CPCCOEt) [ 59 ] or mGluR5 NAM (MPEP) [ 55 , 56 , 59 ] and correlated with activation of extracellular signal-regulated kinases ERK1 and ERK2 in the spinal cord [ 59 ], suggesting that activation of spinal group I mGluRs mediates nociceptive responses. Interestingly, the effects of DHPG were lost in K + channel subunit Kv4.2 knock-out mice, providing evidence that Kv4.2 expression is necessary for DHPG-induced nociceptive behaviors [ 61 ]; moreover, DHPG (i.th.)…”

“…potentiated, in a dose-dependent fashion, the nociceptive responses in the formalin test [ 63 ] and in the CFA inflammatory pain model [ 60 ]; these facilitatory effects were reverted by a group I mGluR antagonist (S-4C3HPG) [ 63 ]. Surprisingly in a recent study the intrathecal application of a group I mGluR agonist (1S,3R-ACPD) had antinociceptive properties in the CFA model of inflammatory pain, suggesting a potential switch of the receptor functions in pathological conditions [ 58 ]. Spinal blockade of group I mGluRs by the application of an antagonist (LY393053, i.th.)…”

Meclizine and metabotropic glutamate receptor agonists attenuate severe pain and primary sensory neuron Ca2+activity in chemotherapy-induced peripheral neuropathy

“…All mGluRs except mGluR6 are found on central and/or peripheral neurons known to be involved in nociception and are known to affect pain (9,(25)(26)(27)(28)(29)(30). In particular, inflammatory pain is attenuated by group II mGluRs (mGluR2 and mGluR3) and group III mGluRs (mGlurR4, mGluR7, and mGluR8) (27,30,31) and enhanced or modulated by group I mGluRs (mGluR1 and mGluR5) (27,(30)(31)(32)(33)(34)(35). Thus, metabotropic glutamate receptors (mGluRs), especially group II and III, are promising therapeutic targets for CIPNinduced neuropathic pain (27,30).…”