Distinct Roles of Group III Metabotropic Glutamate Receptors in Control of Nociception and Dorsal Horn Neurons in Normal and Nerve-Injured Rats

Abstract

Increased glutamatergic input to spinal dorsal horn neurons constitutes an important mechanism for neuropathic pain. However, the role of group III metabotropic glutamate receptors (mGluRs) in regulation of nociception and dorsal horn neurons in normal and neuropathic pain conditions is not fully known. In this study, we determined the effect of the group III mGluR specific agonist L(ϩ)-2-amino-4-phosphonobutyric acid (L-AP4) on nociception and dorsal horn projection neurons in normal rats and a rat model of neuropathic pain. Tactile allodynia was induced by ligation of L5/L6 left spinal nerves in rats. Allodynia was determined by von Frey filaments in nerve-injured rats. The nociceptive threshold was tested using a radiant heat and a Randall-Selitto pressure device in normal rats. Single-unit activity of ascending dorsal horn neurons was recorded from the lumbar spinal cord in anesthetized rats. An intrathecal (5-30 g) L-AP4 dose-dependently attenuated allodynia in nerve-injured rats but had no antinociceptive effect in normal rats. Topical spinal application of 5 to 50 M L-AP4 also significantly inhibited the evoked responses of ascending dorsal horn neurons in nerve-ligated but not normal rats. Furthermore, blockade of spinal group III mGluRs significantly decreased the withdrawal threshold and increased the evoked responses of dorsal horn neurons in normal but not nerve-injured rats. These data suggest that group III mGluRs play distinct roles in regulation of nociception and dorsal horn neurons in normal and neuropathic pain states. Activation of spinal group III mGluRs suppresses allodynia and inhibits the hypersensitivity of dorsal horn projection neurons associated with neuropathic pain.

Dorsal striatum metabotropic glutamate receptor 8 affects nocifensive responses and rostral ventromedial medulla cell activity in neuropathic pain conditions

“…Indeed, intra-DS administration of (S)-3,4-DCPG did not change thermal nociception, MWT, and the ongoing and tail flick-evoked ON and OFF cell activity in sham-operated animals. Evidence that group III mGluR stimulation inhibits pain in different pathological pain states of various etiologies but not in normal conditions has been already reported (Chen and Pan 2005;Goudet et al 2008;Neugebauer 2006;Palazzo et al 2008Palazzo et al , 2011Palazzo et al , 2013Zhang et al 2009). In particular, we have found that intra-CeA (S)-3,4-DCPG failed to change pain and affective behavior, neurotransmitter release, and RVM cell activity in physiological conditions (Palazzo et al 2008.…”

Modulation of pain transmission by G-protein-coupled receptors

“…Activation of group II and III mGluRs also inhibits glutamatergic transmission in many brain regions and in the normal spinal cord (Jane et al, 1996;Conn and Pin, 1997;Gerber et al, 2000). Activation of group II and III mGluRs attenuates the firing activity of spinal dorsal horn neurons in acute and chronic pain models (Neugebauer et al, 2000;Chen and Pan, 2005). Some group II and III mGluRs are also localized on the GABAergic interneurons and terminals in the spinal cord (Jia et al, 1999), and group II and III mGluR agonists decrease synaptic GABA release in normal spinal cord slices (Gerber et al, 2000).…”

Spinal Metabotropic Glutamate Receptors (mGluRs) are Involved in the Melittin-induced Nociception in Rats

“…Intrathecally administered group II and III mGluR agonists inhibit the responses of sensitized spinothalamic tract cells, mechanical hypersensitivity and allodynia induced by nerve injury, interleukin-1β, capsaicin and carrageenan (Neugebauer et al, 2000;Dolan & Nolan, 2002: Fisher et al, 2002Chen & Pan, 2005;Soliman et al, 2005;Jung et al, 2006). These experimental findings in the behavioral and electrophysiological studies indicate that group I, II and III mGluRs in the spinal cord may contribute to the nociceptive responses with a variety of other causes as well as inflammation and nerve injury.…”

“…administration of group I mGluR antagonists (Neugebauer et al, 1994;Bhave et al, 2001;Zhou et al, 2001;Hudson et al, 2002). Group II and III mGluR agonists inhibit peripheral inflammationand nerve injury-induced hyperalgesia as well as responses of spinothalamic tract cells to noxious mechanical stimulation and capsaicin (Dolan & Nolan, 2002;Fisher et al, 2002;Chen & Pan, 2005;Soliman et al, 2005). (2S, 1'R, 2'R, 3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (group II mGluR agonist) and (S)-2-amino-4-phosphonobutanoate (group III mGluR agonist) depress excitatory postsynaptic potential (EPSP) evoked by the stimulation of primary afferent fibers in the spinal cord dorsal horn .…”