Role of central and peripheral mGluR5 receptors in post-operative pain in rats

Abstract

Metabotropic glutamate receptors (mGluRs) have previously been shown to play a role in pain transmission during inflammatory or neuropathic pain states. However, the role of mGluR5 in post-operative pain remains to be fully investigated. The present study was conducted to characterize analgesic activity of 2-methyl-6-(phenylethynyl)-pyridine (MPEP) in the skin-incision-induced post-operative pain model in rats. MPEP is a potent and selective mGluR5 antagonist with high affinity (K(i)=6.3+/-0.9 nM) in rat cortex using [(3)H]-MPEP as a radioligand, while not competing with the mGluR1-selective radioligand [(3)H]-R214127 (K(i)>10,000 nM) in rat cerebellum. Post-operative pain was examined 2 h following surgery using weight-bearing (WB) difference between injured and uninjured paws as a measure of non-evoked pain. In this model, MPEP, as morphine, showed dose-dependent effects and full efficacy after systemic administration (ED(50)=15 mg/kg, i.p. for MPEP, ED(50)=1.3 mg/kg, s.c. for morphine). In addition, intrathecal (i.t.) and intracerebroventricular (i.c.v.) MPEP reduced WB difference (ED(50)=65 microg/rat i.t. and ED(50)=200 microg/rat i.c.v.). Interestingly, intraplantar (i.pl.) injection of MPEP either before or after surgery induced a similar reduction in WB difference (ED(50)=90 microg/rat, i.pl.) while contralateral i.pl. MPEP injection did not produce any effect. These results demonstrate that both peripheral and central mGluR5 receptors play a role in nociceptive transmission observed during post-operative pain. In addition, the data suggest that mGluR5 antagonists could offer a new therapeutic approach to the treatment of post-operative pain.

Metabotropic Glutamate Receptor Subtype 5 Antagonists MPEP and MTEP

“…Finally, it has also been suggested that both peripheral and central mGluR5 receptors may play a role in nociceptive transmission observed during post-operative pain in rats (217). In this model, MPEP (ED 50 = 15 mg/kg, i.p.)…”

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

“…On the other hand, MPEP was found to be inactive in models of acute pain. In addition, systemic, local, and central application of MPEP was found to be efficacious in a model of postoperative pain in rats (Zhu et al, 2005), suggesting a role for both peripheral and central mGlu5 receptors in that condition. The early work on the role of mGlu5 receptors in chronic pain has been summarized by Slassi et al (2005) and seems to indicate that negative allosteric mGlu5 ALLOSTERIC MODULATION OF FAMILY C GPCRS receptor modulators are more effective in reversing thermal hyperalgesia compared with mechanical hyperalgesia or allodynia in both inflammatory and neuropathic pain models.…”

Membrane-Delimited Coupling of TRPV1 and mGluR5 on Presynaptic Terminals of Nociceptive Neurons

“…Indeed, both spinal mGluR5 and TRPV1 have been demonstrated to contribute to pain hypersensitivity under pathological pain conditions (Caterina et al, 2000;Walker et al, 2001a;Zhu et al, 2005;Kanai et al, 2006). Whereas a functional role for mGluR5 in superficial dorsal horn neurons (i.e., postsynaptic neurons) has recently been demonstrated (Hu et al, 2007), relatively little is known about how presynaptic mGluR5 contributes to nociceptive synaptic transmissions in the spinal dorsal horn.…”