The Metabotropic Glutamate Receptor Subtype 5 Antagonist Fenobam Is Analgesic and Has Improved in Vivo Selectivity Compared with the Prototypical Antagonist 2-Methyl-6-(phenylethynyl)-pyridine

Abstract

Metabotropic glutamate receptor subtype 5 (mGlu5) has been demonstrated to play a role in the modulation of numerous nociceptive modalities. When administered via peripheral, intrathecal, or systemic routes, mGlu5 antagonists have analgesic properties in a variety of preclinical pain models. Despite a wealth of data supporting the use of mGlu5 antagonists to treat pain, studies have been limited to preclinical animal models due to a lack of mGlu5 antagonists that are approved for use in humans. It has been demonstrated previously that fenobam [N-(3-chlorophenyl)-NЈ-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea], an anxiolytic shown to be safe and effective in human trials, is a selective and potent noncompetitive antagonist of mGlu5 (J Pharmacol Exp Ther 315:711-721, 2005). Here, we report a series of studies aimed at testing whether fenobam, similar to the prototypical mGlu5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), has analgesic properties in mice. We show that fenobam reduces formalininduced pain behaviors and relieves established inflammationinduced thermal hypersensitivity in mice. Similar results were seen with MPEP. Administration of fenobam resulted in an increase in locomotor activity in the open-field task but did not impair performance on the accelerating Rotarod. Analysis of brain and plasma fenobam levels indicated that fenobam is rapidly concentrated in brain after intraperitoneal administration in mice but is essentially cleared from circulation within 1 h after injection. Fenobam had no analgesic effect in mGlu5 knockout mice, whereas the prototypical antagonist MPEP retained significant analgesic efficacy in mGlu5 knockouts. These results demonstrate that fenobam is analgesic in mice and has an improved in vivo selectivity for mGlu5 over MPEP.

Metabotropic glutamate receptor 5 regulates excitability and Kv4.2-containing K+ channels primarily in excitatory neurons of the spinal dorsal horn

“…Numerous behavioral studies have demonstrated that mGlu5 in the dorsal horn contributes to inflammatory, visceral, and neuropathic pain (Chen et al 2000;Fisher et al 2002;Karim et al 2001;Montana et al 2009;Young et al 1997). We have demonstrated that activation of mGlu5 induces ERK activation, which subsequently inhibits Kv4.2-mediated Atype currents and increases excitability in spinal cord dorsal horn neurons.…”

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

“…In a visceral pain model, MTEP and MPEP have been found to dose-dependently reduce visceromotor and cardiovascular responses evoked by colorectal distension through an action at peripheral afferent endings (Lindström et al, 2008). The early results on the effects of MPEP in inflammatory pain have been confirmed by Montana et al (2009) with fenobam, which reduced formalin-induced pain behaviors (licking or lifting the injected paw) and inflammation-induced thermal hypersensitivity in mice. These effects were not seen in mGlu5 receptor knockout mice.…”

P-Glycoprotein Is a Major Determinant of Norbuprenorphine Brain Exposure and Antinociception

“…A tail-flick assay (Montana et al, 2009) was used to test the antinociceptive effect of norbuprenorphine in mdr1(Ϫ/Ϫ) and mdr1(ϩ/ϩ) mice. Tail-flick latency, defined by the time in seconds for tail withdrawal from a warmwater bath (52°C), was measured as described previously , using an IITC 500 warm-water tail-immersion test analgesia meter (IITC Life Science, Woodland Hills, CA).…”