Allosteric Modulation of Metabotropic Glutamate Receptor 5 as a Treatment for Pain

Metabotropic glutamate receptor 5: mGlu5) has been suggested to play a role in the development and maintenance of chronic pain. mGlu5 is expressed at synapses throughout the pain neuraxis where it is believed to modulate the function of ion channels that underlie nociceptive transduction and transmission. Injections of mGlu5 agonists cause hypersensitivity or nocifensive behavior when administered peripherally, intrathecally, and centrally. In addition, pharmacological antagonism of mGlu5 has been suggested to be analgesic in a variety of animal pain models. Unfortunately, the selectivity of antagonists used in these studies has been called into question, suggesting that at least some of the analgesic properties of putatively selective mGlu5 antagonists may be due to off-target effects. Despite a wealth of data supporting the targeting of mGlu5 to treat pain, both antagonist selectivity issues and the lack of an mGlu5 antagonist approved for use in humans have hindered testing beyond the preclinical stage. To address this issue I assessed the pain behavior of mice with a genetic absence of mGlu5. mGlu5 KO mice exhibit pain-like behaviors, however the duration and intensity of these behaviors are attenuated in multiple nociceptive tests, including spontaneous nociceptive behavior in the formalin test, and mechanical hypersensitivity induced by Complete Freund's Adjuvant. In addition, I assessed the analgesic properties of fenobam, [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea], an anxiolytic recently identified as a selective and potent non-competitive negative allosteric modulator of mGlu5, and previously shown to be safe and effective in clinical trials of human anxiety. I found Fenobam to be analgesic in models of chemical nociception and inflammatory pain. Fenobam was also found to be without analgesic effect in mGlu5 KO mice, suggesting that its analgesic effect is mediated via mGlu5. Further assessment of both mGlu5 KO mice and the effects of fenobam suggested that mGlu5 may play a role in locomotion, weight gain, and appetite. Fenobam increases locomotive behavior, suggesting that antagonists of mGlu5 may exert analgesic effects without causing dose- limiting sedation. Overall these data suggest that mGlu5 is an important modulator of nociceptive plasticity, and that allosteric modulation of mGlu5 may represent a pharmacologic target for the treatment of pain.

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biology and Biomedical Sciences: Neurosciences

Year dc:date.available

2012

Author dc:creator

• Montana, Michael

Contributors dc:contributor

• Robert Gereau

• Neurosciences
• Animal behavior
• Medicine
• Fenobam
• GPCR
• mGlu5
• mGluR5
• Nociception
• Pain

Language dc:language

English (en)

DOI

https://doi.org/10.7936/K7VH5KV9

OAI identifier oai:identifier

oai:openscholarship.wustl.edu:etd-1619