Abstract
Glutamate is the main excitatory neurotransmitter in the nervous system and plays a critical role in nociceptive processing and pain modulation. G-protein coupled metabotropic glutamate receptors (mGluRs) are widely expressed in the central and peripheral nervous system, and they mediate neuronal excitability and synaptic transmission. Eight different mGluR subtypes have been identified so far, and are classified into Groups I–III. Group II mGluR2 and mGluR3 couple negatively to adenylyl cyclase through Gi/Go proteins, are mainly expressed presynaptically, and typically inhibit the release of neurotransmitters, including glutamate and GABA. Group II mGluRs have consistently been linked to pain modulation; they are expressed in peripheral, spinal and supraspinal elements of pain-related neural processing. Pharmacological studies have shown anti-nociceptive/analgesic effects of group II mGluR agonists in preclinical models of acute and chronic pain, although much less is known about mechanisms and sites of action for mGluR2 and mGluR3 compared to other mGluRs. The availability of orthosteric and new selective allosteric modulators acting on mGluR2 and mGluR3 has provided valuable tools for elucidating (subtype) specific contributions of these receptors to the pathophysiological mechanisms of pain and other disorders and their potential as therapeutic targets. This review focuses on the important role of group II mGluRs in the neurobiology of pain mechanisms and behavioral modulation, and discusses evidence for their therapeutic potential in pain.
Highlights
Glutamate is the main excitatory neurotransmitter in the nervous system and plays a critical role in nociceptive processing and pain modulation
This review focuses on the important role of group II metabotropic glutamate receptors (mGluRs) in the neurobiology of pain mechanisms and behavioral modulation, and discusses evidence for their therapeutic potential in pain
The interaction of glutamate with its ligand-gated cation channels (NMDA, AMPA, and kainate) mediates fast transmission and cell signaling while the activation of metabotropic glutamate receptors stimulates intracellular pathways linked to various effector systems involved long-lasting modifications
Summary
The glutamatergic system provides excitatory neurotransmission throughout the central nervous system (CNS), and dysfunction of this system seems is correlated with several disorders such as schizophrenia, depression, and pain states. Group III comprises mGluR4, mGluR7 and mGluR8, which to group II mGluRs are negatively linked to Gi/o type proteins, and mGluR6, which is positively coupled to a cGMP phosphodiesterase (Neugebauer, 2008; Niswender and Conn, 2010). The activity of those receptors can be modulated by pharmacological manipulations of the orthosteric binding sites with agonists, antagonists, or inverse agonists. Current research efforts are focused on the development of new positive and negative allosteric modulators (PAM and NAM) as potential therapeutic tools and strategies
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
