Role of Metabotropic Glutamate Receptors in Pain
Glutamate and Metabotropic Receptors (mGlu) in Neuropathic Pain
Glutamic acid is the most widespread excitatory transmitter in the Central Nervous System (CNS) and plays a key role in multiple functions. In recent years, the discovery of metabotropic glutamate receptors, a class of G-protein-coupled receptors, has led to a significant number of experimental studies aimed at clarifying the role of these receptors in physiological activities and in pathological processes affecting the CNS. Glutamate receptors are divided into two broad functional categories: ionotropic and metabotropic (mGlu) (Conn and Pin, 1997). The group of metabotropic receptors, which includes 8 receptors, is divided into 3 subgroups based on amino acid sequence homology, pharmacological profile, and post-receptor transduction mechanisms.
The Group I includes mGlu1 and mGlu5 receptors, which are activated by agonists specific to these receptor types (DHPG and CHPG). Activation of Group I receptors stimulates the hydrolysis of membrane polyphosphoinositides through a G-protein-dependent mechanism. Group II (mGlu2, mGlu3) and Group III (mGlu4, mGlu6, mGlu7, mGlu8), activated by selective agonists LY379268 and L-SOP, respectively, share the post-receptor transduction mechanism, reducing cAMP synthesis. mGlu receptors regulate neuronal excitability in various areas of the CNS, primarily by modulating ion channel activation (Conn and Pin, 1997). mGlu receptors have been implicated in the pathogenesis of several CNS diseases, including epilepsy, ischemia, and neurodegenerative diseases.
Recent pharmacological, immunohistochemical, and in situ hybridization studies indicate that Group I mGlu receptors play a key role in nociceptive transmission. In addition to their role in pain transmission in the CNS, both at the spinal and thalamic/cortical levels, glutamate has also been shown to excite peripheral nociceptive neurons, mediating responses partially related to ionotropic receptor activation and partially to mGlu receptor activation. Recent advances in pharmacology have made it possible to synthesize more selective molecules for individual receptors, rendering mGlu receptors a new and interesting target for analgesic therapy.