Role of Metabotropic Glutamate Receptors in Pain
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[[|Italian]]Role of Metabotropic Glutamate Receptors in Pain
Glutamic acid represents the most widespread excitatory neurotransmitter 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 substantial body of experimental work aimed at clarifying the role of these receptors in both physiological activities and pathological processes within the CNS . Glutamic acid receptors are divided into two main functional categories: ionotropic and metabotropic (mGlu) .
The metabotropic receptor group, which includes eight receptors, is further subdivided into three subgroups based on amino acid sequence homology, pharmacological profiles, and post-receptor signal transduction mechanisms (Fig. 1). Group I includes mGlu1 and mGlu5 receptors, activated by agonists specific to these receptors (DHPG and CHPG). Activation of Group I receptors stimulates the hydrolysis of membrane phosphoinositides through a G-protein-dependent mechanism. Group II (mGlu2, mGlu3) and Group III (mGlu4, mGlu6, mGlu7, mGlu8), activated by the selective agonists LY379268 and L-SOP respectively, share the mechanism of reducing cAMP synthesis .
mGlu receptors regulate neuronal excitability in various CNS regions, mainly by modulating the activation of ion channels. These receptors have been implicated in the pathogenesis of several CNS disorders, 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 at the CNS level, both at the spinal and cortical-thalamic levels, glutamate has also been shown to excite peripheral nociceptive neurons, mediating responses partly related to ionotropic receptor activation and partly to mGlu receptor activation .
In recent years, pharmacological research has become more effective due to the synthesis of new, more selective molecules for individual receptors. Thus, metabotropic glutamate receptors represent a novel and promising target for analgesic therapy .
Role of Group I mGlu Receptors in Neurophysiopathological Mechanisms: It has been demonstrated that spiny neurons and cholinergic interneurons exhibit different sensitivities to glutamatergic agonists, both ionotropic and metabotropic . These cells respond in opposite ways to energy deprivation , demonstrating a functional substrate, namely glutamatergic receptor sensitivity between spiny neurons and interneurons, capable of determining opposing behaviors between cell types. Furthermore, the functional interaction between ionotropic and mGlu receptors appears significantly different and is certainly one of the possible co-factors responsible for the different striatal neuronal vulnerabilities.
Role of Group I mGlu Receptors in Central Pain Transmission
Experimental evidence suggests a significant involvement of excitatory amino acids, glutamate, and aspartate, in mediating both acute and chronic nociceptive transmission . In fact, a large number of peripheral sensory fibers contain glutamate, including C fibers, and about 80% of Substance P fibers . In the spinal cord, the response to brief acute mechanical or thermal stimuli primarily involves AMPA-type ionotropic receptors. If the stimulus is prolonged or if the frequency or intensity of the stimulus is increased, NMDA-type ionotropic receptors are also activated. This phenomenon results in an enhancement of the sensory response, a mechanism referred to as "sensitization." Sensitization is an increased response to a stimulus and has been experimentally reproduced in spinal cord preparations using the experimental paradigm known as "wind-up" .
Role of mGlu Receptors in Peripheral Nociceptive Transmission Mechanisms: The role of glutamate in the Peripheral Nervous System is still unclear. It has been shown that subcutaneous injection of glutamate in rats reduces the activation threshold for mechanical and thermal stimuli . The application of antagonists for ionotropic glutamate receptors attenuates nociceptive levels in the formalin test, a model used to study inflammatory pain. Additionally, glutamate concentration increases in the cutaneous tissue after sciatic nerve stimulation and during the formalin test in rats . Altogether, this data suggests that glutamate acts as an effective mediator of peripheral inflammation following tissue injury and that peripheral glutamate activates ionotropic receptors.
Conclusions: Understanding the functions of mGlu receptors in the Central and Peripheral Nervous Systems has made significant progress in recent years. In particular, the role of Group I mGlu receptors (mGlu1 and mGlu5) has been extensively investigated at the molecular, cellular, and behavioral levels, highlighting their importance in numerous physiological functions and pathological processes. Both mGlu1 and mGlu5 have been implicated in a variety of brain disorders, including epilepsy, pain, ischemia, and neurodegenerative diseases. The potential of these receptors to modulate glutamatergic transmission and their presence in multiple brain areas could, therefore, represent a genuine target for the treatment of neurological disorders.
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