Role of Group I Metabotropic Glutamate Receptors mGlu1 and mGlu5 in Nociceptive Signalling

Distribution, pharmacological and knockdown studies point to a role of group I receptors in nociceptive processing. mGlu1 and mGlu5 receptors are expressed on peripheral sensory afferents, in dorsal root ganglion neurons, dorsal and ventral horn of spinal cord, rostral ventromedial medulla, periaqeductal gray, amygdala, and ventrobasal thalamus. These receptors are functional: sensory neurons in these regions respond to pain stimuli and / or to mGlu1 and mGlu5 agonists. Intrathecal administration of group I agonists evokes spontaneous pain behaviour. Whereas mGlu1 / 5 antagonists do not alter normal sensation, their effect on acute nociception is controversial. Activation of spinal and peripheral mGlu1 or mGlu5 receptors is sufficient to evoke hyperalgesia and allodynia. Blockade of spinal or peripheral mGlu1 or peripheral mGlu5 receptors was antihyperalgesic in animal models of inflammatory pain. Although the role of supraspinal, spinal and peripheral mGlu1 and mGlu5 receptors in the development and maintenance of neuropathic pain states is not fully elucidated, spinal mGlu1 receptor blockade is effective in all pain states tested. In the periaqueductal gray, a group I agonist attenuates nociceptive responses, indicating that mGlu1 and / or mGlu5 receptors in this structure can activate the descending pathway to dampen pain. The data indicate that mGlu1 and mGlu5 antagonists have therapeutic potential for the treatment of chronic inflammatory and neuropathic pain states. More potent and bioavailable mGlu1 versus mGlu5 antagonists are needed to provide proof of concept.