A possible role for glutamate receptor-mediated excitotoxicity in chronic pain

Abstract

brainstem and targeting pain transmission within the dorsal horn. Significant progress has been made in the study of pain-modulating networks. However, little is understood regarding the spinal circuits through which descending pain modulatory neurons exert their effects. With recent insight into the pharmacology of different neural circuits, the importance of spinal mechanisms of descending modulation in the response of the nervous system to persistent pain after injury is being reevaluated.Evidence that descending systems can selectively modulate pain was first provided by the discovery of stimulation-produced analgesia, which was first elicited by electrical stimulation of the midbrain periaqueductal gray (PAG) [4]. The PAG integrates inputs from the limbic forebrain and diencephalon with ascending nociceptive input from the dorsal horn [5]. The painmodulating action of the PAG upon the spinal cord is relayed through the rostral ventromedial medulla (RVM). Thus, the PAG-RVM connection is critical for pain modulation.The RVM is the major brainstem source of axons that project to the spinal cord dorsal horn. The spinal terminals of RVM descending axons are most dense in dorsal horn laminae I, II (the substantia gelatinosa), and V [6]. These laminae are targets of nociceptive primary afferents (Aδ-and C-fibers), and their consistent neurons respond maximally to stimuli that are noxious [7]. Lamina II is of particular interest, as the sensory input to this area is almost entirely C-fiber in nature. Most lamina II neurons are glutamatergic excitatory interneurons that relay inputs from primary afferents to lamina I projection neurons [8,9]. Other interneurons in laminae I and II contain inhibitory neurotransmitters gamma-amino butyric acid (GABA) [10], glycine, and enkephalin [10,11] and are a likely source of the inhibitory transmitters in terminals on projection neurons. Recent insights into synaptic transmission and plasticity in the superficial dorsal horn and its role in the develop-

Targeting Glutamate Neurotoxicity through Dietary Manipulation: Potential Treatment for Migraine

“…The mGluRs function in two ways, by directly increasing cytosolic Ca 2+ levels via the facilitation of Ca 2+ release from the intracellular stores, and indirectly by promoting NMDA receptor migration to the cell membrane [ 27 ]. Excitotoxicity is one of the leading causes of neuronal damage and death, and this process has been implicated in a variety of neurological diseases including schizophrenia, Alzheimer’s, Parkinson’s, multiple sclerosis (MS), epilepsy, chronic pain, and migraine [ 28 , 29 , 30 , 31 , 32 , 33 ].…”