The role of supraspinal GABA and glutamate in the mediation and modulation of pain

Gamma-aminobutyric acid (GABA) and glutamate play critical roles in the mediation and modulation of nociception at peripheral, spinal and supraspinal levels. Supraspinally, these amino acid neurotransmitters, and their receptors, are present in key brain regions involved in the sensory-discriminative, affective and cognitive dimensions of pain perception. Modulation of central GABAergic and glutamatergic neurotransmission underlies both activation of the endogenous analgesic system and the therapeutic effects of a number of analgesics. Enhancement or suppression of firing of GABAergic and glutamatergic neurons, and associated changes in neurotransmitter release, have been reported in supraspinal sites associated with nociception in animal models of acute, inflammatory and neuropathic pain. Moreover, pharmacological modulation of central GABAergic and glutamatergic signaling results in altered nociceptive behaviour. Here we review recent evidence in this area. We consider how this research has enhanced our understanding of the neurochemical mechanisms underpinning nociception and discuss its implications for the development of novel analgesic agents.