Glutamate and gamma-amino butyric acid (GABA) are respectively two major excitatory and inhibitory neurotransmitters of the adult mammalian central nervous system. These neurotransmitters exert their action through two types of receptors: ionotropic and metabotropic receptors. While ionotropic receptors are ligand gated ion channels involved in fast synaptic transmission, metabotropic receptors belong to the superfamily of G-protein coupled receptors (GPCRs) and are responsible for the neuromodulatory effect of glutamate and GABA. Metabotropic glutamate receptors (mGluRs) and metabotropic GABA receptors (GABA-B) are present at different levels of the pain neuraxis where they regulate nociceptive transmission and pain. The present review will focus on the role of these receptors in the modulation of pain perception.