A number of ionotropic receptors ( receptors with an integral ion channel) have been identified at presynaptic terminals within the nervous system. These include receptors that respond to acetylcholine (nicotinic receptors) to glutamate (AMPA kainate and NMDA receptors) and those that respond to GABA (GABAA receptors). These receptors have been identified variously as autoreceptors (activated by the release of transmitter from the terminal on which they are located) or axo-axonic (as in the schematic below) in which the transmitter is released from a second terminal.

Pre-synaptic inhibition found at primary afferents and first identified by Eccles and Malcolm (1946), is mediated by release of GABA. GABAA receptors mediate an increase in Cl- conductance (Curtis et al. 1970; Alford et al.1991); It is presumed that this leads to a shunt ofthe pre-synaptic membrane resistance to reduce action potential amplitude (Nicoll and Alger, 1979).

More recently ionotropic glutamate receptors have been identified at the presynaptic terminals in a number of systems including the lamprey (Cochilla and Alford 1997; Schwartz and Alford 1998; Cochilla and Alford 1999). Ionotropic glutamate receptors, including kainate receptors (Agrawal and Evans, 1986; Clarke et al. 1997; Dev et al. 1996; Kamiya and Ozua 1998), NMDA receptors (Aoki et al. 1997; Berretta and Jones 1996; Carlton et al. 1998; Chen et al. 1998; Conti et al. 1997; Liu et al. 1997; Robert et al. 1998), NMDA like receptors (Smirnova et al. 1993) and AMPA receptors (Barnes et al. 1994; Bureau and Mulle 1998; Farb et al. 1995) have now been identified at presynaptic terminals throughout the vertebrate neuroaxis. Their actions in locations as diverse as the entorhinal cortex and the spinal dorsal horn may be critical in damping neuronal excitability involved in epilepsy and the regulation of pain pathways. These receptors might also modulate release by altering presynaptic Ca2+ concentrations. This alteration could either be direct, by activating NMDA receptors or Ca2+ permeable AMPA or KA receptors, or indirect, by depolarizing the terminal to activate presynaptic voltage operated Ca2+ channels (VOCCs).