The role of N-acetylaspartylglutamate (NAAG) in the amygdala

Endogenously released dipeptide N-acetylaspartylglutamate (NAAG) is efficacious in animal models of several clinical disorders including inflammatory and neuropathic pain. NAAG peptidase inhibitors prolong the dipeptide's level and function at the synapse. NAAG mediates its analgesic effect by dampening release of neurotransmitter glutamate through activation of presynaptic group II metabotropic glutamate (mGluR2 and mGluR3) autoreceptors. The analgesic effects of NAAG peptidase inhibitors administered systemically, intrathecally, locally and intracerebroventricularly in animal models are reversed by administration of the group II mGluR antagonist, LY341495. Thus, it was hypothesised that the analgesic effect of the peptidase inhibitors are due to the action of the peptide at its receptors within the pain processing pathway. However, the specific sites within the brain through which NAAG mediates analgesia have not been rigrously defined. The central nucleus of amygdala, laterocapsular part (CeLC; nociceptive amygdala) contains neurons that receive purely nociceptive information en route from the spinal cord via the parabrachial nucleus to other brain areas. Importantly, the spinoparabrachial amygdaloid (PB-CeA) pain pathway sends elevated levels of glutamate-mediated excitatory transmission to the amygdala during inflammatory pain states. Given the high concentration of NAAG, its peptidases and the group II mGluRs in the amygdala, this research was undertaken to test the hypothesis that NAAG influences pain processing in this region of the pain perception pathway.;NAAG's effect on the amplitude of evoked excitatory currents in the CeLC region of slices obtained from untreated, and both mice treated with saline and 5% formalin (inflammatory pain model) was measured using patch clamp techniques. The peptide's effect on prolonged mechanical allodynia was investigated. The findings from this research are (1) NAAG released at the PB-CeA synapse inhibits evoked release of its co-transmitter glutamate via presynaptic mGluR3; (2) over 24 hours following induction of peripheral inflammation, PB-CeA afferents progressively exhibit enhanced evoked glutamate release and postsynaptic cells exhibit greater excitability; (3) this enhanced release is blocked by NAAG peptidase inhibition proximate to the time of the inflammatory insult; (4) within 24 hours after onset, peripheral inflammation induces a shift in the relative influence of NAAG peptidase inhibition on glutamate release at the PB-CeA synapse.