This review is focused on the possible interaction between amino acid neurotransmitters and opioid receptors in hyperthermia-induced brain dysfunction. A balance between excitatory and inhibitory amino acids appears to be necessary for normal brain function. Increased excitotoxicity and a decrease in inhibitory amino acid neurotransmission in hyperthermia are associated with brain pathology and cognitive impairment. This is supported by recent data from our laboratory that show a marked increase in glutamate and aspartate and a decrease in GABA and glycine in several brain areas following heat stress at the time of brain pathology. Blockade of multiple opioid receptors with naloxone restored the heat stress-induced decline in GABA and glycine and thwarted the elevation of glutamate and aspartate in the CNS. In naloxone-treated stressed animals, cognitive dysfunction and brain pathology are largely absent. Taken together, these new findings suggest that an intricate balance between excitatory and inhibitory amino acids is important for brain function in heat stress. In addition, opioid receptors play neuromodulatory roles in amino acid neurotransmission in hyperthermia.