Association of Mu-opioid and NMDA Receptors in the Periaqueductal Gray: What Does it Mean for Pain Control?

Abstract

The brain has an endogenous descending control system to modulate pain. This system is thought to arise from the activation of output neurons in the periaqueductal gray area (PAG) that project to the rostroventral medulla, with a relay to the spinal cord to modulate incoming pain signals (Basbaum and Fields, 1984). Electrical stimulation or microinjection of opioids into the ventral portion of the PAG results in analgesia. Opioids activate the pathway by inhibiting tonic GABA release (or disinhibition). The disinhibition hypothesis predicts that morphine and glutamate stimulate the descending pathway via activation of different cell populations, opioids by inhibiting GABA interneurons or inhibitory projection neurons into the PAG, and glutamate by directly activating PAG output neurons. In this issue of Neuropsychopharmacology, Rodriguez-Munoz et al provide evidence for a close association of NMDA and mu-opioid (MOR) receptors in the PAG, suggesting that these two receptors are not only colocalized within the same cell population, but that there is bidirectional regulation of the NMDA/MOR interaction during acute morphine tolerance.