Anatomical evidence for presynaptic modulation by the delta opioid receptor in the ventrolateral periaqueductal gray of the rat

The delta opioid receptor (DOR) modulates nociception and blood pressure in the periaqueductal gray (PAG). To examine the cellular basis for DOR effects, the ultrastructural distribution of DOR immunoreactivity was examined in the caudal ventrolateral PAG. DOR immunoreactivity was located predominantly in axon terminals that formed asymmetric (excitatory-type) synaptic contacts. However, rather then localized to the plasma membrane of synaptic boutons, immunolabeling for the DOR was intracellular, often associated with large dense-core vesicles. This finding suggests that dense-core vesicles may play a role in targeting the DOR, as vesicle fusion would shift the distribution of the DOR to the plasma membrane. To investigate the neural circuits in which DOR may function, dual-immunolabeling was used to determine the relationship of the DOR to an endogenous ligand, enkephalin, and to a potential target, GABAergic neurons. Approximately a third (38 of 127) of DOR containing axons had enkephalin immunoreactivity, indicating DOR may act in part as a presynaptic autoreceptor. Although single axon terminals containing immunoreactivity for both DOR and GABA were not detected, some DOR-immunolabeled axon terminals (26 of 86) contacted soma or dendrites containing GABA. These data suggest that the DOR may act in part as an autoreceptor to regulate synaptic input to GABAergic as well as non-GABAergic PAG neurons. Furthermore, the exposure of the DOR to the extracellular space may be contingent upon dense-core vesicle fusion with the plasma membrane.