Presynaptic and postsynaptic relations of mu-opioid receptors to gamma-aminobutyric acid-immunoreactive and medullary-projecting periaqueductal gray neurons

The ventrolateral portion of the periaqueductal gray (PAG) is one brain reg ion in which ligands of the mu-opioid receptor (MOR) produce analgesia. In the PAG, MOR ligands are thought to act primarily on inhibitory [e.g., gamm a-aminobutyric acidergic (GABAergic)] neurons to disinhibit PAG output rath er than directly on medullary-projecting PAG neurons. In this study, the ul trastructural localization of MOR immunolabeling was examined with respect to either GABAergic PAG neurons or PAC projection neurons that were labeled retrogradely from the rostral ventromedial medulla. Immunoreactivity for M OR and GABA often coexisted within dendrites. Dual-labeled profiles account ed for subpopulations of dendrites containing immunoreactivity for either M OR (65 of 145 dendrites; 45%) or GABA (66 of 183 dendrites; 35%). In additi on, nearly half of PAG neuronal profiles (148 of 344 profiles) that were la beled retrogradely from the ventromedial medulla contained MOR immunoreacti vity. MOR was distributed equally among retrogradely labeled neuronal profi les in the lateral and ventrolateral columns of the caudal PAG. With respec t to the presynaptic distribution of MOR, approximately half of MOR-immunol abeled axon terminals (35 of 69 terminals) also contained GABA. Some MOR an d GABA dual-immunolabeled axon terminals contacted unlabeled dendrites (11 of 35 terminals), whereas others contacted GABA-immunoreactive dendrites (1 5 of 35 terminals). Furthermore, axon terminals synapsing on medullary-proj ecting PAG neurons sometimes contained immunoreactivity for MOR. These data support the model that MOR ligands can act by inhibiting GABAergic neurons , but they also provide evidence that MOR ligands may act directly on PAC o utput neurons. In addition, MOR at presynaptic sites could affect both GABA ergic neurons and output neurons. Thus, the disinhibitory model represents only partially the potential mechanisms by which MOR ligands can modulate o utput of the PAG. J. Comp. Neurol. 419:532-542, 2000. (C) 2000 Wiley-Liss, Inc.