RELATIONSHIP OF MU-OPIOID AND DELTA-OPIOID RECEPTORS TO GABAERGIC NEURONS IN THE CENTRAL-NERVOUS-SYSTEM, INCLUDING ANTINOCICEPTIVE BRAIN-STEM CIRCUITS

Inhibition of neurons containing gamma-aminobutyric acid (GABA) may un derlie some of the excitatory effects of opioids in the central nervou s system (CNS). In the present study, we examined the relationship of the cloned mu- and delta-opioid receptors (MOR1 and DOR1, respectively ) to GABAergic neurons in brain and spinal cord. This was done by comb ining immunofluorescent staining for MOR1 or DOR1 with that for GABA o r glutamic acid decarboxylase (GAD); fluorescent retrograde tract-trac ing was used in some cases to identify neurons with particular project ions. In rats, cells double labeled for GABA and MOR1 were observed in layers II-VI of the parietal cortex and in layers II-IV of the pirifo rm cortex. In the hippocampus, double labeling was observed in the den tate gyrus and in regions CA1 and CA3. Double labeling was very promin ent in the striatum and in the reticular nucleus of the thalamus; it w as also observed in other portions of the diencephalon. However, doubl e labeling for GABA and MOR1 was never observed in the cerebellar cort ex. Cells double labeled for GABA and MOR1 were common in the periaque ductal gray (PAG) and the medial rostral ventral medulla (RVM) of both rats and monkeys, suggesting that involvement of GABAergic neurons wi th supraspinal opioid antinociception may extend to primates. In the R VM of rats, many of those double-labeled neurons were retrogradely lab eled from the dorsal spinal cord. In contrast, double-labeled neurons in the PAG were almost never retrogradely labeled from the RVM. No une quivocal examples of double labeling for DOR1 and GAD were found in an y region of the CNS that we examined in either rats or monkeys. Howeve r, GABAergic neurons were often apposed by DOR1 immunoreactive varicos ities. Our findings suggest that activation of mu-opioid receptors dir ectly modulates the activity of GABAergic neurons throughout the CNS, including neurons involved in the supraspinal component of opioid anal gesia. In contrast, delta-opioid receptors appear to be positioned to modulate the activity of GABAergic neurons indirectly. (C) 1998 Wiley- Liss, Inc.