Synergistic mu-opioid and 5-HT1A presynaptic inhibition of GABA release inrat periaqueductal gray neurons

The periaqueductal gray (PAG) plays a critical role in descending antinocic eption. In mechanically dissociated rat PAG neurons, pharmacologically sepa rated spontaneous GABAergic miniature inhibitory postsynaptic currents (mIP SCs) were recorded using the nystatin-perforated patch technique. Both DAMG O, a specific mu -opioid receptor agonist, and serotonin inhibited mIPSC fr equency in a dose-dependent manner without affecting mIPSC amplitude, respe ctively, in the same PAG neurons. The presynaptic opioid effect was blocked by a specific mu -opioid receptor antagonist, CTOP. The presynaptic seroto nergic effect was mimicked by a specific 5-HT1A receptor agonist, 8-OH-DPAT , and blocked by the specific antagonist, NAN-190. These opioidergic and se rotonergic inhibitions of GABA release employed the similar intracellular m echanism of opening 4-AP-sensitive K+ channels via GTP-binding proteins (G- proteins). Subthreshold concentrations of DAMGO (3 nM) significantly decrea sed mIPSC frequency with subthreshold concentrations of serotonin (3 nM) an d this effect was completely blocked by pretreatment with N-ethylmaleimide (NEM), a PTX-sensitive G-protein inhibitor. In contrast, maximum doses of D AMGO (10 muM) did not further inhibit mIPSC frequency with maximum doses of serotonin (10 muM). In conclusion, activation of presynaptic L-opioid and 5-HT1A receptors synergistically inhibited GABA release. These results sugg est a cellular mechanism within PAG for the analgesic effectiveness of comb ined therapies using opioids in conjunction with classes of anti-depressant s which increase synaptic serotonin levels. (C) 2001 Elsevier Science Ltd. All fights reserved.