GABAergic modulation is involved in the ventrolateral orbital cortex 5-HT 1A receptor activation-induced...

The ventrolateral orbital cortex (VLO) is a component of an endogenous analgesic system consisting of an ascending pathway from the spinal cord to VLO via the thalamic nucleus submedius (Sm) and a descending pathway relaying in the periaqueductal gray matter (PAG). This study examines whether the activation of 5-HT 1A receptors in VLO produces antinociception and whether GABAergic modulation is involved in the VLO 5-HT 1A receptor activation-evoked antinociception. The radiant heat-evoked tail flick (TF) reflex was used as an index of nociceptive response in lightly anesthetized rats. Microinjection of the 5-HT 1A receptor agonist 8-OH-DPAT (1.0, 2.0, 5.0 microg) into VLO produced dose-dependent antinociception, which was reversed by the 5-HT 1A receptor antagonist (NAN-190, 20 mug). We also found that VLO application of the GABA A receptor antagonist bicuculline or picrotoxin (100 ng) enhanced the 8-OH-DPAT-induced inhibition of the TF reflex, whereas the GABA A receptor agonist muscimol (250 ng) or THIP (1.0 microg) significantly attenuated the 8-OH-DPAT-induced inhibition. These results suggest that 5-HT 1A receptors are involved in VLO-induced antinociception and that GABAergic disinhibitory mechanisms participate in the 5-HT 1A receptor-mediated effect. These findings provide support for the hypothesis that 5-HT 1A receptor activation may inhibit the inhibitory action of the GABAergic interneurons on the output neurons projecting to PAG leading to activation of the brainstem descending inhibitory system and depression of nociceptive inputs at the spinal cord level.