BASAL RELEASE OF MET-ENKEPHALIN AND NEUROTENSIN IN THE VENTROLATERAL PERIAQUEDUCTAL GRAY-MATTER OF THE RAT - A MICRODIALYSIS STUDY OF ANTINOCICEPTIVE CIRCUITS

The periaqueductal gray (PAG) contains neural circuits that participat e in descending antinociception. Anatomical and electrophysiological e vidence suggests that these circuits might employ opioid peptides and GABA in series to remove a tonic inhibition of descending FAG output n eurons. The present studies examined the release of the antinociceptiv e peptides Met-enkephalin and neurotensin in the ventrolateral FAG, an d investigated the interaction between GABA and Met-enkephalin release . In awake and freely moving rats the ventrolateral FAG was dialysed u sing 25 ga. concentric probes. Basal release of peptide in 12 min or 4 0 min fractions was determined using radioimmunoassays. To establish h ow the ventrolateral FAG responds to nociception, dialysis was perform ed following unilateral hindpaw inflammation using Complete Freund's A djuvant. Twenty-four hours after inflammation was induced, neurotensin release was increased 133% and Met-enkephalin release was increased 3 53% compared to control animals. Seven days after inflammation was ind uced, neurotensin release declined precipitously, while basal Met-enke phalin release remained elevated 313% above controls. Thus, unlike enk ephalin, increased basal neurotensin release is not sustained with per sistent tonic nociception. In addition, we confirmed in normal animals that the ventrolateral FAG is induced to release Met-enkephalin by sy stemic morphine. A 43% increase in basal Met-enkephalin release was ob served immediately following a 12 mg/kg i.p., morphine injection. Morp hine should have the opposite effect (inhibit peptide release) if it a cts directly on the enkephalinergic neurons. Thus, we examined the hyp othesis that GABAergic interneurons in the FAG mediated morphine-stimu lated enkephalin release. When the GABAantagonist bicuculline (0.25 mu M to 25 mu M) was co-infused with the dialysis medium, Met-enkephalin release increased in a dose-dependent fashion and peaked 68% above pr e-infusion levels. These data elucidate the reciprocal inhibitory rela tionship between GABA and enkephalin in the ventrolateral FAG. We hypo thesize that, when nociception induces Met-enkephalin release within t his region, the tonic GABAergic inhibition is overcome, resulting in g reater sensitivity of FAG enkephalinergic neurons. Ultimately, this en hanced enkephalin release should result in greater excitability of the descending FAG output neurons that are responsible for antinociceptio n.