Budai, Dénes, Ichiro Harasawa, and Howard L. Fields. Midbrain periaqueductal gray (PAG) inhibits nociceptive inputs to sacral dorsal horn nociceptive neurons through α₂-adrenergic receptors. J. Neurophysiol. 80: 2244–2254, 1998. Modulation of sacral spinal dorsal horn neurons by the ventrolateral PAG was studied by extracellular recording combined with microiontophoretic applications of α-adrenergic agonists or antagonists. Bicuculline (BIC, 15 ng) microinjected into the ventrolateral PAG produced a consistent inhibition of the responses of nociceptive dorsal horn neurons. After PAG–BIC applications, the total number of spikes per heat stimulation period was significantly decreased to a mean of 37 ± 19% (n = 8) of the pre-BIC control. Local iontophoresis of the selective α₂-adrenoceptor antagonists idazoxan or yohimbine but not the selective α₁ antagonist benoxathian significantly reversed PAG–BIC-evoked inhibition. At low ejection currents, clonidine, an α₂-adrenoceptor agonist, markedly reduced noxious heat-evoked responses but had no consistent action on the responses to iontophoresed excitatory amino acids [EAA; N-methyl-d-aspartate (NMDA) or kainic acid]. At ejection currents higher than required to block descending inhibition, idazoxan potentiated responses to both heat and EAA iontophoresis. At higher ejection currents, EAA responses were inhibited by clonidine. This indicates that both presynaptic and postsynaptic α₂ receptors are capable of inhibiting the recorded neurons. Activation of the α₁ adrenoceptors by iontophoresis of methoxamine often led to a marked increase in the responses to kainic acid and, to a lesser extent, to NMDA iontophoresis or noxious heat. Together with previously reported work, the current experiments demonstrate that PAG neurons inhibit nociceptive dorsal horn neurons primarily through an indirect α₂ adrenoceptor mechanism. In this same population of dorsal horn neurons, norepinephrine has a direct α₁-mediated excitatory effect.