Stimulation of neurons in the periaqueductal gray (PAG) produces antinociception that is mediated in part by noradrenergic neurons that innervate the spinal cord dorsal horn. Because norepinephrine-containing neurons are not found in the PAG, noncatecholamine neurons in the PAG must project to, and activate, spinally projecting catecholamine neurons located in the pons or medulla. The present studies determined the projections of neurons in the ventrolateral PAG to the A5, A6 (locus coeruleus), and A7 catecholamine cell groups that are known to contain spinally projecting noradrenergic neurons. The anterograde tracer biotinylated dextran amine (BDA) was injected into the ventrolateral PAG, and labeled axon terminal profiles were identified near noradrenergic neurons that were visualized by processing tissue sections for tyrosine hydroxylase immunoreactivity. Highly varicose, anterogradely labeled terminal profiles were found apposed to the dendrites and somata of tyrosine-hydroxylase-immunoreactive neurons and non-tyrosine-hydroxylase-immunoreactive neurons in the dorsolateral and ventrolateral pontine tegmentum. These axon terminal profiles were more dense on the side ipsilateral to the BDA deposit, and both A7 and locus coeruleus neurons received a more dense innervation than did the A5 neurons.
Although definitive evidence for a direct pathway from PAG neurons to spinally projecting A7 neurons requires ultrastructural studies, the results of the present studies provide presumptive evidence for direct projections from neurons in the PAG to noradrenergic A7 neurons that innervate the spinal cord dorsal horn and modulate pain perception. If neurons in the ventrolateral PAG do form synapses with noradrenergic A7 neurons, these spinally projecting catecholamine neurons may mediate part of the analgesic effect produced by systemic administration of morphine. In contrast, the projections of PAG neurons to the A5 cell group and the locus coeruleus may mediate the cardiovascular and motor effects produced by stimulation of sites in the ventrolateral PAG.