Organization of tyrosine hydroxylase- and serotonin-immunoreactive brainstem neurons with axon collaterals to the periaqueductal gray and the spinal cord in the rat.

Retrograde tracing and immunocytochemistry were used to examine the axon collateralization of brainstem serotonin (5-HT) and norepinephrine (NE) cells to the periaqueductal gray (PAG) and spinal cord. Tyrosine hydroxylase (TH)-immunofluorescent neurons which collateralize to the PAG and the cervical spinal cord were found in all brainstem catecholamine cell groups previously shown to contain neurons which project to the spinal cord, including the A5 and A7 cell groups, locus coeruleus, subcoeruleus and the C1 cell group. Many TH-immunofluorescent cells which project to the PAG but not to the spinal cord were also found. The region of the nucleus raphe magnus (NRM) also contained many neurons retrogradely labeled from the PAG. These overlapped with the distribution of spinally projecting 5-HT-immunofluorescent cells in the NRM, however, less than 1% of the PAG projecting cells in this region were 5-HT-immunofluorescent. In contrast, many 5-HT-immunofluorescent cells in the more rostral nucleus raphe pontis and nucleus raphe dorsalis were retrogradely labeled from the PAG but not from the spinal cord. Finally, a population of neurons in the NRM and adjacent reticular formation and in the region of several pontomedullary catecholamine cell groups collateralized to the PAG and spinal cord, but were neither 5-HT nor TH-immunofluorescent. Taken together, these findings raise the possibility that the noradrenergic contribution to the spinal antinociceptive effects produced by PAG electrical stimulation results, in part, from antidromic activation of brainstem noradrenergic neurons that have axon collaterals projecting to the PAG and spinal cord. In contrast, the 5-HT contribution to the spinal antinociceptive effects produced by PAG electrical stimulation is more likely to derive, as previously proposed, from orthodromic activation of raphe-spinal serotonergic axons.