Direct evidence of an extensive GABAergic innervation of the spinal dorsal horn by fibres descending from the rostral ventromedial medulla.

Abstract

A long line of studies emphasizes the contribution of serotonergic fibres descending from the rostral ventromedial medulla in the control of spinal nociceptive information processing. A growing body of evidence, however, suggests that the relative contribution of serotonin to the mediation of spinal neuronal activity from the rostral ventromedial medulla may require re-evaluation. It has recently been substantiated that, in addition to the serotonergic fibres, the spinal dorsal horn receives an abundant non-serotonergic projection from the rostral ventromedial medulla. Furthermore, stimulation in the rostral ventromedial medulla could result in a powerful inhibition of nociceptive spinothalamic tract cells without any detectable serotonin release in the dorsal horn. After labelling raphe-spinal axons and axon terminals in the rat by iontophoretic injections of the anterograde axonal tracer Phaseolus vulgaris leucoagglutinin into the central region of the rostral ventromedial medulla (nucleus raphe magnus) and revealing GABA and glycine immunoreactivities of the labelled raphe-spinal terminals and their postsynaptic targets by postembedding immunocytochemical methods, here we demonstrate an extensive GABAergic projection from the rostral ventromedial medulla to the spinal dorsal horn. We show that the majority of the labelled raphe-spinal terminals in laminae I-IIo and IV-V contain GABA and some of the GABA-immunoreactive terminals are also immunoreactive for glycine. We also disclose that GABA-immunoreactive raphe-spinal terminals establish synaptic contacts primarily with GABA- and glycine-negative, presumably excitatory, spinal neurons, including Calbindin-D28k- as well as parvalbumin-immunoreactive cells in both laminae I-IIo and IV-V. The results suggest that volleys in fibres descending from the rostral ventromedial medulla may evoke GABA release from raphe-spinal terminals, and the released GABA, in some cases probably acting together with glycine, might play a crucial, as yet mostly unidentified, role in the inhibition of nociceptive information processing in the dorsal horn of the spinal cord.