Direct and Indirect Nociceptive Input from the Trigeminal Dorsal Horn to Pain-Modulating Neurons in the Rostral Ventromedial Medulla

Abstract

The brain is able to amplify or suppress nociceptive signals by means of descending projections to the spinal and trigeminal dorsal horns from the rostral ventromedial medulla (RVM). Two physiologically defined cell classes within RVM, “ON-cells” and “OFF-cells”, respectively facilitate and inhibit nociceptive transmission. However, sensory pathways through which nociceptive input drives changes in RVM cell activity are only now being defined. We recently showed thatindirectinputs from the dorsal horn via the parabrachial complex (PB) convey nociceptive information to RVM. The purpose of the present study was to determine whether there are alsodirectdorsal horn inputs to RVM pain-modulating neurons. We focused on the trigeminal dorsal horn, which conveys sensory input from the face and head, and used a combination of single-cell recording with optogenetic activation and inhibition of projections to RVM and PB from the trigeminal interpolaris-caudalis transition zone (Vi/Vc) in male and female rats. We determined that a direct projection from ventral Vi/Vc to RVM carries nociceptive information to RVM pain-modulating neurons. This projection included a GABAergic component, which could contribute to nociceptive inhibition of OFF-cells. This approach also revealed a parallel, indirect, relay of trigeminal information to RVM via PB. Activation of the indirect pathway through PB produced a more sustained response in RVM compared to activation of the direct projection from Vi/Vc. These data demonstrate that adirecttrigeminal output conveys nociceptive information to RVM pain-modulating neurons with a parallelindirectpathway through the parabrachial complex.Significance StatementRostral ventromedial medullapain-modulatingneurons respond to noxious stimulation, which implies that they receive input frompain-transmissioncircuits. However, the traditional view has been that there is no direct input to RVM pain-modulating neurons from the dorsal horn, and that nociceptive information is carried by indirect pathways. Indeed, we recently showed that noxious information can reach RVM pain-modulating neurons via the parabrachial complex. Usingin vivoelectrophysiology and optogenetics, the present study identified a direct relay of nociceptive information from the trigeminal dorsal horn to physiologically identified pain-modulating neurons in RVM. Combined tracing and electrophysiology data revealed that the direct projection includes GABAergic neurons. Direct and indirect pathways may play distinct functional roles in recruiting pain-modulating neurons.