PT - JOURNAL ARTICLE AU - QiLiang Chen AU - Zachary Roeder AU - Ming-Hua Li AU - YangMiao Zhang AU - Susan L. Ingram AU - Mary M. Heinricher TI - Optogenetic Evidence for a Direct Circuit Linking Nociceptive Transmission through the Parabrachial Complex with Pain-Modulating Neurons of the Rostral Ventromedial Medulla (RVM) AID - 10.1523/ENEURO.0202-17.2017 DP - 2017 Jun 19 TA - eneuro PG - ENEURO.0202-17.2017 4099 - http://www.eneuro.org/content/early/2017/06/19/ENEURO.0202-17.2017.short 4100 - http://www.eneuro.org/content/early/2017/06/19/ENEURO.0202-17.2017.full AB - The parabrachial complex (PB) is a functionally and anatomically complex structure involved in a range of homeostatic and sensory functions, including nociceptive transmission. There is also evidence that PB can engage descending pain-modulating systems, the best characterized of which is the rostral ventromedial medulla (RVM). Two distinct classes of RVM neurons, “ON-cells” and “OFF-cells,” exert net pro-nociceptive and anti-nociceptive effects, respectively. PB was recently shown to be a relay of nociceptive information to RVM ON- and OFF-cells. The present experiments used optogenetic methods in a lightly anesthetized rat and an adult RVM slice to determine whether there are direct, functionally relevant inputs to RVM pain-modulating neurons from PB. Whole-cell patch-clamp recordings demonstrated that PB conveys direct glutamatergic and GABAergic inputs to RVM neurons. Consistent with this, in vivo recording showed that nociceptive-evoked responses of ON- and OFF-cells were suppressed by optogenetic inactivation of ArchT-expressing PB terminals in RVM, demonstrating that a net inhibitory input to OFF-cells and net excitatory input to ON-cells are engaged by acute noxious stimulation. Further, the majority of ON- and OFF-cells responded to optogenetic activation of channelrhodopsin-expressing terminals in the RVM, confirming a direct PB influence on RVM pain-modulating neurons. These data show that a direct connection from the PB to the RVM conveys nociceptive information to the pain-modulating neurons of RVM under basal conditions. They also reveal additional inputs from PB with the capacity to activate both classes of RVM pain-modulating neurons and the potential to be recruited under different physiological and pathophysiological conditions.Significance Statement Pain-modulatory circuits receive input from ascending pain transmission pathways as part of a recurrent network. Using optogenetics with whole-cell patch-clamp recording and in vivo single-cell recording, the present studies identified direct functional connections from the parabrachial complex (PB), a major target of ascending nociceptive pathways, to physiologically identified pain-modulating neurons of the rostral ventromedial medulla (RVM), the primary output node of a major descending pain-modulating system. These data for the first time point to an identified nociceptive synapse in RVM that could be probed in relevant physiologic contexts, and set the stage for a dissection of the links between nociceptive transmission and nociceptive modulation in the transition from acute to chronic pain.