Bi-directional changes in affective state elicited by manipulation of medullary pain-modulatory circuitry

The rostral ventromedial medulla contains three physiologically defined classes of pain-modulating neuron that project to the spinal and trigeminal dorsal horns. OFF cells contribute to anti-nociceptive processes, ON cells contribute to pro-nociceptive processes (i.e. hyperalgesia) and neutral cells tonically modulate spinal nociceptive responsiveness. In the setting of noxious peripheral input, the different cell classes in this region permit bi-directional modulation of pain perception (analgesia vs hyperalgesia). It is unclear, however, whether changes in the activity of these neurons are relevant to the behaving animal in the absence of a painful stimulus. Here, we pharmacologically manipulated neurons in the rostral ventromedial medulla and used the place-conditioning paradigm to assess changes in the affective state of the animal. Local microinjection of the alpha(1)-adrenoceptor agonist methoxamine (50.0 microg in 0.5 microl; to activate ON cells, primarily), combined with local microinjection of the kappa-opioid receptor agonist U69,593 (0.178 microg in 0.5 microl; to inhibit OFF cells), produced an increase in spinal nociceptive reactivity (i.e. hyperalgesia on the tail flick assay) and a negative affective state (as inferred from the production of conditioned place avoidance) in the conscious, freely moving rat. Additional microinjection experiments using various concentrations of methoxamine alone or U69, 593 alone revealed that the rostral ventromedial medulla is capable of eliciting a range of affective changes resulting in conditioned place avoidance, no place-conditioning effect or conditioned place preference (reflecting production of a positive affective state). Overall, however, there was no consistent relationship between place-conditioning effects and changes in spinal nociceptive reactivity. This is the first report of bi-directional changes in affective state (i.e. reward or aversion production) associated with pharmacological manipulation of a brain region traditionally associated with bi-directional pain modulation. We conclude that, in addition to its well-described pain-modulating effects, the rostral ventromedial medulla is capable of modifying animal behavior in the absence of a painful stimulus by bi-directionally influencing the animal's affective state.