Endogenous descending inhibitory and facilitatory control pathways, which originate in brain stem and higher brain areas and project to and terminate in the dorsal horn of the spinal cord, can alter spinal outputs and pain levels. Changes in descending pathways can lead to chronic pain syndromes. The pre-clinical investigation of such changes can be translated and utilized in the clinic such that successful targeted pharmacological treatment outcomes are more quickly recognized and prescribed to maximize patient benefit. This is no more apparent than when considering the phenomenon of diffuse noxious inhibitory controls (DNIC) and the patient equivalent, conditioned pain modulation (CPM). DNIC are a unique form of endogenous descending inhibitory control acting on spinal and trigeminal wide dynamic range neurons. One pain inhibits another. Previously we have shown that DNIC are present in normal animals, lost after neuropathy but are still present in sham-operated animals that show no persistent pain phenotype. It is known historically that in neuropathic animals there is a loss of descending inhibitory noradrenaline controls alongside a gain of 5-HT3 receptor-mediated facilitations. We investigated the pharmacological basis of DNIC and whether it could be restored after neuropathy (Bannister et al., 2015). In isoflurane-anaesthetized rats we activated deep dorsal horn neurones with von Frey filaments applied to the hind paw, and DNIC were induced by a noxious pinch applied to the ear. We proposed that α2-adrenoceptor mechanisms underlie DNIC because the antagonists yohimbine and atipamezole attenuated this descending inhibition. DNIC was restored in spinal nerve ligated (SNL) rats by blocking 5HT-3 receptor-mediated facilitations with the antagonist ondansetron, or by enhancing noradrenaline modulation through the use of reboxetine (noradrenaline reuptake inhibitor, NRI) or tapentadol (dual function as a μ opioid receptor agonist, MOR, and NRI). After neuropathy (in terms of descending facilitations) block of facilitatory 5HT3 receptors allows DNIC to be induced, suggesting that excitations can swamp inhibitions. The proposed underlying noradrenergic mechanisms explain the relationship between CPM and the use of tapentadol and duloxetine (a serotonin-NRI) in patients. Presently we are investigating the effects of spinal citalopram (a serotonin reuptake inhibitor, SRI) on the expression of DNIC in SNL animals. Interestingly, despite a larger available pool of serotonin in these animals, DNIC are now revealed, but are abolished following dual application of spinal citalopram and 5HT-7 receptor antagonist SB-269970, or spinal citalopram and atipamezole. This preliminary data suggests that in SNL animals, in the presence of a deluge of serotonin in the spinal cord, inhibitory 5HT7 receptors are activated such that DNIC are now expressed. Further, the data points towards a tonic inhibitory noradrenergic component in SNL animals that must be present for the DNIC-revealing actions of citalopram. Ultimately, balancing excitations and inhibitions with drugs acting on monoamine systems may be of benefit not only in restoring normal descending inhibitory balance but also conceivably in prevention of persistent post-surgical and other pains because CPM is a predictor.