Pain from peripheral nerve injury, inflammation and cancer, characterised by ongoing pain, hyperalgesia and allodynia arise from peripheral and central processes. There is clear evidence from both preclinical and clinical studies that both peripheral and central hyperexcitability play important roles in determining the level of pain perceived. Rightly, much emphasis has been put on spinal cord mechanisms in central excitability such as wind-up and long term potentiation but it also clear that spinal excitability can be regulated by descending pathways from the brain. These originate from predominantly monoamine systems which are additionally implicated in control of emotions, fear, anxiety, thermoregulation and the sleep cycle and so may mediate these pain induced co-morbidities. Furthermore, they are likely targets for antidepressants used in pain states. Much of the early work in this area concentrated on descending inhibitions, now known to be predominantly noradrenergic, and failure of descending inhibitions has been reported in patients. However, pain could equally be increased by enhanced descending facilitations and data is accumulating on exactly this. Thus, increases in pain sensitivity that follow injury can be regulated by superficially located projection neurons of the dorsal horn of the spinal cord that express the NK1 receptor. These neurones project through the parabrachial area, an area activated in humans in hyperalgesic states, to the amyglada and hypothalamus where they engage systems related to the affective, autonomic and aversive aspects of pain. Following selective ablation of these neurons we have identified changes in receptive field size, mechanical and thermal coding and central sensitisation of deeper lying dorsal horn neurons in the rat, important for both pain sensations and reflexes. The pathways relay on 5HT positive and other neurones in the brainstem rostroventromedial medulla (RVM). The final arm is a descending serotinergic facilitatory pathway terminating on excitatory 5HT3 receptors in the spinal cord that has a major influence on mechanical and chemical evoked responses of deep dorsal horn neurones and also enhances their thermal responses. 5HT3 receptors therefore play a pronociceptive role in the spinal cord as supported by previous studies. Interestingly, these 5HT facilitations are not required for either windup or long term potentiation, reinforcing the idea that these are intrinsic spinal events. Further we have demonstrated that in animal models of neuropathic and bone cancer pain states there are enhanced descending facilitatory controls of mechanical responses of spinal neurones, mediated through the activation of these spinal 5HT3 receptors. Depletion of spinal 5HT reduces behavioural hypersensitivity after peripheral nerve injury. After inflammation, the changes seen are minor, suggesting that these facilitations impact more upon pathophysiological processes. Finally, based on the changes in these controls after nerve injury and the ability of gabapentin to modulate neuropathic pain, we have shown that this 5HT3 mediated descending pathway plays a major role in the state-dependent actions of this drug.Since gabapentin binds to a subunit of calcium channels and some 5HT3 receptors are on afferent terminals, this interaction may occur on the terminals of afferent fibres as they enter the spinal cord. These excitatory influences are likely to contribute to the development and maintenance of central excitability in the spinal cord, and furthermore, to the behavioural manifestation of tactile allodynia. These pathways, therefore form a link between emotional states and levels of pain and when dysfunctional, could contribute to pains where there are mood and sleep disturbances such as fibromyalgia.