The perception of pain is a dynamic process that is subject to ongoing modulation by central pro- and anti-nociceptive control systems. Diverse factors that may be genetic, gender specific, environmentally determined, psychological or, indeed, engendered by already existing pain-related neuronal activity influence the level of descending control on spinal nociceptive processing. In particular, pain is exacerbated by anxiety. This review examines the evidence for cholecystokinin (CCK)-evoked activation of descending pro-nociceptive facilitatory pathways from the midbrain periaqueductal grey matter (PAG) in mediating anxiety-induced hyperalgesia as well as in the development and maintenance of hyperalgesia associated with peripheral neuropathy. CCK drives a spinal-PAG-medullo-spinal pro-nociceptive positive feedback loop that potentiates spinal transmission of nociceptive afferent input, whilst at the same time suppressing activity in the opioid-driven anti-nociceptive descending pathway from the PAG. In females, responsiveness of PAG neurones to CCK is further modulated by changes in the levels of circulating ovarian hormones, an effect that could underlie the changes in pain sensitivity and responsiveness to opiates that occur during the menstrual cycle and postpartum period.