Animal models of inflammatory
pain are characterized by the release of inflammatory mediators such as
cytokines and
neurotrophic factors, and enhanced
analgesic sensitivity to
opioids. In this study, we examine the mechanisms underlying this effect, in particular the roles of
cholecystokinin (CCK) and
nerve growth factor (
NGF), in an animal model of central nervous system (CNS)
inflammation induced by spinal administration of
lipopolysaccharide (LPS). Although spinal administration of LY-225910 (25 ng), a CCK-B antagonist, enhanced
morphine analgesia in naïve rats, it was unable to do so in LPS-treated animals. Conversely, spinal
CCK-8S administration (1 ng) decreased
morphine analgesia in LPS-treated rats, but not in naïve animals. Further, spinal anti-
NGF (3 microg) was able to reduce
morphine analgesia in LPS-treated rats, but not in naïve animals, an effect that was reversed by spinal administration of LY-225910. While
CCK-8S concentration was increased in spinal cord extracts of LPS animals as compared to controls,
morphine-induced spinal CCK release in the extracellular space, as measured by in-vivo spinal cord microdialysis was inhibited in LPS animals as compared to controls, and this was reversed by anti-
NGF pretreatment. Finally, chronic spinal administration of beta-
NGF (7 microg/day) for 7 days enhanced spinal
morphine analgesia, possibly by mimicking a CNS inflammatory state. We suggest that in intrathecally LPS-treated rats, spinal CCK release is altered resulting in enhanced
morphine analgesia, and that this mechanism may be regulated to an important extent by
NGF.