The roles of nerve growth factor and cholecystokinin in the enhancement of morphine analgesia in a rodent model of central nervous system inflammation.
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.
Xanthos
Dimitris N
DN
Department of Anesthesia, McGill University, Montreal, Quebec, Canada.
Kumar
Naresh
N
Theodorsson
Elvar
E
Coderre
Terence J
TJ
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002493:Central Nervous System Diseases / Q000139:chemically induced / Q000188:drug therapy*; D002766:Cholecystokinin / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D007278:Injections, Spinal; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D009020:Morphine / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D020932:Nerve Growth Factor / Q000494:pharmacology / Q000502:physiology*; D051381:Rats; D020318:Rats, Long-Evans; D012844:Sincalide / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D013116:Spinal Cord / Q000378:metabolism
C090019:8-sulfocholecystokinin octapeptide; D000700:Analgesics; D008070:Lipopolysaccharides; D009020:Morphine; D002766:Cholecystokinin; D020932:Nerve Growth Factor; D012844:Sincalide