The roles of nerve growth factor and cholecystokinin in the enhancement of morphine analgesia in a rodent model of central nervous system inflammation

Abstract

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 naıve animals. Further, spinal anti-NGF (3 mg) 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 b-NGF (7 mg/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.

Impacts of anti-nerve growth factor antibody on pain-related behaviors and expressions of opioid receptor in spinal dorsal horn and dorsal root ganglia of rats with cancer-induced bone pain

“…When the tissues were under noxious stimuli, NGF could bind with the receptors, activated neuronal terminal TrkA and P75 receptors, 21,22 and regulated the internal flow of calcium ions, thereby activating the intracellular signaling cascade reaction, modulating and activating different ion channels, causing central sensitization, and resulting in pain-related hypersensitivity or allodynia. 23,24 In this study, the doses of intrathecally injected anti-NGF and NGF were 10 mg, which is consistent with that of Obata et al 25 and Xanthos et al 26 in studying inflammatory pain and neuropathic pain. The pain-related behavioral tests showed that after intrathecally injected anti-NGF, the number of spontaneous foot constriction was decreased, the heat radiation latency was prolonged, and PWMT was increased, suggesting that anti-NGF could significantly alleviate the effects of CIBP in rats; while the intrathecal injection of anti-NGF into the sham group showed no pain-related behavioral changes, suggesting that NGF did not participate the pain signal transduction in normal rats or could not play a major role, meanwhile, it is also suggested that NGF played an important role in the occurrence and development of CIBP.…”

“…25 and Xanthos et al. 26 in studying inflammatory pain and neuropathic pain. The pain-related behavioral tests showed that after intrathecally injected anti-NGF, the number of spontaneous foot constriction was decreased, the heat radiation latency was prolonged, and PWMT was increased, suggesting that anti-NGF could significantly alleviate the effects of CIBP in rats; while the intrathecal injection of anti-NGF into the sham group showed no pain-related behavioral changes, suggesting that NGF did not participate the pain signal transduction in normal rats or could not play a major role, meanwhile, it is also suggested that NGF played an important role in the occurrence and development of CIBP.…”

Neuroplastic alteration of TTX-resistant sodium channel with visceral pain and morphine-induced hyperalgesia

“…Recent studies show that many animal models of inflammatory pain are characterized by the release of neurotrophic factors, 28 , 38 , 40 , 42 and that nerve growth factor may function as a key molecular switch that alters dopamine receptor, DOPr, function under sustained opioid stimulation. 42 , 45 Therefore, we also think that the mechanisms in both our models are all involved in the changes among the neurotrophic factors.…”