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Current Topics in Neurochemistry   Volumes    Volume 1 
Abstract
Neurochemical and phenotypic characteristics of isolated chromaffin cells as cellular implants for analgesia
Jacqueline Sagen, Anne L. Cahill, Biljana Pavlovic-Surjancev, John D. Ortega, Robert L. Perlman
Pages: 167 - 184
Number of pages: 18
Current Topics in Neurochemistry
Volume 1 

Copyright © 1997 Research Trends. All rights reserved

ABSTRACT
 
Chromaffin cells have been used as a source of therapeutic neuroactive agents for improving function following implantation in the CNS. In particular, chromaffin cells have been shown to produce analgesia when implanted into CNS pain modulatory regions. These cells possess a great deal of neurochemical and phenotypic plasticity in response to environmental cues. In addition, chromaffin cells of the adrenal medulla are not a homogeneous populationm and are composed of at least 2 major catecholamine-producing cell types which may have different complements of pharmacologically active agents. The aim of these studies was to more completely characterize the influence of neurotrophic factor exposure and chromaffin cell subpopulations on potential analgesic function in CNS implants. The response of bovine chromaffin cells to exogenous neurotrophic factors NGF, bFGF, NGF and bFGF combination, or sciatic nerve segment explants was compared in vitro and in vivo in transplants to the rat midbrain periaqueductal gray. In vitro, bovine chromaffin cells responded to NGF-bFGF combinations or sciatic nerve explants by acquiring a neuronal-like phenotype with numerous bouton-containing neuritic processes. This differentiation was not apparent when transplanted bovine chromaffin cells were exposed to any of these treatments. In addition, there was no obvious effect on chromaffin cell survival in the grafts. These findings suggested that neurotrophic factor treatment does not provide further beneficial effects on grafted bovine chromaffin cell survival or host-grant integration. In a second group of studies, proenkephalin A regulation and analgesic potency was characterized in bovine chromaffin cell subpopulations. Bovine chromaffin cells which stored predominantly epinephrine (epinephrine-rich cells) had a higher catecholamine content and contained more proenkephalin A and its proteolytically derived peptides than did norepinephrine-rich cells. The differential expression of proenkephalin A in the two chromaffin cell subtypes was studied by measuring steady-state levels of mRNA and immunoreactive protein. Proenkephalin A mRNA levels increased in both epinephrine-rich and norepinephrine-rich cell populations when the cells were cultured in vitro, and proenkephalin A mRNA levels were increased even further by treatment of the cultured cells with forskolin, angiotensin II, histamine, and carbachol, but decreased by phorbol dibutyrate. Proenkephalin A protein levels were increased by forskolin, histamine, and the nicotinic agonist dimethylphenylpiperazinium. Thus environmental factors may influence the production of pain-reducing neuroactive substances in chromaffin cells. Epinephrine-rich and norepinephrine-rich chromaffin cell subpopulations were implanted into the spinal subarachnoid space of immunosuppressed rats. Analgesic responses following nicotinic stimulation were determined in these animals 2-6 weeks following implantation. Both subgroups of chromaffin cells produced analgesia of equivalent potency. Adrenergic antagonist phentolamine attenuated this analgesia in both groups, but opiate antagonist naloxone attenuated the analgesia in the epinerphrine, but not norepinephrine cell-implanted group, consistent with the presence of higher levels of proenkephalin products in the epinephrine-rich cells. However, the full analgesic potency may require the combination of pain-reducing neuroactive agents from both bovine chromaffin cell subpopulations.
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