Transplantation of same species (allogeneic) chromaffin cells from the adrenal gland to the central nervous system has been widely shown to produce profound analgesia. This was first demonstrated in rats, but the technique has also successfully alleviated pain in more than 35 cancer patients. After spinal transplant, these patients show a distinct increase in spinal fluid levels of endogenous opioids and catecholamines, with a robust analgesic effect. The effects last many months and are accompanied by a definite inhibition in the development of tolerance to exogenous opiate analgesic drugs, a common problem with these patients. Thus transplantation of allogeneic chromaffin cell graft clearly shows potential as a means of treating chronic, intractable pain. Unfortunately, transplantation of allogeneic chromaffin cells has limitations similar to other transplants, e.g., the availability of suitable human tissue. To meet this challenge, xenogeneic (cross-species) transplants have demonstrated clear analgesic effects in rodents. However, there are significant roadblocks in transferring this method to humans. Earlier work indicates that purification of bovine or porcine cells minimizes rejection potential in rats. Preliminary work also indicates that embedding cells in a collagen matrix may improve their viability and analgesic potential. However, prior to attempting cross-species transplants in humans, it is critical to examine these effects in detail in species that are much closer to man immunologically and neurophysiologically, namely nonhuman primates. Thus, the work proposed here entails investigations designed to optimize the analgesic potential of xenogeneic chromaffin cells when transplanted into primates. The experiments will determine, in vitro, the effects of seeding cells in collagen matrices on the viability, integrity, and rejection potential of purified chromaffin cells. In vivo experiments will take these preparations to monkeys, investigating cell-dose dependence and collagen matrix effects on the analgesic efficacy of xenogeneic transplants. In this way, we hope to move much closer to the capability of treating patients with severe chronic pain with a novel treatment that is long-lasting and not only does not precipitate tolerance, but also appears to impede its development.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA015511-03
Application #
6864828
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Thomas, David A
Project Start
2003-04-01
Project End
2008-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
3
Fiscal Year
2005
Total Cost
$511,480
Indirect Cost
Name
University of Illinois at Chicago
Department
Psychiatry
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Shi, Guangbin; Ma, Ke; Pappas, George D et al. (2008) Phenotypic characteristics of hybrid cells produced by cell fusion of porcine adrenal chromaffin cells with human mesenchymal stem cells: a preliminary study. Neurol Res 30:217-22
Yeomans, David C; Lu, Ying; Laurito, Charles E et al. (2006) Recombinant herpes vector-mediated analgesia in a primate model of hyperalgesia. Mol Ther 13:589-97
Sugaya, Ikuko; Qu, Tingyu; Sugaya, Kiminobu et al. (2006) Genetically engineered human mesenchymal stem cells produce met-enkephalin at augmented higher levels in vitro. Cell Transplant 15:225-30
Kriebel, Mahlon E; Keller, Bruce; Silver, Robert B et al. (2005) Porocytosis: a transient pore array secretes the neurotransmitter packet. Anat Rec B New Anat 282:38-41
Lu, Ying; Jing, Runfeng; Yeomans, David C et al. (2004) Porcine chromaffin cells, culture, and transplant for antinociceptive effects in rodents and primates. Neurol Res 26:707-12
Kriebel, Mahlon E; Keller, Bruce; Silver, Robert B et al. (2004) The synaptic bouton acts like a salt shaker. Cell Biochem Biophys 41:259-64
Silver, Robert B; Kriebel, Mahlon E; Keller, Bruce et al. (2003) Porocytosis: secretion from small and medium-diameter vesicles and vesicle arrays without membrane fusion. J Neurocytol 32:277-91
Elcin, Y Murat; Elcin, A Eser; Pappas, George D (2003) Functional and morphological characteristics of bovine adrenal chromaffin cells on macroporous poly(D,L-lactide-co-glycolide) scaffolds. Tissue Eng 9:1047-56