The transplantation of cells or tissue into the CNS is a potential means of achieving sustained delivery of naturally derived pharmacologically active substances for the alleviation of chronic disorders. Work in our laboratory has demonstrated that adrenal medullary or chromaffin cell transplants in the spinal subarachnoid space can alleviate pain symptoms in several animal models. This most likely involves the release of pain-reducing neuroactive substances, such as opioid peptides and catecholamines, from the transplanted cells. A significant advantage of the transplant approach for the chronic pain patient is the potential ability to provide a continually renewable source of analgesic agents, reducing or eliminating the need for repeated narcotic administration. As a result of promising findings in animal studies, clinical studies have been initiated at several centers in patients with cancer pain, with encouraging results. The goals of the proposed studies are to understand the mechanisms, long-term consequences, and potential limitations of these transplants in the CNS. Pharmacologic and biochemical analyses will be done in order to determine transplant interactions with host spinal receptors, the contribution of opioid and other neuropeptides to pain reduction, and tolerance and cross-tolerance to traditional pharmacotherapies. The mechanisms of the transplants in reducing both acute and chronic pain processes may be distinct, and will be evaluated using selective nociceptor activation and acute and chronic pain models. It is thought that chronic pain such as that consequent to peripheral nerve injury or inflammation results from a cascade of neuropathological events leading to persistent hyperexcitability, including activation of NMDA receptors and the production of nitric oxide and cyclic GMP. Clinically, in spite of advances in pain management, some of the most debilitating disorders are those associated with peripheral or central nerve lesions and chronic inflammation, and are poorly or inadequately controlled by traditional pharmacotherapies. Recent studies in our laboratory have suggested that adrenal medullary or chromaffin cell transplants can alleviate symptoms of chronic pain due to peripheral nerve injury and inflammation, and may do so via intervening in the NMDA/NO cascade. Thus, if successful, the findings from these studies could lead to a novel approach in the long term therapeutic intervention for alleviation of chronic pain syndromes, particularly those refractory to traditional pharmacotherapies, who would benefit greatly by improved quality of life free from pain.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA010546-05
Application #
6150470
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Thomas, David D
Project Start
1997-04-10
Project End
2002-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
5
Fiscal Year
2000
Total Cost
$246,888
Indirect Cost
Name
University of Miami School of Medicine
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33146
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Hama, Aldric; Sagen, Jacqueline (2007) Antinociceptive effect of cannabinoid agonist WIN 55,212-2 in rats with a spinal cord injury. Exp Neurol 204:454-7
Guenot, Marc; Lee, Jeung Woon; Nasirinezhad, Farinaz et al. (2007) Deafferentation pain resulting from cervical posterior rhizotomy is alleviated by chromaffin cell transplants into the rat spinal subarachnoid space. Neurosurgery 60:919-25;discussion 919-25
Hama, Aldric; Basler, Adam; Sagen, Jacqueline (2006) Enhancement of morphine antinociception with the peptide N-methyl-D-aspartate receptor antagonist [Ser1]-histogranin in the rat formalin test. Brain Res 1095:59-64
NasiriNezhad, Farinaz; Sagen, Jacqueline (2005) NMDA antagonist peptide supplementation enhances pain alleviation by adrenal medullary transplants. Cell Transplant 14:203-11
Caban, Alberto J; Hama, Aldric T; Lee, Jeung Woon et al. (2004) Enhanced antinociception by nicotinic receptor agonist epibatidine and adrenal medullary transplants in the spinal subarachnoid space. Neuropharmacology 47:106-16
Hama, Aldric; Woon Lee, Jeung; Sagen, Jacqueline (2003) Differential efficacy of intrathecal NMDA receptor antagonists on inflammatory mechanical and thermal hyperalgesia in rats. Eur J Pharmacol 459:49-58
Sagen, Jacqueline (2003) Cellular therapies for spinal cord injury: what will the FDA need to approve moving from the laboratory to the human? J Rehabil Res Dev 40:71-9
Hama, Aldric; Sagen, Jacqueline (2002) Selective antihyperalgesic effect of [Ser1] histogranin on complete Freund's adjuvant-induced hyperalgesia in rats. Pain 95:15-21
Vizzardelli, C; Potter, E D; Berney, T et al. (2001) Automated method for isolation of adrenal medullary chromaffin cells from neonatal porcine glands. Cell Transplant 10:689-96

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