One-year chromaffin cell allograft survival in cancer patients with chronic pain: Morphological and functional evidence

Laboratory of Pain and Cell Therapy, Faculty of Medicine, University Paul Sabatier, Toulouse, France.
Cell Transplantation (Impact Factor: 3.13). 05/1998; 7(3):227-38. DOI: 10.1016/S0963-6897(97)00161-9
Source: PubMed


The control of chronic pain through transplantation of chromaffin cells has been reported over the past few years. Analgesic effects are principally due to the production of opioid peptides and catecholamines by chromaffin cells. Clinical trials have been reported with allografts consisting of whole-tissue fragments implanted into the subarachnoid space of the lumbar spinal cord (14,19,36). In the present study, allogeneic grafts were successfully used to control chronic pain in two patients over a period of 1 yr based on patient reported pain scores, morphine intake, and CSF levels of Met-enkephalin. Macroscopic examination at autopsy located the transplanted tissue fragments in the form of multilobulated nodules at the level of the spinal axis and cauda equina. Immunocytochemical microscopy showed neuroendocrine cells are positive for chromagranin A (CGA), and enzymes tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DbetaH). The results suggest that there is a relationship between analgesic effect, Met-enkephalin levels in CSF, and the presence of chromaffin cells surviving in spinal subarachnoid space.

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    • "For example, it has been shown that transplants of adrenal medullary tissue or of isolated chromaffin cells into the subarachnoid space produce longlasting and significant analgesia without neurotoxicity (Décosterd et al., 1998; Herzberg et al., 2008; Lindner et al., 2000; Pacheco-Cano et al., 1990; Sagen et al., 1990; Siegan and Sagen, 1997; Wang and Sagen, 1994). Importantly, positive results have been reported in patients suffering from cancer related pain following adrenal tissue transplant (Bés et al., 1998; Buchser et al., 1996; Lazorthes et al., 1995; Winnie et al., 1993). Studies suggest the role of opioid peptides and cathecolamines through chromaffin cells since the antinociceptive effect can be reversed or attenuated by their respective receptor antagonists (Ortega and Sagen, 1993; Siegan and Sagen, 1997; Yu et al., 1998a, 1998b). "
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    ABSTRACT: In the present study, the effect of chromaffin cell transplant in the spinal cord was evaluated on formalin-induced mechanical secondary allodynia in the rat. Chromaffin cells were transplanted into the lumbar subarachnoid space before or after formalin injection. Subcutaneous formalin injection (50 μl, 1%) produced long-lasting secondary allodynia in the ipsilateral and contralateral hind paws. Once secondary allodynia was established, treatment with chromaffin cells produced a significant reduction in the nociceptive behavior in both hind paws. The antiallodynic effect was time-dependent since it was observed 15 days after chromaffin cell transplants but not before. On the other hand, pre-treatment with chromaffin cells prevented the expression of secondary allodynia in both hind paws in the rat. Antiallodynic effect of chromaffin cells was reverted with the non-selective opioid receptor antagonist naltrexone and the non-selective α(2)-adrenoceptor antagonist rauwolscine. Clusters of viable chromaffin cells labeled with anti-tyrosine hydroxylase antibodies were observed in the retrieved transplants 15 days after transplant. These results establish the analgesic efficacy of intrathecal chromaffin cells on formalin-induced secondary allodynia. Our data suggest that chromaffin cells release neuroactive substances including opioid peptides and adrenergic amines that reduce secondary allodynia in rats through activation of their receptors.
    European journal of pharmacology 07/2011; 668(1-2):147-54. DOI:10.1016/j.ejphar.2011.06.030 · 2.53 Impact Factor
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    • "Clinical trials with allografts consisting of whole-tissue fragments implanted into the subarachnoid space of the lumbar spinal cord showed that the allogeneic grafts could control cancer pain in two patients over 1 year based on patient reported pain scores, morphine intake, and CSF levels of met-enkephalin [38]. A Phase II open study in France showed the feasibility and the safety of chromaffin cell allografts administered intrathecally to cancer patients to relieve intractable pain [39]. "
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    ABSTRACT: The management of chronic pain, particularly neuropathic pain, still has significant unmet needs. In addition to inadequate symptomatic relief, there are concerns about adverse effects and addiction associated with treatments. The transplantation of cells that secrete neuroactive substances with analgesic properties into the central nervous system has only become of practical interest in more recent years, but provides a novel strategy to challenge current approaches in treating chronic pain. This review covers pre-clinical and clinical studies from both allogeneic and xenogeneic sources for management of chronic refractory pain.
    Korean journal of anesthesiology 01/2011; 60(1):3-7. DOI:10.4097/kjae.2011.60.1.3
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    • "Studies reporting analgesic effects either make no mention of experimenter blinding, or simply state that the studies were conducted blind, with no description of the extent to which such blinding was carried out. Numerous uncontrolled, non-blinded clinical trials (no placebo, openlabel Phase I) have suggested that adrenal chromaffin cell transplants produce analgesic effects (Winnie et al., 1993; Aebischer et al., 1994; Lazorthes et al., 1995, 2000; Buchser et al., 1996; Pappas et al., 1997; Bes et al., 1998), but the results of our carefully blinded experiments are consistent with the negative results of the only well-controlled and double-blinded clinical trial of adrenal chromaffin cells. This suggests that rigorous blinding may be important in preclinical experiments as well as in clinical trials. "
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    ABSTRACT: The present experiments were conducted to identify analgesic agents for transfection into immortalized adrenal chromaffin cell lines to maximize their analgesic potential. Analgesic agents known to be produced by adrenal chromaffin cells were infused intrathecally at a low dose (0.2 microg) which might conceivably be attained by adrenal chromaffin cell transplants. Numerous agents, administered individually and in two-factor combinations, produced significant analgesic effects in the formalin test. Before assessing the potential additive or synergistic effects of these analgesic agents with adrenal chromaffin cells, studies were conducted to demonstrate analgesic effects with adrenal chromaffin cells alone. Analgesic effects were previously reported in the literature with 80-100k intrathecal bovine adrenal chromaffin (BAC) cells; but in the present study 500k purified BAC cells failed to produce detectable analgesic effects. One million purified BAC cells also failed to produce analgesic effects in the formalin test. In a final study, even nicotine-stimulated release from one million purified BAC cells failed to produce analgesic effects in the formalin test. The fact that even one million nicotine-stimulated BAC cells failed to demonstrate therapeutic potential in these blinded experiments under conditions which were clearly sensitive to the analgesic agents produced by BAC cells, raises serious questions about the clinical utility of this experimental treatment.
    Pain 10/2002; 99(1-2):263-71. DOI:10.1016/S0304-3959(02)00120-3 · 5.21 Impact Factor
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