Optimization of adrenal medullary allograft conditions for pain alleviation

Previous findings in our laboratory have demonstrated that transplants of adrenal medullary tissue into the spinal subarachnoid space can alleviate pain, most likely via sustained local release of pain-reducing neuroactive substances from the transplanted chromaffin cells. The success of this work in animal models has led to preliminary clinical trials with promising results. However, before large-scale clinical studies are undertaken, numerous issues should be resolved, many of which can be readily addressed initially in the laboratory. One of these is the amount of donor adrenal medullary tissue necessary to produce long-term antinociception. Although tissue from two adrenal glands has generally been used, it is unknown whether less would be equally effective, or more could increase analgesic potency. To address this, various amounts of adrenal medullary tissue, ranging from one to ten donor glands, were used. Results showed lowered antinociceptive benefits when only one adrenal medulla was used, but only small and short-lived increases when donor material was increased substantially. In addition, assays of catecholamine and Met-enkephalin release in the host spinal CSF revealed only slight further increases following the transplantation of more than 2-4 glands. These results indicate that a small amount of adrenal medullary tissue is necessary and sufficient to produce sustained antinociception, and suggest that higher amounts may result in tolerance development or feedback inhibition. Another important issue is the ability to retain antinociceptive potency if donor tissue is maintained in culture prior to transplantation, since the coordination of donor harvesting and recipient availability is often difficult. To address this, donor adrenal medullary tissue was maintained in explant culture for various periods following dissection. Results indicated that adrenal medullary tissue can be maintained in culture for up to 30 days prior to transplantation without decrement in antinociceptive potency, and that a period of 7-21 days results in improved graft viability. Results of this study indicate that some of the critical issues for successful neural transplantation outcomes can be initially addressed in pre-clinical studies.