Absence of appreciable tolerance and morphine cross-tolerance in rats with adrenal medullary transplants in the spinal cord.

ABSTRACT

Adrenal medullary transplants in the spinal subarachnoid space may be a means of achieving sustained local delivery of pain-reducing neuroactive substances on a continually renewable basis. However, a potential limitation of this approach is tolerance development to agents released from the transplanted cells. In particular, since adrenal medullary chromaffin cells release opioid peptides, reduced antinociceptive efficacy of opioids is possible. To determine this, alterations in the dose-effectiveness of morphine were assessed in animals with adrenal medullary transplants. Results indicated that, not only was there no apparent tolerance, but that adrenal medullary transplants could potentiate the analgesic efficacy of morphine. An additional goal of these studies was to determine whether chronic or intermittent nicotine could produce increased antinociception, since stimulation of cell surface nicotinic receptors increases release of neuroactive substances from chromaffin cells. This was assessed using subcutaneously implanted nicotine pellets or repeated systemic administration of nicotine. Findings indicated that exposure to nicotine results in an acute tolerance, or tachyphylaxis, to nicotine which is rapidly reversed following cessation of nicotinic stimulation. Together, these results suggest that adrenal medullary transplants may provide a constant source of opioid peptides, augmentable by intermittent nicotinic stimulation, without the development of appreciable tolerance to these pain-reducing neuroactive substances.