Sources of Opioid-Producing Cells

Adrenal Medulla

Chromaffin cells of the adrenal medulla produce and secrete a variety of neuroactive substances in addition to the traditionally recognized catecholamines. Most notably, these cells are a rich source of neuropeptides and neurotrophic factors (see Carmichael and Stoddard, 1993, and Unsicker, 1993, for reviews). Although several of these latter agents may be useful in pain control, the adrenal medulla has been well characterized as a rich source of opioid peptides (Viveros et al., 1979; Hexum et al., 1980; Lewis et al., 1980; Yang et al., 1980; Kilpatrick et al., 1982). These are primarily derived from the proenkephalin A precursor; thus, the active peptides are predominantly those of the enkephalin-containing family. In bovine adrenal gland, proenkephalin mRNA levels are 20–400 times higher than in the brain (Pittius et al., 1985). Levels of opioid peptide production in the adrenal medulla is species dependent to some extent, with high levels found in bovine, porcine, and canine glands and lower levels in rodents (Hexum et al., 1980; Yang et al., 1980). However, both proenkephalin mRNA and opioid peptide levels increase in the rat adrenal with denervation and with time in tissue culture, suggesting that environmental factors have a strong influence on opioid peptide production (Kilpatrick et al., 1984; Zhu et al., 1992).

In contrast to the CNS, where proenkephalin is processed nearly completely to the pentapeptides, Met5-enkephalin and Leu5-enkephalin, the adrenal medulla in addition processes this precursor to several small, intermediate, and larger peptides that may contain single or multiple encrypted pentapeptide sequences (Lewis et al., 1980; Stern et al., 1980; Liston et al., 1984; Wilson, 1991).