Opiates induce long-term increases in prodynorphin-derived peptide levels in the guinea-pig myenteric plexus

The subcutaneous administration of a single dose of an opiate agonist (levorphanol) or antagonist (naloxone) to guinea pigs results in an at least 3-fold elevation of dynorphin and alpha-neoendorphin-immunoreactivity in the longitudinal muscle myenteric plexus preparation. The effects are time- and dose-dependent, significant elevations first being observed 6 h after treatment and lasting for up to 24 h. Pretreatment levels of opioid peptides were observed after 8 days. Combined injection of the narcotic agonist and antagonist, at sufficiently high doses, resulted in an additive effect of the individual drugs. The respective stereoisomers dextrorphan and (+)-naloxone did not affect prodynorphin-derived peptide concentrations. An increase of endogenous opioids was also observed after administration of the nonopiate clonidine, a compound which, like opiates, alters the activity of the myenteric plexus. It is suggested that feedback mechanisms in the myenteric plexus are responsible for the elevation of endogenous opioid peptides following exposure to exogenous opiates. Using a monoclonal antibody (3-E7), which recognizes virtually all endogenous opioid peptides, it was found that levels of higher molecular material were also increased upon opiate challenge. This suggests that a single dose of an exogenous opiate results in an increase in peptide synthesis.