Effects of morphine treatment on pro-opiomelanocortin systems in rat brain

In previous studies to determine whether chronic opiate administration might negatively feedback upon endogenous opioid systems in the CNS, investigators found no changes in steady-state concentrations of opioid peptides following morphine pelleting. However, since only steady-state levels were measured, it was still not clear whether morphine treatment altered the release and/or biosynthesis of opioid-containing neurons. The goal of the present study was to assess the effects of chronic morphine pelleting on the dynamics of β-endorphin (βE) biosynthesis in rats. Hence, at several times during a 7-day morphine treatment, concentrations of total βE-immunoreactivity (-ir), as well as chromatographically sieved forms of βE, were determined by RIA, and mRNA levels of pro-opiomelanocortin (POMC) were measured by a solution phase protection assay using a mouse or rat POMC³²P-labelled riboprobe. Concentrations of total βE-ir or different forms of βE-ir peptides (i.e. β-lipotropin,βE_1–31,orβE_1–27/βE_1–26) in the hypothalamus or midbrain following either 1 or 7 days of treatment were similar in morphine- and placebo-pelleted animals. However, a significant increase in total hypothalamic βE-ir was observed following 3 days of morphine pelleting; chromatographic analyses indicated that this was primarily due to a selective increase in the opiate inactive forms of βE, i.e.βE_1–27/βE_1–26. After 7 days of pelleting, morphine-treated animals tended to have lower POMC mRNA levels than those of placebo controls (20 to 50% decrease in different studies). The accumulation of hypothalamic βE-ir at 3 days, and the apparent decline in POMC mRNA levels at 7 days, lend support to the hypothesis that morphine negatively feeds back upon POMC neurons in the brain by inhibiting βE release and biosynthesis.