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It has long been speculated that feedback inhibition of endogenous opioid neurons may have a role in opiate tolerance and dependence. However, in studies in which opiates or opioid antagonists have been administered to animals, mixed results have been obtained on the ability of these drugs to regulate endogenous opioids. The present studies were undertaken to determine the effects of chronic administration of opiate drugs on opioid peptides. These studies focused on the regulation of prodynorphin (Prodyn) and proenkephalin (Proenk) peptides in striatal tissue. Morphine, whether administered by chronic infusion or repeated injection, was found to increase the concentration of Prodyn peptides in striatum. Increases were statistically significant in the sensorimotor dorsal striatum (caudate-putamen) but not in the limbic-motor ventral striatum (nucleus accumbens-olfactory tubercle). No changes in Prodyn peptides were found following chronic administration of the opioid antagonist naltrexone. No changes in the Proenk peptide MERGL were found following chronic treatment with morphine or naltrexone. These studies are consistent with the suggestion that Prodyn neurons may have a role in the consequences of long-term opiate administration.

Conflicting results exist concerning the issues of whether chronic nociceptive stimulation (a) increases or decreases the effectiveness of morphine analgesia, and (b) facilitates or inhibits the development of narcotic tolerance. We carried out a series of experiments with appropriate controls in order to examine these two issues and their possible relationship. In experiment 1, rats received complete Freund's adjuvant (CFA), a chronic nociceptor, injected into a single hind paw or anesthesia without injection, together with morphine or placebo pellets in a 2 x 2 study design. The data indicate that the presence of the chronic nociceptive stimulus significantly facilitated the development of tolerance to morphine analgesia as measured using tail-flick latency (TFL) testing. Experiment 2 was designed to compare the analgetic effectiveness of an acute injection of morphine in rats experiencing chronic nociceptive stimulation and in controls. CFA was injected in the right hindpaw, and nine days later TFLs were tested after morphine doses of 1 and 2 mg/kg s.c. The data obtained showed that chronic nociceptive stimulation significantly reduced the effectiveness of morphine at the 1 mg/kg dose. However, baseline TFLs appeared to be shorter in rats treated with CFA, suggesting that the decrease in morphine effectiveness could be due to a general increase in pain sensitivity. Therefore, a third experiment was performed, using a less intense thermal stimulus to prolong baseline TFLs and accentuate any potential differences. Sixteen rats either received CFA or served as controls. TFLs were then measured at baseline and one hour after a 0.5 mg/kg dose of morphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Our laboratory and others have previously reported that the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, interferes with the development of tolerance to the analgesic effects of morphine. The present studies were performed in order to further characterize the role of NMDA receptors in opiate tolerance. The results demonstrate that opiate tolerance is inhibited rapidly, and at low doses, by four different non-competitive NMDA receptor antagonists (MK-801, ketamine, dextrorphan and phencyclidine), suggesting that this inhibition results from blockade of NMDA receptors rather than from the 'side-effect' of a particular drug. The NMDA antagonists were found to inhibit the development but not the expression of opiate tolerance; i.e. they were able to prevent but not reverse tolerance. Finally, the results suggest that NMDA receptor antagonists do not interfere with associative tolerance; instead it appears that these drugs may specifically inhibit non-associative tolerance. It thus appears that NMDA receptors may have a fundamental role in the development of opiate tolerance, and that non-competitive NMDA receptor antagonists may be effective adjuncts to opiates in the treatment of chronic pain.

The N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 has been shown to attenuate tolerance development in rats. In this study, we show that MK-801 inhibits tolerance to the antinociceptive effects of morphine, as assessed by the tail-flick test, in spinalized rats. These results suggest that NMDA receptor antagonists inhibit opiate tolerance at spinal sites, and also provide strong evidence that the effects of MK-801 are not due to its ability to interfere with associative learning, but instead to inhibition of non-associative mechanisms of opiate tolerance.

The primary purpose of this study was to examine the regulation of prodynorphin peptides by dopaminergic agents in the central nervous system. The indirectly acting catecholamine agonist D-amphetamine sulfate (AMPH) and the dopamine receptor antagonist haloperidol (HAL) were administered to rats across a variety of treatment schedules and drug doses. The striatum, substantia nigra and hippocampus were dissected and examined by radioimmunoassay for 5 different prodynorphin peptides, covering all 3 opioid domains in the prodynorphin precursor: dynorphin A(1-8) and dynorphin A(1-17) of the dynorphin A domain, dynorphin B(1-13) of the dynorphin B domain, and alpha-neo-endorphin and beta-neo-endorphin of the neo-endorphin domain. In addition, the proenkephalin peptide Met-enkephalin-arg6-gly7-leu8 (MERGL) was examined in the striatum. AMPH administered one hour prior to sacrifice caused a dose-dependent depletion of prodynorphin peptides in both the striatum and substantia nigra. In animals treated with AMPH once each day for 7 days and sacrificed 24 h later, a dramatic dose-dependent increase in prodynorphin peptides was observed in these brain regions. Animals treated with AMPH once each day for 7 days and sacrificed one hour after the final injection showed no changes in prodynorphin peptides. In addition to changes in individual prodynorphin peptides, AMPH treatment caused alterations in the relationships between intermediate peptides (dynorphin A(1-17) and alpha-neo-endorphin) and their immediate products (dynorphin A(1-8) and beta-neo-endorphin). AMPH caused no consistent changes in prodynorphin peptides in the hippocampus, or in MERGL in the striatum. Taken together these data suggest that acute dopaminergic activation causes depletion of dynorphins from striatonigral prodynorphin neurons, presumably due to dopamine-dependent release of these peptides; repeated activation causes repeated release, with a rebound increase in biosynthesis. HAL, in contrast to AMPH caused relatively subtle changes in striatonigral prodynorphin peptides. Although no significant changes in individual prodynorphin peptides were observed, HAL treatment caused a change in the relationship between dynorphin A(1-17) and dynorphin A(1-8), a change opposite in direction to that observed with AMPH treatment. As has been previously reported, repeated HAL administration caused a dose-dependent increase in the proenkephalin peptide MERGL. The relatively subtle effects of HAL on prodynorphin peptides suggests that tonic dopamine activity is not important in the regulation of striatonigral prodynorphin neurons. The potential functional and behavioral significance of the present results are discussed.

The present study investigated the response decrement patterns produced by opiate antagonists on intracranial self-stimulation behavior, in order to determine if these drugs affect the reinforcement value of the stimulation or interfere with the ability of the animal to respond. Male rats lever-pressed in 60-min sessions on a continuous reinforcement schedule for self-stimulation of the nucleus accumbens. Naloxone (2.0 and 20 mg/kg) and naltrexone (2.0 and 20 mg/kg) suppressed self-stimulation only after a significant delay, in an extinction-like response decrement pattern, mimicking the effects of reductions in current intensity (75% and 50% of baseline). The increasing behavioral effects characteristic of the extinction pattern were observed despite the fact that testing began after the time point at which maximal suppression of self-stimulation occurs with these drugs, and when brain concentrations of these drugs were declining. Since normal responding was observed for several minutes after the beginning of the session, the results may explain why long sessions are necessary to observe suppression of self-stimulation by opiate antagonists. The extinction-like pattern produced by these drugs suggests that opiate antagonists suppress self-stimulation by reducing the reinforcement value of the stimulation, rather than by interfering with the ability of the animal to respond. These findings are consistent with a role for endogenous opioid peptides in brain stimulation reward.