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Purpose: The development of antinociceptive tolerance to morphine is one of the major problems in its clinical use. Therefore, exploring effective measures to prevent morphine tolerance is of great clinical relevance. We evaluated whether pentazocine could prevent morphine tolerance in mice., Methods: Five groups of male ICR mice received repeated subcutaneous (s.c.) injections of morphine at a high dose (10 mg x kg(-1)) or saline, concomitantly with s.c. injections of pentazocine at low, subanalgesic doses (0.1, 0.3, or 1.0 mg x kg(-1)) or saline, respectively, once daily for 14 days. On day 15, mice received co-injections of morphine and pentazocine 120 min after pretreatment with nor-binaltorphimine (5 mg x kg(-1)), a selective kappa-opioid receptor antagonist. The tail pressure threshold was measured before and 60 min after the daily drug co-injections., Results: Repeated s.c. co-injections of morphine and saline resulted in a progressive decrease in morphine-induced antinociception, due to the development of morphine tolerance. Co-injections of pentazocine (0.1, 0.3, and 1.0 mg x kg(-1)) with morphine potentiated the morphine-induced antinociception dose-dependently by preventing the development of morphine tolerance. Nor-binaltorphimine completely inhibited the chronic antinociception maintained by co-injections of morphine and pentazocine., Conclusion: When chronically co-administered with morphine, pentazocine at low, subanalgesic doses dose-dependently potentiated morphine-induced antinociception in morphine-tolerant mice, through its kappa-opioid-receptor-mediated tolerance-preventing activity. Because pentazocine is the only agonist-antagonist analgesic that has an effective oral formulation suitable for chronic administration, the results of the present study warrant clinical trials of pentazocine to assess its tolerance-preventing activity in patients with cancer pain.

Recent studies indicate that an endogenous co-agonist for an N-methyl-D-aspartate (NMDA) receptor-related glycine site, D-serine, is synthesized by serine racemase and is metabolized by D-amino acid oxidase (DAO) and that acute treatment with morphine augments the gene expression of serine racemase and DAO in rat brain. To further elucidate the mechanism underlying the activation of NMDA receptors following chronic opioid administration, we have evaluated the effects of the chronic administration of morphine on the mRNA and protein expressions of serine racemase and DAO and on the contents of D-serine in several areas of the rat brain. Repeated administration of morphine for 30 days produced a significant augmentation of both the mRNA and protein expressions of serine racemase in all the brain regions, whereas no significant change in the protein expression of DAO was observed in all the brain regions. Furthermore, the chronic administration caused a slight but significant elevation in the concentration of D-serine in the cortex, striatum, and hippocampus. These results indicate the elevated D-serine level following the chronic morphine treatment could at least in part be involved in the activation of NMDA receptors via the glycine site.

Our recent study has shown that the intracerebroventricular administration of d-serine, an endogenous and selective agonist for the glycine site of the N-methyl-d-aspartate receptor, alone or in combination with morphine, leads to the potentiation of antinociception on the tail-flick response. Although there is a variety of information concerning the effects of benzodiazepines on opioid-induced antinociception, little is known about the effect of benzodiazepines on the N-methyl-d-aspartate receptor agonist-induced antinociception. To clarify the analgesic interactions among the benzodiazepine/GABA(A), N-methyl-d-aspartate and opioid receptors at the supraspinal level, we investigated the effects of intracerebroventricular administration of midazolam, a benzodiazepine receptor agonist, on the antinociception evoked by the intracerebroventricular application of d-serine or morphine. The intracerebroventricular administration of midazolam alone produced hyperalgesia on the tail-flick response in a benzodiazepine receptor antagonist, flumazenil-reversible manner. The antinociception induced by the intracerebroventricular application of d-serine or morphine was attenuated by the intracerebroventricular administration of midazolam. In addition, this inhibitory effect of midazolam on the antinociception of d-serine or morphine was antagonized by the intracerebroventricular administration of flumazenil. Together with the facts that d-serine and midazolam act as selective agonists for the glycine site of the N-methyl-d-aspartate receptor and benzodiazepine/GABA(A) receptor, respectively, these observations suggest a functional interaction between the NMDA and benzodiazepine/GABA(A) receptors in the regulation of antinociception at the supraspinal level.

Although there is a variety of information concerning the effects of the N-methyl-D-aspartate (NMDA) receptor on opioid-induced antinociception at the spinal level, little is known about the effects at the supraspinal level. To clarify the role of the NMDA receptor on the morphine-induced antinociception at the supraspinal level, we investigated the effects of the intracerebroventricular (i.c.v.) administration of D-serine, a selective agonist for the glycine site of the NMDA receptors, alone or in combination with morphine using the tail-flick test. The i.c.v. administration of D-serine, but not L-serine, alone produced a dose-dependent antinociception in the tail-flick response. D-Serine also dose-dependently potentiated the antinociceptive effect induced by the i.c.v. administration of morphine and the simultaneous administration produced an additive effect. The potentiation of the antinociception produced by both D-serine alone or in combination with morphine was dose-dependently attenuated by the i.c.v. administration of L-701,324, a selective antagonist for the glycine site of the NMDA receptors. In addition, the potentiation of the D-serine-induced antinociception was antagonized by the i.c.v. administration of naloxone, a nonselective opioid receptor antagonist. These observations, together with the fact that D-serine is an endogenous and selective co-agonist for the glycine site of the NMDA receptors, strongly suggested that the activation of the supraspinal NMDA receptors by D-serine leads to the potentiation of the antinociception in the tail-flick test and that endogenous D-serine could modulate the mu-opioid receptor mediated antinociception via the glycine site of the NMDA receptors at the supraspinal level.

To obtain further insight into the interactions between the N-methyl-D-aspartate receptor and opioid receptor systems, we have investigated the effects of the acute treatment of morphine on the expression of serine racemase and D-amino acid oxidase mRNAs in several brain areas of rats. The morphine administration produced a dose-dependent and transient elevation in the levels of serine racemase and D-amino acid oxidase mRNAs in all the brain areas. The present results are the first to suggest an interaction between the expression of the mRNAs for the D-serine-related enzymes and the opioid receptor activation.

Purpose: In a previous study using the tail-flick test, we found that intracerebroventricular administration of d-serine, an endogenous co-agonist at the glycine sites of N-methyl- d-aspartate (NMDA) receptors, elicited an antinociceptive effect on thermal nociception. The purpose of the present study was to evaluate the effect of intracerebroventricular administration of d-serine on nociception induced by tissue damage or inflammation using the formalin test. Methods: Infusion of drugs into the third ventricle in rat was performed via indwelling cannulae. Drugs were infused at a volume of 10 μl over 2 min, and the infusion cannula was left in place for 2 min before removal. The formalin test was performed 10 min after drug administration. Results: Intracerebroventricular administration of d-serine significantly and dose-dependently decreased the number of flinches in both the early and late phases in the formalin test. This antinociceptive effect was antagonized by intracerebroventricular administration of L-701,324, a selective antagonist at the glycine sites of NMDA receptors. Conclusion: The present data suggest that activation of NMDA receptors via glycine sites at the supraspinal level induces an antinociceptive effect on both acute and tonic pain. [ABSTRACT FROM AUTHOR]