Morphine tolerance inhibition

An interesting set of central nervous system properties has also been discovered and studied (Table VI-10). The work devoted to piscaine must be emphasized besides finding hypnotic properties of 2-amino-4-phenyl-thiazole on fish, the authors studied the structure of the metabolite, as well as the localization of the (radio labeled) metabolic product in various organs. Recently, thiazol-4-yl methoxyamine was shown to inhibit the development of morphine tolerance (1607). 5-Aminothiazole derivatives such as 419a were proposed as cardiovascular agents (1608, 1610). Substitution of the 5-aminothiazole radical on the cephalophosphorin structure gives a series of antibacterial products (1609). 

Opioids also interact with excitatory amino acid neurotransmitters. At lower micromolar concentrations, p agonists (e.g., DAMGO) enhance NMDA activity in the nucleus accumbens, but inhibit non-NMDA activity (Martin et al. 1997). At higher concentrations (5 pM), NMDA currents are reduced. Conversely, central administration of glutamate can precipitate a withdrawal syndrome in morphine-dependent animals, similar to the opioid antagonist naloxone. NMDA mechanisms also appear to be involved in the development of morphine tolerance. Competitive and noncompetitive NMDA antagonists and inhibitors of nitric oxide synthase reduce or eliminate tolerance to morphine (Elliott et al. 1995 Bilsky et al. 1996). However, this does not occur for tolerance to k opioids. Pharmacokinetics... 

Trouvin JH, Jacqmin P, Rouch C, Lesne M, Jacquot C. (1987). Benzodiazepine receptors are involved in tabernanthine-induced tremor in vitro and in vivo evidence. EurJ Pharmacol. 140(3) 303-9. Trujillo KA, Akil H. (1991). Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science. 251(4989) 85-7. 

Lutfy, K., Shen, K.-Z., Woodward, R. M., Weber, E. Inhibition of morphine tolerance by NMDA receptor antagonists in the formalin test, Brain Res. 1996, 731, 171-181. 

The development of acute tolerance and dependence evoked in mice by morphine can be suppressed by pretreatment with NTI. Multiple administration of either NTI or 5 NTII before and during chronic implantation with morphine pellets also substantially inhibits the development of morphine tolerance and dependence. These results suggest the use of 8 antagonists to be useful for the prevention of opioid tolerance and physical dependence without compromising the antinociceptive potency of p opioid receptor agonists (Abdelhamid et al., 1991). 

Trujillo, K. A., and Akil, H. (1991). Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 251, 85-87. 

Kaku et al. (55) reported that acute in vivo or in vitro morphine treatment inhibited Ca uptake into mouse brain synaptosomes, an effect which disappeared with tolerance development. A series of experiments have been conducted in this laboratory in order to examine opiate effects on Ca fluxes in synaptosomes. Morphine caused dose-dependent decreases in synaptosomal Ca uptake at low K+ concentrations (in the presence of ATP and Mg2+) after in vitro or acute in vivo treatment (58). This effect was naloxone reversible and stereospecific, with levorphanol also causing inhibition but not dextrorphan. Uptake was apparently inhibited in a noncompetitive fashion. In contrast, mice made tolerant by morphine pellet implantation showed progressive increases in ca uptake with increasing degrees of tolerance that had developed, p-endorphin similarly inhibited Ca uptake into synaptosomes after in vitro treatment or after i.c.v. injection (59). 

Clouet t al. (108) reported that both methadone and morphine inhibited A23187-stimulated phosphorylation of SPM in rat striatal synaptosomes later the same workers showed that in vitro phosphorylation was decreased in SPM from morphine tolerant rats (109). Morphine in vitro did not affect protein kinase activity and although high doses of morphine did inhibit Ca -stimulated phosphorylation, the effect was not naloxone reversible. More recently, Clouet and Williams (110) have... 

Inhibition of nitric oxide synthase attenuates the development of morphine tolerance and dependence in mice... 

Inhibition of morphine tolerance and physical dependence development and brain serotonin synthesis by cycloheximide Loh, Horace H. Shen, Fu-Hsiung Way, E. Leong Biochem. Pharmacol. (1969), 18(12), 2711-21... 

Tolerance to morphine is a further form of synaptic plasticity in which NO may be involved. The mechanisms of morphine tolerance are poorly understood, but glutamate acting at NMDA receptors is probably involved, because development of tolerance can be inhibited by NMDA antagonists. It has recently been shown that NOS inhibitors given with morphine completely prevent tolerance without affecting the actions of morphine itself, suggesting a selective effect on the tolerance mechanism. 

Kulkami. S.K. "Inhibition of morphine tolerance and dependence by Wllhania somnifera in mice," Journal of Elhnopharmacology, 1997, vol. 57 pp. 213-217. 

Dynorphin may also influence nociception at the spinal level. The levels of prodynorphin mRNA and immunoreactive dynorphin increase in the chronic inflammatory arthritic model (158). Dynorphin also inhibits morphine or P-endorphin-induced analgesia in naive animals and enhances analgesia in tolerant animals, indicating that this peptide may have a regulatory role in opioid analgesia (159). This effect does not appear to be mediated by a classical opioid receptor, since des-tyrosine dynorphin, which does not bind to opioid receptors, also antagonizes morphine analgesia (160). 

There are two main treatments for the opiate withdrawal syndrome. One is replacement therapy with methadone or other X agonists that have a longer half-life than heroin or morphine, and produce mild stimulation rather than euphoria. They also produce cross-tolerance to heroin, lessening heroin s effect if patients relapse. Withdrawal is also treated with the 0C2 agonist clonidine, which inhibits LC neurons, thus counteracting autonomic effects of opiate withdrawal — such as nausea, vomiting, cramps, sweating, tachycardia and hypertension — that are due in part to loss of opiate inhibition of LC neurons. 

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