Morphine tolerance development

Belozertseva IV, Danysz W, Bespalov AY (2000a) Effects of short-acting NMDA receptor antagonist MRZ 2/576 on morphine tolerance development in mice. Naunyn Schmiede-bergs Arch Pharmacol 361 573-577... 

Tolerance development and physical and mental dependence are among the most well-known of the undesirable effects of morphine. Tolerance development refers to the phenomenon that prolonged medication to attain a particular effect requires higher and higher doses. For morphine, such dose escalations amount to a 10- or 20-fold increase. 

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). 

The CCK system shares one property with the opioid system, ie, the existence of selective nonpeptide antagonists. These include aspedicine, a natural benzodiazepine (136), and Devazepide (L-364,718 MK-329) (137). Selective, potent peptide antagonists for CCK, eg, Cl-988 and PD 134308, have been developed that maybe useful as anxiolytics and as dmgs which increase the analgesic effect of morphine but at the same time prevent morphine tolerance (138) (see Hypnotics, sedatives, anticonvulsants, and anxiolytics). 

C. Effect of 5-Opioid Antagonists on the Development of Morphine Tolerance and Dependence... 

Abdelhamid EE, Sultana M, Portoghese PS, Takemori AE. Selective blockage of delta opioid receptors prevents the development of morphine tolerance and dependence in mice. J Pharmacol Exp Ther 1991 258 299-303. 

Like <5 selective agonists, k agonists have few of the side effects of morphine and recent studies have suggested that k selective agonists may be effective analgesics [2]. However, a limitation to the clinical use of k agonists is tolerance development. 

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... 

Morphine also causes nausea and vomiting by stimulation of the area postrema. Nausea is a common reaction to intravenous injection, but tolerance develops to this effect over repeated use. 

It is beheved that phenomena such as sensitization, tolerance and drug-dependence might also involve synaptic plasticity. In fact, numerous studies indicate that NMDA receptor antagonists block sensitization to amphetamine and cocaine as well as tolerance and dependence to ethanol and opioids in animal models (Trujillo and Akil 1991 Pasternak and Inturrisi 1995 Trujillo and Akil 1995 Mao 1999). Recent studies indicate that the uncompetitive NMDA receptor antagonists dextromethorphan, memantine and neramexane not only prevent the development of morphine tolerance, but also reverse estabhshed tolerance in the continuing presence of this opioid, prevent the expression of withdrawal symptoms in rats (Popik and Skolnick 1996 Popik and Danysz 1997 Popik and Kozela 1999 Houghton et al. 2001) and attenuate the expres-... 

Tach5 hylaxis is the rapid development of tolerance in which there is a marked reduction in response even after repeated doses of a drug. It is not necessary that tolerance develop equally to all the action of the drug, e.g. tolerance of morphine occurs to its analgesic and euphoric action and not to its constipating and miotic actions. Likewise in phenobarbitone, tolerance occurs to its sedative action and not to its anti-epileptic action. 

Houghton, A. K., Parsons, C. G., Headley, P. M. Mrz2/576, a fast kinetic NMDA channel blocker, reduces the development of morphine tolerance in awake rats, Pain 2001, 91, 201-207. 

Mao, J., Price, D. D., Mayer, D. J. Thermal hyperalgesia in association with the development of morphine tolerance in rats roles of excitatory amino acid receptors and protein kinase C, J. Neurosci. 1994, 14, 2301-2312. 

Marek, P., Ben-Eliyahu, S., Vaccarino, A. L., Liebeskind, J. C. Delayed application of MK-801 attenuates development of morphine tolerance in rats, Brain Res. 1991, 558, 163-165. 

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). 

The effectiveness of a drug may diminish with continual use. Tolerance denotes a decreased pharmacological responsiveness to a drug. This is demonstrated by several drugs of abuse including ethanol and heroin. The degree of tolerance varies but is never complete. For example, tolerance to the effects of morphine quickly develops, but the user is not totally unresponsive to the pharmacological effects. To compensate for the development of tolerance, the dose is increased. Tolerance may develop slowly, such as in the case of tolerance to the CNS effects of ethanol, or can... 

Tolerance develops to the narcotic and analgesic actions of morphine, so that increasingly larger doses are needed to render patients pain free. Tolerance develops to many effects of morphine such as analgesia, euphoria, narcosis, respiratory depression, hypotension, and antidiuresis. Morphine-induced bradycardia may be experienced. However, no tolerance develops to morphine-induced miosis or constipation. If the administration of morphine is discontinued, the tolerance is lost and the preaddiction analgesic doses of morphine become effective once more. 

Metopon (methyldihydromorphinone) manifests the properties of tolerance and liability to addiction, but it is about twice as effective as an analgesic, and its duration of action is equal to that of morphine. Tolerance to metopon and physical dependence on the drug develop more slowly than in the case of morphine. In therapeutic doses, it produces little or no respiratory depression and still less mental dullness. Metopon thus possesses many advantages over morphine but is no longer available commercially. 

Miosis is a characteristic symptom of opiate administration, and while tolerance develops to many of the pharmacological effects of this class of drugs, tolerance to the miotic effects occurs at a much slower rate. Miosis is due to an excitatory action of the autonomic segment of the nucleus of the oculomotor nerve, an effect attributed to the stimulation of the mu receptors. In general, it would appear that the actions of morphine and its analogues on the brain, spinal cord and gastrointestinal tract are due to stimulation of the mu receptors. 

The important role of delta receptors in the development of morphine tolerance and physical dependence has prompted the search for mixed mu... 

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