Morphine opioid antagonists

The term opioid refers to any exogenous substance that acts as an agonist at any of several receptors. Opioid antagonists are drugs that bind to a receptor but produce no actions. The poppy plant, Papaver somniferum, from which opium is obtained, is grown in many areas of the world. Morphine constitutes 10% of opium, and codeine can be obtained direcdy from opium. Semisynthetic opioids such as heroin and oxycodone are obtained directly or indirectly from morphine. There are other distinct chemical classes of drugs with opioid actions, including the methadones. 

Administration of sufficient doses of an opioid antagonist after only a single therapeutic dose of morphine results in withdrawal phenomena (Bickel et al. 1987 Heishman et al. 1989 Jones 1979). Some degree of physical dependence... 

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

Fundytus ME, Schiller PW, Shapiro M, Weltrowska G, Coderre TJ. The highly selective 6-opioid antagonist H-Tyr-Tic1P[CH2-NH]Phe-Phe-OH (TIPP[Tf]) attenuates morphine tolerance and dependence. Eur J Pharmacol 1995 286 105-108. 

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... 

Apomorphine, a derivative of morphine, acts directly on the CTZ. It also is more effective if water is first administered before oral or subcutaneous dosing. Excessive dosage may cause respiratory depression and circulatory collapse. Opioid antagonists such as naloxone usually reverse the depressant actions of apomorphine. Because of the possibility of respiratory depression, apomorphine is infrequently used as an emetic. 

DMHP was found to be 20 times as potent as THC in prolonging hex-obarbital sleep time in mice. The drug produced EEG changes similar to those produced by morphine. In an experiment that ight link some of DMHP s effects to opiate receptors, DMHP-induced sedation, ataxia, and analgesia were significantly reversed by the mixed-opioid antagonist nalorphine.I ... 

The A -allyl derivative nalorphine (3-2) is prepared from A -demethylmorphine (3-1) by alkylation with allyl bromide [2]. The discovery that this compound proved to antagonize the activity of morphine in experimental animals led to the synthesis of the potent opioid antagonist naloxone (8-3), which is discussed below. Nalorphine (3-2), in marked contrast to the latter, does show some modest analgesic activity in humans. 

Methyinaltrexone is a quaternary derivative of the opioid antagonist, naltrexone. The addition of the methyl group forms a compound with greater polarity and lower lipid solubility, so that it is poorly absorbed, and does not cross the blood-brain barrier. Methyinaltrexone distributes selectively (>200-fold selectivity) to peripheral receptors. In human trials it prevented morphine-induced delay in gastrointestinal transit time, while sparing centrally mediated analgesic effects. 

The pure opioid antagonist drugs naloxone,naltrexone, and nalmefene are morphine derivatives with bulkier substituents at the l l17 position. These agents have a relatively high affinity for - opioid binding sites. They have lower... 

The opioid antagonist naloxone reverses the effects of a dose of morphine or heroin within minutes. This may be life-saving in the case of a massive overdose (see Chapters 31 and 59). Naloxone administration also provokes an acute withdrawal (precipitated abstinence) syndrome in a dependent person who has recently taken an opioid. 

Frances, B., Gout, R., Monsarrat, B., Cros, J., and Zajac, J. M. (1992). Further evidence that morphine-6/3-glucronide is a more potent opioid antagonist than morphine. J. Pharmacol. Exp. Ther. 262, 25-31. 

Selective delta opioid antagonists have also been shown to modulate the development of tolerance and dependence to morphine [48,49], cocaine... 

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