Morphine, and the opioid receptors

The term opioid (synonym, narcotic analgesic) includes both natural and synthetic agents with morphine-type pain-relieving properties. Their action is exerted on the central nervous system and on smooth muscle. 

Pethidine has no stereoisomers and, perhaps as a consequence, it has a rather weak analgesic action. The most potent of the synthetic analgesics. 

The most convincing demonstration that analgesic action is independent of the conformation of the aromatic ring was furnished by the synthesis of I-methyl-4-phenyl-rram-decahydro-4-propionoxyquinoline, where the two conformers [(13,68) equatorial and (13.69) axial] are separable and, because of close steric crowding, cannot be interconverted. Although possessing only one-tenth of the analgesic action of morphine (mouse), there was no difference in potency between the two conformers (Smissman and Steinman, 1966). 

What task has morphine to perform in its medicinal uses Administration of a prostaglandin, either or Eg, to the rat brain elicited the main symptoms that morphine is used clinically to subdue, namely pain, diarrhoea, and cough. This was accompanied by liberation of cyclic adenosine monophosphate, a flux which was terminated by giving morphine in small doses (Collier and Roy, 1974). 

Although no clear picture has yet emerged, there is a current tendency to think of enkephalins as neurotransmitters, and of beta-endorphin as a hormone that suppresses the output of many other neurotransmitters. It is not at all clear what might cause the body to liberate a pain-neutralizing substance under some conditions and not under so many others. 

By serial replacement, it was found that the three active parts of the enkephalins are the —OH and —NH of the tyrosine fragment, and the lipophilic area in the phenylalanine residue (successfully replaceable by other lipophilic groups) (Gorin et al., 1980). Swiss workers who made stepwise changes to the molecule of Af enkephalin, produced FK 33-824 which is 1000 times as potent as morphine by intra-cerebroventricular injection in laboratory animals (Roemer et al., 1977), but has anaphylactoid side effects in Man. A French group then discovered thiorphan, an (artificial) dipeptide that 

Different kinds of opioid receptors have been distinguished in mammals. This classification, which is based on pharmacological behaviour, may be accepted (but with reserve) until the receptor structures are better known. There may, for example, be grouping, or conformational equilibria of a smaller number. of receptors l ord et al, 1977 Iwamotoand Martin, 1981). 

The sigma (o ) receptor, activation of which causes hallucination and respiratory stimulation, is activated by nalorphine and pentazocine. It is uniquely stimulated by A -allylnormetazocine, but no unique antagonist is known. 

The delta (8) receptor appears to be physically attached to the mu receptor (Smith, Lee and Loh, 1983). j8-Endorphin binds to both the mu and the delta receptor. Enkephalins bind mainly to the delta receptor (Chang et aL, 1981  

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Accordingly, library 2 in contrast to library 1 must contain (at least) one ligand that, in concentrations of 1 pM and 10 nM, is capable of reducing the specific binding of morphine to the //-opioid receptor. Considering the composition of the two libraries, the conclusion that the component with an affinity for the //-opioid receptor must be naloxone is naturally trivial, but this issue could also be addressed by further examining the relevant binding samples (Fig. 7.12). 

Papaver somniferum Papaveraceae (opium poppy) has been used as an analgesic since 3000 BC [26]. The opium latex contains many alkaloids, including codeine, thebaine, papaverine and morphine - its main analgesic constituent [27]. Although morphine has found large clinical use, its analgesic mechanism was first elucidated only with the discovery of both endogenous peptide opioids (such as enkephalins, dynorphins, endorphins and nociceptin) and the opioid receptors, p, 8, k... 

The substitution of an allyl moiety for the methyl group on the nitrogen atom of morphine produced the opioid receptor antagonists, nalorphine and naloxone (Fig. 14.15). 

Major gastrointestinal effects include decreased gut motility and changes in secretion of gastric and intestinal fluids. Morphine and most p receptor agonists cause pupillary constriction. Some tolerance to this effect may develop, but addicts with high opioid levels will still have miosis. Respiratory depression is the usual cause of death from opioid overdose. 

Based upon recent controlled studies, there is considerable evidence that opioids such as morphine induce substantial effects on immune status. For example, it has been shown that morphine administration is associated with alterations in a number of immune parameters, such as natural-killer cell activity [12,13], proliferation of lymphocytes, [13, 14] antibody production [15,16], and the production of interferon [17]. Studies in our laboratory have shown that acute morphine treatment in rats suppresses splenic lymphocyte proliferative responses to both T- and B-cell mitogens, splenic natural-killer cell activity, blood lymphocyte mitogenic responsiveness to T-cell mitogens, and the in vitro production of the cytokines interleukin-2 and interferon-y [18-22], Furthermore, the immune alterations induced by morphine are dose-dependent and antagonized by the opioid-receptor antagonist, naltrexone (e.g., [22]). 

Fecho, K. et al., Assessment of the involvement of central nervous system and peripheral opioid receptors in the immunomodulatory effects of acute morphine treatment in rats, J. Pharmacol. Exp. Ther., 276, 626, 1996a. 

Morphine and other opioids work by activating a family of opioid receptors in the brain. These fall into three classes and morphine activates all of them. It has proved possible to design and synthesize opioids that are more-or-less specihc for snbsets of the opioid receptors. However, none of these has proved to have the right set of activities to retain the potent analgesic power of morphine withont the addiction potential and respiratory depression potential. Finding such a molecule remains on ongoing challenge. 

To this end, the pellets remaining from the competitive MS binding assay were, after several washing steps, resuspended in binding buffer and incubated with a great excess of competitor (50 pM (+)-methadone) to liberate the unknown bound ligand (as well as the bound marker). Then the supernatants obtained by centrifugation were analyzed by LC-ESl-MS/MS. In addition to morphine as the marker, naloxone was identified as the hit that had been searched for. Thereby, the relative concentrations of marker (2.93 nM) and hit (2.30 nM) pointed to the fact that the hit had a similar affinity to the //-opioid receptor as the marker [65]. 

The opium alkaloid morphine is representative for this group of opiates and also for other opioid analgesics. Morphine is a full agonist for both the jx and the k receptors. It is used to relieve severe acute pain, or chronic pain in terminally ill patients. Its oral bioavailability varies from 15% to 35% and its... 

The action profile of synthetic opioids reinforced speculation, that more than one type of opioid receptor exists and is involved in the analgesic activity of these compounds. Martin and co-workers in 1960 investigated these differences in a specially developed test model, the chronic spinal dog (Martin et al., 1976). According to the analgesia and side-effect profile they postulated three types of opioid receptors, the p-receptor (ligand = morphine), the K-receptor (ligand = ketazocine) and the [Pg.128]

Opioid receptor binding Codeine has a low affinity at j-, 5-, and K-opioid receptors and the in vivo effects are predominantly induced by morphine, formed by metabolic O-demethylation. 

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