Opiate binding site

In the first section of the Review, the basic neurobiology of PCP was emphasized. Studies on the binding of PCP to specific receptor molecules in brain have been confounded by the presence of two types of PCP-binding molecules. GUNDLACH reported that he was able to distinguish a PCP-binding site from an opiate-binding site that also binds PCP. The two sites had different localizations in brain and produced different behaviors. ZUKIN also separated the two receptors and reported on the early development of the PCP receptor in brain. He described the isolation from brain of a substance that reacts specifically with the PCP receptor. 

Chang, K.J., and Cuatrecasas, P. Novel opiate binding sites selective for benzomorphan drugs. J Biol Chem 254 2610-2618, 1979. 

Opiate narcotics are thought to act at specific receptors in the brain since they exhibit stereospecific binding (1) and have been shown by fluorescence techniques to be localized at discrete regions in the central nervous system (2). While much effort has been made to isolate and characterize the opiate receptor C3), relatively little detailed information exists about the nature of the opiate binding site. Some investigators describe the receptor as a membrane bound protein or proteo-lipid (4) while others have used nerve cell components such as cerebroside sulfate or phosphatidyl inositol as models for the opiate receptor (5). 

Explicit studies of opiate-receptors interactions should be very useful in continuing to explore the factors that modulate the extent of agonism and antagonism in a given opiate and the variation in this ratio among closely related analogues. Such studies are severely hampered on the experimental side by the lack of a detailed description of the opiate binding site. 

Kream, R.M., Zukin, R.S. and Stefano, G.B. (1980) Demonstration of two classes of opiate binding sites in the nervous tissue of the marine molluscs Mytilus edulis. J. Biol. Chem., 255, 9218-9224. 

Fig. 24. Patch and matrix striatal compartments are labeled with neurochemical markers. A) The patch compartment is labeled with 3H-naloxone binding to mu opiate receptors (white in the darkfield photomicrograph). B) The matrix compartment is labeled with calbindin-immunoreactivity, which labels spiny projection neurons that provide inputs to the substantia nigra pars reticulata. The correspondence between calbindin-poor zones (black arrows) and mu opiate binding sites (white arrows) is seen to occur in all regions of the striatum. Calbindin-immunoreactivity is relatively weak in the dorso-lateral striatum, which nonetheless contains opiate receptor patches.

Zukin, R.S., and Zukin, S.R. Demonstration of 3H-cyclazocine binding to multiple opiate receptor sites. Mol Pharmacol 20 246-254, 1981a. 

Research into the properties of opiates has provided more insights into the processes that make up psychopharmacological actions than any other class of drug this is because opiates bind to receptor sites that are affected by endorphins - the brain s indigenous opiates. These endorphins are implicated in pain thresholds, natural highs and our capacity for addiction to opiates. 

Befort K, Tabbara L, Bausch S et al. The conserved aspartate residue in the third putative transmembrane domain of the <5-opioid receptor is not the anionic counterion for cationic opiate binding but is a constituent of the receptor binding site. Mol Pharmacol 1996 49 216-223. 

Careful analyses of the pharmacologic properties of 3H-hailucinogen binding sites indicated that they may correspond to 5-HT receptors (in the case of 3H-LSD), sigma opiate receptors (in the case of 3H-PCP), or even GABA receptors (in the case of 3H-muscimol). Such data recall that hallucinogens should interfere markedly with the metabolism of neurotransmitters in the CNS. These hallucinogen-induced alterations of neurotransmitter metabolism and functions are summarized below. 

The basis for this technique lies in the competition between the test antigen and a labelled antigen for the available binding sites on a fixed amount of antibody. While the binding sites are traditionally associated with an antibody, any source of specific reversible binding sites may be used to create an assay in this format. Examples of such are specific transport proteins such as thyroxine-binding globulin and certain cellular receptors such as opiate or benzodiazepine receptors. Under these circumstances the equilibrium mixture may be represented thus ... 

Mechanism of Action An opioid that binds to opiate receptor sites in the CNS. Reduces intensity of pain stimuli incoming from sensory nerve endings. Therapeutic Effect Alters pain perception and emotional response to pain. 

Figure 4.4 Brain showing binding sites and pathways of opiate drugs. Kairos, Latin Stock/Photo Researchers, inc.

Bayer Laboratories, 55-56 Belgium, 71 Bengal, 29 binding sites, 39 binding sites and pathways for opiates, 40 blood test, 90, 92 Booth, Martin, 78 brain, 40. See also nervous system... 

Figure 3.7 The binding sites and pathways (in red) of opiate (morphine-type) drugs, in the brainstem (rightmost two red spheres), sites invoived in the transmission of pain inciude the nucieus raphe magnus and iocus ceruieus, with other nuciei in the hypothaiamus and thaiamus (spheres to the ieft). Nerve pathways (red) extend to the frontai cortex (far ieft) and up into the iimbic system (center-ieft). Kairos, Latin Stock/Photo Researchers, inc.

Simon EJ, Hiller JM. Solubilization and Purification of opioid binding sites. In Pasternak GW, ed. The Opiate Receptors. Clifton, NJ Humana Press, 1988 165-194. 

Cannabinoids may share at least some common neuronal mechanisms with opioid compounds. Studies of intracellular events associated with ligand binding to either cannabinoid or opiate receptors indicate that these receptors are linked via G proteins to the production of cAMP. Certain studies have also indicated that there may be some interaction between cannabinoid binding sites and opiate receptors in the reward pathway. In addition, there is increasing evidence that cannabinoids interact with opiate systems involved in the perception of pain. In fact, cannabinoids clearly produce analgesic effects in both experimental animals and humans, and of all the potential clinical uses of cannabinoids, the mediation of analgesia has received the most attention. Some evidence also indicates that the cannabinoid receptor system is an analgesic system. 

Clonidine [KLOE ni deen] is an a2 agonist that is used in essential hypertension to lower blood pressure because of its action in the CNS (see p. 189). It can be used to minimize the symptoms that accompany withdrawal from opiates or benzodiazepines. Clonidine acts centrally to produce inhibition of sympathetic vasomotor centers. Recently, an endogenous substance, agmantine, which appears to be the natural ligand at clonidine binding sites, has been identified. 

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