Modulation of mu, delta and kappa opioid receptors in rat brain by metal ions and histidine

doi:10.1016/0028-3908(90)90166-O

Neuropharmacology

Volume 29, Issue 5, May 1990, Pages 445-452

https://doi.org/10.1016/0028-3908(90)90166-O Get rights and content

Abstract

The effect of zinc (Zn²⁺) and several other trace elements was studied on the binding of the opioid receptor agonists [³H] DAGO ([Tyr-d-Ala-Gly-Methyl-Phe-Olyol]-enkephalin)^a, [³H] DSTLE ([Tyr-d-Ser-Gly-Phe-Leu-Thr]-enkephalin) and [³H] EKC (ethylketocyclazocine), which are specific for the mu, delta and kappa opioid receptors, respectively, in the cerebral cortex of the rat. Physiological concentrations of zinc were inhibitory to mu receptor binding, whereas the delta and kappa receptors were relatively insensitive to this inhibition. Scatchard analysis, using these opioid agonists, revealed curvilinear plots; concentrations of zinc equal to or less than the IC₅₀ (the concentration of cation which caused 50% inhibition of the binding of opioid ligand to its receptor), increased the K_D (the dissociation constant) of all three subtypes of receptor, with no effect on the B_max (the maximum number of binding sites) and abolished the high affinity sites of the delta and kappa receptors. Copper, cadmium and mercury also inhibited the binding of these ligands to their receptors. Histidine was most effective in preventing the inhibitory effects of zinc and copper, whereas it was less effective on cadmium and without any effect on the inhibition caused by mercury. Magnesium and manganese were stimulatory to opioid receptor binding, whereas cobalt and nickel had dual (stimulatory and inhibitory) effects. Non-inhibitory concentrations of zinc significantly decreased the stimulatory effects of magnesium and manganese on the mu and delta receptors, suggesting that part of the effect of zinc was through prevention of the actions of stimulatory cations. The reducing reagent dithiothreitol partially protected against inhibition by zinc and the oxidizing reagent dithiobisnitrobenzoic acid potentiated the inhibitory effects of zinc on the binding of [³H] DSTLE and [³H] DAGO. These results suggest that physiological concentrations of free zinc can inhibit mu but not delta and kappa receptors. The lower susceptibility of delta and kappa receptors to inhibition by zinc may be due to the presence of fewer sulfhydryl-groups in these receptors, or due to their inaccessibility to binding by zinc. Relative physiological concentrations of free zinc and histidine may govern the extent of binding of the mu ligands to their receptors.

References (25)

M. David et al.
[³H]Tyr-d-Ser-Gly-Phe-Leu-Thr: A specific probe for the delta-opiate receptor subtype in brain membranes
Eur. J. Pharmac.
(1982)
A. Goldstein
Binding selectivity profiles for ligands of multiple receptor types: Focus on opioid receptors
Trends Pharmac. Sci.
(1987)
S.H. Hanissian et al.
Histidine abolishes the inhibition by zinc of naloxone binding to opioid receptors in rat brain
Neuropharmacology
(1988)
H.I. Mosberg et al.
[d-Pen², l-Cys⁵]-enkephalinamide and [d-Pen², d-Cys⁵]-enkephalinamide, conformationally constrained cyclic enkephalinamide analogs with delta receptor specificity
Biochem. biophys. Res. Commun.
(1982)
B.P. Roy et al.
Chemical modification of opiate receptors with ethoxyformic anhydride and photooxidation: Evidence for essential histidine residues
Biochem. biophys. Res. Commun.
(1982)
P.K. Smith et al.
Measurement of protein using bicinchoninic acid
Analyt. Biochem.
(1985)
K. Stengaard-Pedersen et al.
Enkephalin and zinc in the hippocampal mossy fiber system
Brain Res.
(1981)
K.K. Vaswani et al.
Stress induced differential intake of various diets and water by rats: The role of opiate system
Life Sci.
(1983)
M. Baraldi et al.
Reduction of withdrawal symptoms in morphine-dependent rats by zinc: Behavioral and biochemical studies
Neurosci. Lett.
(1984)
I.L. Crawford et al.
Distribution and accumulation of zinc in whole brain and subcellular fractions of hippocampal homogenates

J. Donaldson et al.

Determination of Na⁺, K⁺, Mg²⁺, Cu²⁺, Zn²⁺ in rat brain regions

Can. J. Biochem.

(1973)

I.F. James et al.

Site-directed alkylation of multiple opioid receptors. I. Binding selectivity

Molec. Pharmac.

(1984)

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This modulation occurs through interaction between Zn ions and the SH groups of opioid receptors and affects both the number of receptors and their affinity [60]. This ion, at physiological concentrations, also inhibits the binding of μ receptor agonists [61] and acts as an NMDA receptor antagonist [61–67]. The highest concentrations of Zn are found in the hippocampus, in mossy fibers whose synapses are mostly stimulatory and act through the secretion of glutamate [78].
Addiction is a pressing social problem worldwide and opioid dependence can be considered the strongest and most difficult addiction to treat. Mesolimbic and mesocortical dopaminergic pathways play an important role in modulation of cognitive processes and decision making and, therefore, changes in dopamine metabolism are considered the central basis for the development of dependence. Disturbances caused by excesses or deficiency of certain elements have a significant impact on the functioning of the central nervous system (CNS) both in physiological conditions and in pathology and can affect the cerebral reward system and therefore, may modulate processes associated with the development of addiction. In this paper we review the mechanisms of interactions between morphine and zinc, manganese, chromium, cadmium, lead, fluoride, their impact on neural pathways associated with addiction, and on antinociception and morphine tolerance and dependence.
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S) – ketamine has a much greater affinity for the NMDA-receptor, and (R) – ketamine has a greater opioid action [67]. Animal studies indicated that copper may inhibit the binding of agonistic ligands to the opioid receptors, including mu receptor [68]. Ketamine and copper directly interact with NMDAR as antagonist.
Depression is one of the most common psychiatric issues with a proportion of adults with major depressive disorder who fail to achieve remission with index pharmacological treatment. There are unmet needs in ADT focus on non-monoaminergic agents. Accumulating evidence suggests that the N-Methyl-d-aspartate receptor (NMDAR) plays an important role in the neurobiology and treatment of major depressive disorder. The role of copper ions in pathogenesis and treatment of depression is not fully clarified, however interaction between copper and NMDAR is of prime importance. Release of copper ions inhibits NMDAR and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor function thus protects neurons from glutamatergic excitotoxity. Abnormalities in glutamatergic transmission are the key of glutamate hypothesis of depression. Some authors revealed that NMDARs are also regulated by cellular prion protein (PrP^C) and indicated that interactions of copper, glycine and NMDARs subunits are vital for the regulation of the receptor. As NMDAR antagonist ketamine is known to produce rapid antidepressive effect, observation of copper serum levels in patients treated with ketamine may provide important information about connections between NMDAR antagonistic agents and trace elements antagonistic to that receptor. It is necessary to carry out further studies related to copper and ketamine in depression treatment.
Effect of metal chelating agents on pentylenetetrazole-induced seizure threshold in cholestatic mice
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On the other hand, some studies have reported that NO generators can produce accumulation of chelatable zinc.28,51,52 Moreover, there is increasing evidence of the interaction between zinc and opioidergic system; Tejwani and Hanissian35 reported that physiological concentrations of zinc were inhibitory to mu-opioid receptor binding. A recent study reported that cholestasis-induced increase in clonic seizure threshold was, in part, reversible by opioid antagonists and NOS inhibitors.32,37
Zinc has been proven to be anticonvulsant in several studies which indicate that diphenylthiocarbazone (dithizone) and diethyldithiocarbamate (DEDTC), zinc chelating agents, enhance seizure activities. There is also evidence that nitric oxide (NO) generators increase zinc concentration in the brain. On the other hand, the increased level of NO in the nervous system and the consequently increased seizure threshold in cholestatic mice have been well studied. Thus, it could be hypothesized that one of the reasons for the increased seizure threshold in cholestasis is partly the enhanced endogenous zinc concentration, at least in part, due to the overproduction of NO. In this study, we examined the hypothesis that zinc chelating agents might decrease seizure activity to its pre-cholestatic level in bile duct-ligated (BDL) mice. Mice were intra-peritoneally injected with dithizone and diethyldithiocarbamate (DEDTC) before the induction of seizure by pentylenetetrazole (PTZ) and then the seizure activity was recorded. Dose response (dithizone: 5, 30, 100 and 200 mg/kg; DEDTC: 25, 50 and 100 mg/kg) and time course (only for dithizone: 15, 30, 60 and 120 min) studies were performed first. Then, the effects of cholestasis, with and without dithizone injection, on seizure activity were assessed. Proconvulsant effect of dithizone and DEDTC was proved to be dose dependent although time interval between dithizone and PTZ injections did not play any significant role in the seizure activity. Cholestasis decreased seizure activity and increased lag phase before seizure and both effects were decreased by dithizone injection. It is elicited that zinc may mediate the cholestasis-induced decrement in seizure activity.
Developmental exposure to cadmium alters responsiveness to cocaine in the rat
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The purpose of the present report was to investigate the potential interactive relation between perinatal (gestation/lactation) cadmium exposure and changes in responsiveness to cocaine. In Experiment 1, adult female rats were exposed to a diet containing 50 ppm cadmium (as cadmium chloride) or a diet containing no added cadmium for 30 days prior to breeding with nonexposed males. The metal-exposure regimen continued throughout gestation, and for 15 days of lactation, at which time all animals were placed on standard rat chow diets containing no added cadmium for the remainder of the investigation. Atomic absorption assays confirmed that cadmium concentrations were significantly elevated in metal-exposed dams, littermates, and test animals. Offspring were weaned on postnatal day (PND) 21 and commenced cocaine sensitization testing on PND 70. Testing operations for controls and animals perinatally exposed to cadmium consisted of 21 daily i.p. injections of vehicle (saline) or 10 mg/kg cocaine HCl, and subsequent recording of locomotor activity. Subsequently, across successive days, all animals received 0, 10, and 20 mg/kg cocaine challenges. The results showed that cocaine sensitization was attenuated in animals perinatally exposed to cadmium. A similar pattern of antagonism was observed in Experiment 2 where a higher dose of cocaine was required to produce conditioned place preference (CPP) in cadmium-exposed animals. The implications of these findings with respect to the interactive role of cadmium in the dynamics of cocaine use/abuse remain unclear.
Central administration of zinc reduces salt intake in rats
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The aim of the present study was to investigate the effect of third ventricle injections of zinc on salt intake in rats in the three different experimental models where sodium appetite is increased: fluid deprivation, central angiotensinergic stimulation and sodium depletion. Adult Wistar male rats received third ventricle injections of Zn(Ac)₂ in three different doses (0.03, 0.3 and 3.0 nmol/rat). Central angiotensinergic stimulation was achieved by third ventricle injections of angiotensin II in the dose of 25 ng/rat 30 min before central zinc administration. As expected, fluid deprivation, central angiotensinergic stimulation and sodium depletion significantly increased sodium appetite. Water intake was also enhanced after fluid deprivation and central angiotensinergic stimulation. After sodium depletion, no increase in water intake was observed. Third ventricle injections of zinc inhibited salt intake in all three experimental models studied. Water intake was also inhibited by central zinc administration after fluid deprivation and central angiotensinergic stimulation. Conversely, third ventricle injections of zinc were unable to modify food intake or body temperature. It is suggested that zinc, acting on central structures related to the control of body fluid homeostasis, inhibits the drive for salt intake that is normally observed during fluid deprivation, central angiotensinergic stimulation and sodium depletion.
The effects of developmental cadmium exposure on morphine sensitization and challenge with selective D<inf>1</inf> and D<inf>2</inf> antagonists
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The purpose of this investigation was to determine the effects of developmental (perinatal) cadmium exposure on the development and expression of behavioral sensitization to morphine. Adult female rats were maintained ad libitum on diets containing 0, 25, or 50 ppm added cadmium (administered as cadmium chloride) for 30 days prior to breeding with nonexposed males. This exposure regimen continued throughout the gestational period and for 15 days postnatally during lactation, at which time regular rat chow was provided. On postnatal day (PND) 21, male pups from the respective litters were weaned and placed on an unadulterated food supply (no added cadmium) and tap water for the remainder of the study. Beginning on PND 70, animals from each exposure condition (0, 25, 50 ppm exposure conditions) received, for 21 consecutive days, either vehicle (distilled water) or 10 mg/kg morphine sulfate injections (ip) prior to being monitored for locomotor activity during 80-min test sessions. Following this 21-day period of morphine sensitization training, dose–effect profiles were determined for each exposure condition with successive daily challenges of 0, 10, and 20 mg/kg morphine. Subsequently, different doses of the D₁ antagonist SCH 23390 (0.01, 0.056, and 0.10 mg/kg) and the D₂ antagonist eticlopride (0.01 and 0.056 mg/kg) were presented prior to administration of the training dose of morphine (10 mg/kg). The results of the investigation revealed that developmental cadmium exposure attenuated the development/expression of morphine sensitization. Furthermore, it was found that the suppressive effects of the D₂ antagonist eticlopride were decreased by early cadmium exposure.

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^†: Present address: Division of Cell Biology, Burroughs Wellcome Co., 3030 Cornwallis Road, Research Triangle Park, North Carolina 27709, U.S.A.

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Modulation of mu, delta and kappa opioid receptors in rat brain by metal ions and histidine

Abstract

Eur. J. Pharmac.

Trends Pharmac. Sci.

Neuropharmacology

Biochem. biophys. Res. Commun.

Biochem. biophys. Res. Commun.

Analyt. Biochem.

Brain Res.

Life Sci.

Reduction of withdrawal symptoms in morphine-dependent rats by zinc: Behavioral and biochemical studies

Neurosci. Lett.

Distribution and accumulation of zinc in whole brain and subcellular fractions of hippocampal homogenates

Determination of Na+, K+, Mg2+, Cu2+, Zn2+ in rat brain regions

Can. J. Biochem.

Site-directed alkylation of multiple opioid receptors. I. Binding selectivity

Molec. Pharmac.

Determination of Na⁺, K⁺, Mg²⁺, Cu²⁺, Zn²⁺ in rat brain regions