Stimulation Of Mu Research Articles

Role of Opiate Receptors and ATP-Dependent Potassium Channels of Mitochondria in the Formation of Myocardial Adaptive Resistance to the Arrhythmogenic Effect of Ischemia and Reperfusion

Preliminary stimulation of opiate receptors (ORs) by intravenous administration of mu agonist DALDA (0.5 mg/kg), delta 1 agonist DPDPE (0.5 mg/kg), and kappa agonist (-)-U-50.488 (1 mg/kg) increases rat myocardial resistance to arrhythmogenic effect of coronary occlusion (10 min) and reperfusion (10 min). Activation of delta 2 ORs (DSLET, 0.5 mg/kg) has no effect on the incidence rate of ischemic and reperfusion arrhythmias. Preliminary administration of glibenclamide (0.3 mg/kg), an inhibitor of KATP channels, blocks the antiarrhythmic effect of DALDA and DPDPE. Repeated short-term exposures of rats to immobilization within two weeks increases the heart tolerance to the arrhythmogenic effect of coronary occlusion and reperfusion. This effect disappears after administration of CTAP (0.5 mg/kg), a mu antagonist, or injection of 5-hydroxydecanoate (5 mg/kg), an inhibitor of mitochondrial KATP channels. The selective antagonists of delta and kappa ORs have no effect on cardiac adaptation-induced resistance to the arrhythmogenic effect of ischemia and reperfusion. We believe that stimulation of mu, delta, and kappa ORs increases myocardial tolerance to the arrhythmogenic effect of ischemia and reperfusion through activation of KATP channels. The antiarrhythmic effect of the adaptation is mediated by stimulation of mu ORs and mitochondrial KATP channels.

Stimulation of mu and delta-Opiate Receptors and Tolerance of Isolated Heart to Oxidative Stress: the Role of NO-Synthase.

Preliminary intravenous injection of delta-opiate receptor (OR) agonists DSLET (0.1 mg/kg) or DTLET (0.1 mg/kg) increased tolerance of isolated perfused myocardium to damage by oxidative stress simulated in vivo with FeSO4 + ascorbic acid. This manifested itself by a decreased level of creatine phosphokinase (CPK) in the perfusate flowing out of the heart during the oxidative exposure. The preliminary systemic injection of mu-agonists DAMGO (0.1 mg/kg) or DALDA (0.1 mg/kg) failed to affect the release of CPK from the myocardium. The cardioprotective effect of the delta-agonist DSLET was completely abolished by preliminary intravenous injection of the delta-OR antagonist ICI 174,864 (2.5 mg/kg). The intravenous injection of the NO-synthase inhibitor L-NAME (50 mg/kg) also completely abolished the cardioprotective effect of delta-OR stimulation. The preliminary injection of DSLET but not of DAMGO prevented an increase in the level of diene conjugates and a decrease in the activity of superoxide dismutase (SOD) in the isolated myocardium tissue. Thus, the in vivo stimulation of delta-OR increased the tolerance of the heart to oxidative stress through activation of NO-synthase and SOD.

Overexpression of Dynamin Is Induced by Chronic Stimulation of μ- but Not δ-Opioid Receptors: Relationships with μ-Related Morphine Dependence

Several studies using selective opioid agonists or mice with a deletion of the mu-opioid receptor, have shown that morphine dependence is essentially due to chronic stimulation of mu- but not delta-opioid receptors. Because dependence is assumed to be related to persistent intracellular modifications, we have investigated modifications putatively induced by chronic activation of mu receptors with morphine or selective agonists in vitro in SH-SY5Y cells and in vivo in different strains of mice, including mice lacking the mu-opioid receptor gene. The results show a similar down-regulation and desensitization of mu and delta binding sites, whereas an overexpression of dynamin occurred only with mu agonists, strongly suggesting the relevance of this up-regulation with the opiate dependence. Moreover, translocation of overexpressed dynamin from intracellular pools to plasma membranes was observed in chronic morphine-treated rats. This recruitment could be critically involved in long-lasting changes such as alterations of axonal transport observed in opioid dependence.

The antinociception induced by \-endorphin administered intrathecally is mediated by the activation of ? and ?-opioid receptors in the rat

The antinociception induced by beta-endorphin given supraspinally has been previously demonstrated to be mediated by the stimulation of epsilon-, but not mu-, delta- or kappa-opioid receptors in rats and mice. The present study was designed to determine what types of opioid receptors in the spinal cord are involved in the antinociception induced by intrathecally (i.t.) administered beta-endorphin. Antinociception was assessed by the tail-flick test in male Sprague-Dawley rats. CTOP (0.9-6.6 nmol), a selective mu-opioid receptor antagonist, or nor-BNI(13.6-95.3 nmol), a selective kappa-opioid receptor antagonist, given i.t. dose-dependently reversed i.t. administered beta-endorphin-induced inhibition of the tail-flick response. On the other hand, naltrindole (6.6-44.4 nmol), a selective delta-opioid receptor antagonist, or beta-endorphin (1-27) (1-6.7 nmol), a selective epsilon-opioid receptor antagonist given i.t., did not antagonize the inhibition of the tail-flick response induced by i.t. administered beta-endorphin. The results are consistent with the previous study in mice [Tseng LF and Collins KA (1992) Eur J Pharmacol 214: 59-65] that the antinociception induced by beta-endorphin given i.t. is mediated by the stimulation of mu- and kappa-, but not delta- and epsilon-opioid receptors.

DAMGO ([ d-ALA 2, nmephe 4, Gly-ol]enkephalin), but not DPLPE ([ d-pen 2, l-pen 5enkephalin), specifically inhibits methamphetamine-induced behavioral responses in the mouse

The effects of intracerebroventricular (i.c.v.) injections of mu- and delta-selective opioid agonists on the methamphetamine-induced behavioral alterations in the mouse were determined by using multi-dimensional behavioral analyses. Methamphetamine (1.0 mg/kg) produced a marked increase in linear locomotion, circling, rearing and grooming behavior. Although the mu-selective opioid agonist [ d-Ala 2, NMePhe 4, Gly-ol]enkephalin (DAMGO) (0.003 and 0.01 μg) itself did not significantly affect different behavioral responses, DAMGO (0.003 and/or 0.01 μg) antagonized the methamphetamine (1.0 mg/kg)-induced increase in behavioral responses such as linear locomotion, circling, rearing and grooming. Additionally, the effects of DAMGO (0.01 μg) on the methamphetamine (1.0 mg/kg)-induced behavioral responses were fully reversed by pretreatment with the mu-selective alkylating agent β-funaltrexamine (β-FNA) (5.0 μg). In contrast, the delta-selective opioid agonist [ d-Pen 2, l-Pen 5]enkephalin (DPLPE) (0.3 or 1.0 μg) had no marked effects on the methamphetamine (1.0 mg/kg)-induced behavioral responses. These results suggest that the stimulation of mu but not delta opioid receptors plays an inhibitory role in the methamphetamine-induced behavioral responses.

Differential inhibitory/stimulatory modulation of spinal CCK release by mu and delta opioid agonists, and selective blockade of mu-dependent inhibition by kappa receptor stimulation.

Opioid-cholecystokinin (CCK) interactions at the spinal level were investigated by looking for possible modulations by various opioid agonists of the release of cholecystokinin-like material (CCKLM) from slices of the dorsal zone of the rat lumbar enlargement. K(+)-evoked CCKLM overflow was reduced by 0.1-10 microM of the mu agonist DAGO or 10 nM to 3 microM of the delta agonist DTLET. By contrast, at a higer concentration (10 microM), the latter drug as well as morphine enhanced CCKLM overflow. Although inactive alone, the kappa opioid agonist U 50488 H (1 microM) prevented the inhibitory effect of DAGO without affecting that of DTLET. These data suggest that an opioid acting through the stimulation of mu, delta and kappa receptors (such as morphine) should produce a net increase in the spinal release of CCK.

Different profile of electrocortical power spectrum changes after micro‐infusion into the locus coeruleus of selective agonists at various opioid receptor subtypes in rats

1. The effects of various opioid receptor agonists given directly by means of a chronically implanted cannula into the locus coeruleus (LC) on behaviour and ECoG activity, continuously analysed, and quantified as total power spectrum (0-16 Hz) and in preselected frequency bands (0-3; 3-6; 6-9; 9-12 and 12-16 Hz), were studied in rats. 2. Dermorphin (0.05, 0.5, 1, 2 and 5 pmol) and Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol (DAMGO; 1, 10, 30, 100 pmol and 1 nmol), two typical mu-receptor agonists, applied unilaterally or bilaterally directly into the LC, produced a typical dose-dependent ECoG synchronization with a significant increase in total power spectrum as well as in the lower frequency bands. Dermorphin was found to be approximately 30 times more powerful than DAMGO in producing similar quantitative ECoG changes. 3. D-Ala-D-Leu-Thr-Gly-Gly-Phe-Leu (DADLE; 1, 10, 50 and 100 pmol), a selective delta-receptor agonist, micro-infused into the LC produced dose-dependent behavioural soporific effects and ECoG increase in total power spectrum as well as in 3-6, 6-9, 9-12 Hz frequency bands. In comparison to dermorphin, the ECoG power spectrum effects of DADLE were 10 fold less potent, whereas in comparison to DAMGO it was approximately 3 times more potent. A lower dose (0.1 pmol) was ineffective in changing behaviour and ECoG power spectrum. 4. The microinfusion into the LC of U 50, 488H, a selective Kappa-opioid receptor agonist, (0.25, 1, 2.5, 5 and lOpmol) produced a typical pattern characterized by a first short-lasting (3-25 min) phase of behavioural arousal and ECoG desynchronization, followed by a longer lasting (20-130min according to the dose) phase of behavioural sleep and ECoG synchronization. A lower dose (0.1 pmol) was ineffective in changing behaviour and ECoG power spectrum. 5. Dextromethorphan and ketamine, two selective agonists at sigma-receptors given into the LC (1, 5 and 1Opmol) induce behavioural arousal, increase in locomotor activity and an intense pattern of stereotypedm movements. However, by increasing the dose of ketamine (50 and lOOpmol), marked sedation, postural changes and an increase in low frequency ECoG bands, sometimes associated with high amplitude fast frequency potentials, were observed. 6. Naloxone applied directly into the LC (1 and 2 pmol 15min before) was able to prevent the behavioural and ECoG effects induced by dermorphin, DAMGO and DADLE. Higher doses of naloxone (1Opmol into the LC) were however, required to antagonize the behavioural and ECoG soporific effects induced by the Kappa-receptor agonist U 50,488H. In contrast, naloxone (1Opmol into the LC) was unable to prevent or reduce the behavioural and ECoG effects induced by subsequent administration into the same site of dextromethorphan and ketamine. 7. In conclusion, the present experiments confirm that behavioural and ECoG effects elicited following stimulation of mu-, delta-, Kappa- and sigma-opioid receptors located in the LC are quite different. Activation of ,mu-, band Kappa-receptors induced sedative effects whereas dextromethorphan and ketamine, two sigma-receptor agonists, induced behavioural arousal and ECoG desynchronization. In addition, the present results strongly support the crucial role played by opioid mechanisms, in the locus coeruleus, in the mediation of the soporific effects of drugs acting as agonists at opioid receptors.

MU and delta opioid receptors control differently the horizontal and vertical components of locomotor activity in mice

The present study investigated the role of mu and delta opioid receptors in the control of the horizontal and vertical components of locomotion. Mice received intracerebroventricularly (i.c.v.) enkephalin analogs specific for either the mu or delta opioid receptors. The administration of the specific mu agonist [D-Ala 2-NMePhe 4-Gly 5(ol)] enkephalin (DAGO) induced a dose-dependent increase in horizontal activity and a decrease in vertical activity. The specific delta agonist [D-Pen 2, D-Pen 5] enkephalin (DPDPE) increased both components of motor activity. The opiate antagonist naltrexone reversed the effects of DAGO, but did not influence the effects of DPDPE on motor activity. The pretreatment with the delta opiate antagonist ICl 154, 129 completely reversed the effects of DPDPE on locomotion but antagonized only partially the effects of DAGO on locomotion. These results indicate that the two components of locomotor activity — horizontal and vertical activity — are modulated differently by the stimulation of mu or delta opioid receptors.

β-Endorphin-(1–27) antagonizes β-endorphin- but not morphine-, D-PEN 2- D-PEN 2-enkephalin- and U50, 488H-induced analgesia in mice

β-Endorphin-(1–27), administered intraventricularly has been previously reported to block the analgesia induced by β-endorphin injected intraventricularly. The present study was to determine if the blocking effect of β-endorphin-(1–27) was specific to β-endorphin which stimulates epsilon receptors, but not to other opioids with activity at different opioid receptors. The antagonistic effects of β-endorphin-(1–27) on the analgesia induced by β-endorphin (epsilon-opioid receptor agonist), d-Ala 2-NMePhe 4-Gly-ol-enkephalin (DAGO) and morphine, (mu-opioid receptor agonists), d-Pen 2- d-Pen 5-enkephalin (DPDPE) and d-Ala 2- d-Leu 5-enkephalin(DADLE) (delta-opioid receptor agonists) and U-50, 488H (kappa-opioid receptor agonist) were studied. β-Endorphin-(1–27) injected intraventricularly, at doses which, when injected alone did not produce analgesia, antagonized the analgesia induced by β-endorphin given intraventricularly. However, the analgesia induced by DAGO, morphine, DPDPE, DADLE and U-50,488H given intraventricularly was not antagonized by β-endorphin-(1–27). The data suggest that β-endorphin-(1–27) selectively blocks the analgesia induced by the stimulation of epsilon receptors but not by the stimulation of mu, delta, and kappa receptors. The results support the previously proposed hypothesis that β-endorphin produces its analgesia by stimulating specific epsilon receptors.