Delta Opiate Receptor Agonist Research Articles

Possible role of the phosphoinositide pathway for signal transduction in changes in the sensitivity of delta-opiate receptors during diabetes mellitus.

We studied the effects of selective delta-opiate receptor agonists and antagonists on the phosphoinositide pathway in lymphocytes from healthy donors and patients with diabetes mellitus. The test compounds probably play a role in changes in the sensitivity to pharmacological substances binding to delta-opiate receptors during diabetes mellitus.

Effect of opiate peptide dalargin and des-Tyr-dalargin on cardiac pump function during ischemia-reperfusion.

Experiments on isolated perfused rat heart showed that nonselective micro- and delta-opiate receptor agonist dalargin decreased contractility of the intact heart, but had no effect on pump function of the ischemic myocardium. Dalargin analogue des-Tyr-dalargin not binding to opiate receptors decreased contractility of intact myocardium and isolated heart exposed to 45-min total ischemia. We hypothesize that the influence of dalargin is related to activation of cardiac delta-opiate receptors, while the inotropic effect of des-Tyr-dalargin is mediated by other receptors.

Endomorphins exit the brain by a saturable efflux system at the basolateral surface of cerebral endothelial cells

Endomorphin-1 (EM-1) and endomorphin-2 (EM-2) are two highly selective mu-opiate receptor agonists. We recently demonstrated that EM-1 and EM-2 have a saturable transport system from brain-to-blood in vivo. Since the endothelial cells are the main component of the non-fenestrated microvessels of the blood-brain barrier (BBB), we examined whether these endogenous tetrapeptides have a saturable transport system in cultured cerebral endothelial cells. EM-1 and EM-2 binding and transport were studied in a transwell system in which primary mouse endothelial cells were co-cultured with rat glioma cells. We found that binding of both endomorphins was greater on the basolateral than the apical cell surface. Flux of EM-1 and EM-2 occurred predominantly in the basolateral to apical direction, each showing self-inhibition with an excess of the respective endomorphin. Transport was not influenced by the addition of the P-glycoprotein inhibitor, cyclosporin A. Neither the mu-opiate receptor agonist DAMGO nor the delta-opiate receptor agonist DPDPE had any effect on the transport. Thus, the results show that a saturable transport system for EM-1 and EM-2 occurs at the level of endothelial cells of the BBB, and unlike beta-endorphin and morphine, P-glycoprotein is not needed for the brain-to-blood transport. Cross-inhibition of the transport of each endomorphin by the other suggests a shared transport system that is different from mu- or delta-opiate receptors. As endormorphins are mainly produced in the CNS, the presence of the efflux system at the BBB could play an important role in pain modulation and neuroendocrine control.

Beta-endorphin enhances Concanavalin-A-stimulated calcium mobilization by murine splenic T cells.

Intracellular calcium mobilization is an important early event involved in T cell activation. The endogenous opioid peptide beta-endorphin is known to modulate immune functions that depend on T cell activation, therefore its effect on intracellular calcium mobilization was investigated. The intracellular calcium concentration ([Ca2+]i) of T cell-enriched splenocytes was measured by flow cytofluorometric analysis using the calcium-sensitive dye, Fluo-3. By gating on the T cell marker, Thy-1, a 95%-pure population of T cells was identified for study. Cells preincubated with beta-endorphin showed significantly enhanced [Ca2+]i responses to the mitogen, Concanavalin A (Con A). This was detectable with concentrations of beta-endorphin as low as 10(-13) M; maximal enhancement required 10(-10) to 10(-9) M doses. The efficacy of beta-endorphin was dependent on the duration of pretreatment. beta-Endorphin amplified the Con A-induced increase in [Ca2+]i by reducing the lag time for the response to Con A and by increasing the mean [Ca2+]i of the cells. N-Ac-beta-endorphin, which shows minimal potency at neuronal opiate receptors, was unable to substitute for beta-endorphin. Naltrindole, a highly selective delta opiate receptor antagonist, inhibited the action of beta-endorphin, whereas a selective mu opiate receptor antagonist was ineffective. Although less potent than beta-endorphin, the delta opiate receptor agonist D-Ala2-D-Leu5-enkephalin also significantly enhanced [Ca2+]i responses. In summary, concentrations of beta-endorphin, within the physiological range found in the systemic circulation, modulate the increase in T cell [Ca2+]i induced by Con A. Both the efficacy of D-Ala2-D-Leu5-enkephalin alone and the antagonism of beta-endorphin by naltrindole suggest that a delta-type opiate receptor may mediate these effects.

Comparison of delta opiate receptor agonist induced reward and motor effects between the ventral pallidum and dorsal striatum

The role of the ventral pallidum and the dorsal striatum in mediating the rewarding effects of the delta receptor specific agonist [2-D-penicillamine, 5-D-penicillamine]enkephalin (DPDPE) were evaluated in the rat using the intracranial self-stimulation paradigm. Reward shifts were indicated by the change in frequency required to maintain half-maximal responding while motor/performance changes were identified by increases or decreases in the maximum responding. Each hour-long test session consisted of three identical, consecutive 20 min rate-frequency curves. In an effort to ascertain possible heterogeneity of function along the rostrocaudal axis, DPDPE (0.0 nmol = saline dose, 0.3 nmol = low dose, 1.0 nmol = medium dose, 3.0 nmol = high dose) was microinjected into either the rostral or caudal region of the two structures. Microinjections into the caudate were positioned directly above the ventral pallidum placements resulting in centromedial or caudomedial caudate placements. DPDPE microinjections into the rostral ventral pallidum resulted in a significant reward increase (28% increase or -0.14 log Hg shift) only at the high dose. In contrast, caudal ventral pallidal DPDPE microinjections showed a dose-response effect with reward increases of 19, 22 and 31% (-0.09, -0.11 and -0.16 log Hz) for the low, medium and high dose, respectively. DPDPE microinjections into the centromedial caudate resulted in a large reward increase (29% or -0.15 log Hz) at the high dose, while caudomedial caudate DPDPE microinjections had no effect on reward. Motor/performance effects tended to follow the pattern of reward effects, with most regions showing motor increases ranging from 25 to 75% over baseline activity. The only exception was found in the caudomedial caudate, where microinjections of the high dose of DPDPE resulted in an approximate 20% suppression of motor/performance activity. These results demonstrate that the ventral pallidum and the mediocentral caudate play a role in modulating opiate rewards, and adds to the growing body of literature regarding the regional heterogeneity within the caudate and ventral pallidum.

Mesoaccumbens dopamine-opiate interactions in the control over behaviour by a conditioned reinforcer

These experiments examined the role of dopamine-opiate interactions in the ventral tegmental area (VTA) and nucleus accumbens in the mediation of reinforcement-related behaviour. It has been shown previously that opiates induce a dopamine-dependent increase in locomotor activity in rats when infused into the VTA, and a dopamine-independent hyperactivity when infused into the nucleus accumbens. The present study investigated the generality and significance of these two findings, by examining dopamine-opiate interactions in the control over behaviour exerted by a conditioned reinforcer (CR), an arbitrary stimulus which gains control by association with primary reinforcement. Rats were trained to associate a light/noise stimulus with sucrose reinforcement, and the efficacy of the CR in controlling behaviour was assessed by measuring its ability to support a new lever pressing response. Responding on one lever (CR lever) produced the CR, responding on the other lever had no programmed consequences. In experiment 1, intra-accumbens infusions of d-amphetamine (10 micrograms), the D1 dopamine receptor agonist SKF-38393 (0.1 microgram), the D2 dopamine receptor agonist LY-171555 (quinpirole; 0.1 microgram) or the opiate receptor agonist [D-Ala2]-methionine enkephalinamide (DALA; 1 microgram) selectively increased responding on the CR lever. Infusion with DALA intra-VTA had no effect. However, pretreatment with DALA intra-VTA (10 x 1 microgram/day) subsequently reduced the selectivity of the response to infusions intra-accumbens with d-amphetamine or SKF-38393, and blocked the response to LY-171555 or DALA. Pretreatment also shifted to the right the dose-response function for DALA intra-accumbens. In experiment 2, intra-accumbens infusions of d-amphetamine, SKF-38393, LY-171555 or DALA again increased responding on the CR lever only. Pretreatment with intra-accumbens d-amphetamine (5 x 1 microgram/day) reduced the selectivity of the response subsequently to d-amphetamine, and blocked the response to SKF-38393, LY-171555 or DALA. In experiment 3, intra-accumbens infusions of the mu-opiate receptor agonist [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (0.003-0.1 microgram), or the delta-opiate receptor agonist [D-Pen2,5]-enkephalin (0.03-1 microgram) enhanced selectively responding on the CR lever. Thus, the dopamine-dependent locomotor-stimulant properties of intra-VTA infusions of opiates are associated with impaired conditioned reinforcer efficacy. Finally, repeated stimulation of the mesoaccumbens dopamine pathway may compromise the dopamine-independence of the opiate system within the nucleus accumbens.

Cellular adaptation to opiates alters ion-channel mRNA levels.

The chronic use of several drugs, including opiates, results in the stereotypical behaviors characteristic of addiction. Alterations in gene expression have been associated with the use of these addictive drugs. Previous studies, however, have been limited to describing changes in amounts of individual mRNAs from single tissue samples. Cellular adaptation to opiates, reflected in the regulation of the expression of many different mRNAs, seems likely to contribute to the complicated behaviors of addiction. The present studies examined coordinate alterations in the amounts of multiple mRNAs in the rat striatum and in NG108-15 cells after opioid stimulation or the precipitated withdrawal of opioid use. The experimental approach combined amplification of the poly(A)+ RNA population with reverse Northern blot analysis to simultaneously characterize the relative changes in several mRNAs. Morphine treatment of rats for 5 days was associated with a reduction in the amount of striatal RNA for the voltage-sensitive K+ channel without significant changes in other ion channels. In NG108-15 cells stimulation with the delta-opiate receptor agonist [D-Ala2,D-Leu5]enkephalin (DADLE) alone and followed by naloxone (precipitated withdrawal) caused relative changes in the abundances of several mRNAs. The composite effects of alterations in the abundance of multiple mRNAs (and the proteins they encode) in response to opioid use likely contribute to the development and maintenance of opiate-mediated behaviors.

U50, 488 increases ultrasonic vocalizations in 3‐, 10‐, and 18‐day‐old rat pups in isolation and the home cage

Separation-induced calling in the young of many species can be modulated by the opioid system. Morphine reduces ultrasonic vocalizations (USVs) produced by isolated rat pups, an effect blocked by naltrexone. Central administration of the mu and delta opiate receptor agonists DAMGO and DPDPE reduce USV; kappa receptor agonist U50,488 increases them. We now find that peripheral U50,488 not only boosted calling rates in isolated 3-, 10-, and 18-day-old rat pups, but also induced calling in pups of these ages tested in the home cage with their littermates, where USVs are seldom heard in nature. U50,488 lowered rectal temperature, although temperature loss and USV were not correlated within drug treatment groups.

Opiate receptor agonists regulate phosphorylation of synapsin I in cocultures of rat spinal cord and dorsal root ganglion.

Kappa opiate receptor agonists applied to cocultures of spinal cord and dorsal root ganglion neurons have been previously shown to inhibit voltage-dependent Ca2+ influx and adenylate cyclase activity. Here we describe the effect of kappa opiate receptor agonists on phosphorylation of synapsin I, a synaptic-vesicle-associated protein whose phosphorylation was shown to be regulated by cAMP and Ca2+ concentrations. Depolarization of spinal cord-dorsal root ganglion cocultured cells (by high K+ or veratridine) and the addition of forskolin (which activates adenylate cyclase) led to increased phosphorylation of synapsin I. Addition of kappa opiate agonists attenuated both the depolarization- and the forskolin-induced phosphorylation of synapsin I. This attenuation was blocked by the opiate antagonist naloxone. mu and delta opiate receptor agonists had much weaker effects on the depolarization-induced phosphorylation of synapsin I. Similarly, kappa opiate agonists decreased (by 40-60%) the high-K+- or veratridine-induced phosphorylation of synapsin I in spinal cord synaptosomes. These results show that opiate ligands modulate synapsin I phosphorylation. Moreover, the data could explain the reduction in synaptic efficacy observed after opiate treatment.

Binding of 3H-D-Pen2-D-Pen5-enkephalin to brain regions and spinal cord membranes of spontaneously hypertensive and normotensive Wistar-Kyoto rats.

The binding of 3H-D-Pen2-D-Pen5-enkephalin (DPDPE), a highly selective delta-opiate receptor agonist, to membranes of discrete brain regions and spinal cord of 10-week-old spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats was determined. The brain regions examined were amygdala, hippocampus, hypothalamus, pons and medulla, corpus striatum, midbrain and cortex. 3H-DPDPE bound to membranes of brain regions and spinal cord at a single high affinity site with apparent dissociation constant value of 4 nmol/l, except in cortex where the values were higher. The highest density of 3H-DPDPE binding sites were in hypothalamus and lowest in pons and medulla. The receptor density (Bmax value) and apparent dissociation constant (Kd value) of 3H-DPDPE to bind to delta-opiate receptors on the membranes of hippocampus, hypothalamus, corpus striatum, midbrain, cortex, pons and medulla and spinal cord of WKY and SHR rats did not differ. The Bmax value of 3H-DPDPE in amygdala of SHR rats was higher than in WKY rats, but the Kd values in the two strains did not differ. It is concluded that SHR rats have a higher density of delta-opiate receptors, labeled with 3H-DPDPE, in amygdala in comparison with WKY rats. Whether such a difference in the density of delta-opiate receptors is related to the elevated blood pressure of SHR rats is not clear.

Ethanol-induced increase in endogenous dopamine release may involve endogenous opiates.

The effect of opiate peptides on basal and potassium-stimulated endogenous dopamine (DA) release from striatal slices was studied in vitro. Dual stimulation of the striatal slices gave a reproducible increase in DA release that was calcium dependent. Addition of the delta-opiate receptor agonists Met5-enkephalin, [D-Ala2,D-Leu5]enkephalin (DADLE), and [D-Ser2]Leu-enkephalin-Thr (DSLET), increased the basal DA release without affecting potassium-stimulated release in a dose-dependent manner. The effect of DADLE was antagonized by the addition of naloxone. In contrast, the mu-opioid receptor agonist [D-Ala2,N-MePhe4,Gly-ol5]enkephalin (DAGO) and the epsilon-opioid agonist beta-endorphin inhibited the stimulated DA release without changing the basal release. The inhibitory effect of DAGO on potassium-stimulated release was antagonized by naloxone. The addition of ethanol (75 mM) to the incubation media produced a delayed increase of both the basal and stimulated DA release. There was no change in stimulated DA release when the change in basal release was subtracted, suggesting that ethanol produced a dose-dependent, selective increase in basal DA release. Naloxone and the selective delta-opiate antagonist ICI 174864 inhibited the ethanol-induced increase in basal DA release. Naloxone and ICI 174864 added alone did not alter either basal or stimulated DA release. We therefore suggest that the ethanol-induced increase in basal DA release is an indirect effect involving an endogenous delta-opiate agonist.

Presynaptic inhibitory action of enkephalin on excitatory transmission in superficial dorsal horn of rat spinal cord.

1. Tight-seal whole-cell recordings were made from marginal neurones visually identified in thin slices of 1- to 2-week-old rat lumbar spinal cord. Excitatory postsynaptic currents (EPSCs), either evoked by extracellular stimulation or those arising spontaneously in tetrodotoxin, i.e. miniature EPSCs (mEPSCs), were recorded after blocking inhibitory synaptic inputs with strychnine and bicuculline. 2. The EPSCs were abolished reversibly by kynurenic acid or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) but not affected by (+)-2-amino-5-phosphonovalerate (APV), suggesting that they were mediated by non-NMDA (N-methyl-D-aspartate) glutamate receptors. Micromolar concentrations of methionine [Met5]enkephalin reversibly reduced the magnitude of evoked EPSCs and the frequency of mEPSCs. 3. The enkephalin action on the mEPSC frequency was blocked by naloxone. A specific agonist of mu-opiate receptor, [D-Ala2,N-Me-Phe4, Gly5]enkephalin-ol (DAGO) suppressed the mEPSC frequency. In contrast, neither a delta-opiate receptor agonist, [D-Pen2, L-Pen5]enkephalin (DPLPE) nor a kappa-opiate receptor agonist, (5 alpha, 7 alpha, 8 beta)-(-)-N-methyl-N-[7-(1-pyrrolidinyl)-1- oxaspiro(4,5)-dec-8-yl]benzeneacetamide (U-69,593) significantly affected the mEPSC frequency. 4. The amplitude of mEPSCs or of currents induced by exogenous L-glutamate, was not affected by [Met5]enkephalin. It is suggested that [Met5]enkephalin presynaptically inhibits glutamatergic EPSCs by activating the mu-opiate receptor. 5. The frequency of mEPSC was reduced by about 50% by replacement of external Ca2+ with Mg2+ or by addition of Cd2+. In Ca(2+)-free-Mg2+ solution, [Met5]enkephalin did not reduce the remaining mEPSCs' frequency any further. 6. It is concluded that the opiates may suppress presynaptic Ca2+ entry, thereby inhibiting synaptic transmission.

Striatal opiate mu-receptors are not located on dopamine nerve endings in the rat

In rat striatal slices, the autoradiographic analysis of [ 3H]naloxone binding allows one to define highly labelled patches corresponding to the striosomes and representing about 17% of the total striatal volume, surrounded by a poorly labelled zone, the matrix. Previous studies have shown that the density of these mu-opiate receptor binding sites is decreased by about 28% following destruction of the striatal dopamine innervation suggesting a partial localization of these receptors on dopamine presynaptic nerve endings. These results were confirmed but, in addition, we have shown that a chronic (30 days) blockade of dopamine transmission obtained by treatment of the animals with a long acting neuroleptic induces a similar decrease of mu binding sites. Further experiments made with d-Pen 2, d-Pen 5-[tyrosyl-3-5(n)- 3-H] enkephalin, a selective delta opiate receptor agonist, have revealed that the density of delta opiate binding sites is decreased (30%) in rats with striatal dopamine denervation but not in those treated with the long acting neuroleptic. These data indicate that part of these delta receptors is located on dopamine nerve terminals but are not in favour of the presence of mu receptors on these nerve terminals. The decrease in [ 3H]naloxone binding sites induced by prolonged interruption of dopamine transmission can be attributed to postsynaptic events.

Mechanism of “substance P”: On mesenteric blood flow; Interactions with opioid peptides

The effects of close intra arterial injection of substance P (SP) and the interaction of SP with opioid peptides, have been studied on mesenteric blood flow in the anaesthetized dog. Injection of SP into the superior mesenteric artery caused a dose dependent increase in mesenteric blood flow. This effect was enhanced by pretreatment with the alpha 2 adrenergic antagonist yohimbine. The action of SP was significantly reduced by pretreatment with muscarinic and nicotinic cholinergic, dopamine and histamine (H 1) receptor antagonists. Beta adrenergic, histamine (H 2) and opiate receptor antagonists did not influence the action of SP. Pretreatment with tetrodotoxin partially inhibited the effect of SP, indicating that as well as a neurogenic action, it has a direct action on the vascular smooth muscle. The effect of SP was enhanced by D-Met 2-NleS 5-enkephalinamide, a delta opiate receptor agonist. The actions of D-Met 2-NleS 5-enkephalinamide were abolished by pretreatment with hexamethonium, partially abolished by naloxone but were unaffected by atropine. The mu opiate receptor agonist, D-Met 2-Pro 5-enkephalinamide, inhibited the effects of SP.

Changes in limb tone produced by regional injections of opiates into rat brain.

A mechanical apparatus was used to measure the resistance of the hindlegs to flexion in conscious rats. Systemically-administered morphine (7.5-12.5 mg/kg) caused increased muscle tone in the limbs. In rats with intracerebral cannulae, intrastriatal morphine (5-15 micrograms) had no effect on limb tone, whereas in increase in limb tone was induced by morphine (1-30 micrograms) in the globus pallidus. A strong and sustained increase in limb tone developed when morphine (0.2-2.5 micrograms) and the mu opiate receptor agonist DAGO (1.5-2.5 micrograms) were administered into the periaqueductal gray region of the midbrain, whereas the delta opiate receptor agonist DADLE (2.5-8 micrograms) was ineffective. The increased limb tone induced by opiates may be generated by mu-type receptors in at least two areas of brain.

Metabolic rate in different rat brain areas during seizures induced by a specific delta opiate receptor agonist

The glucose utilization during specific δ opiate agonist-induced epileptiform phenomena, determined by the [ 14C]2-deoxyglucose technique (2-DG), was examined in various rat brain areas at different time intervals. The peak in EEG spiking response and the most intensive 2-DG uptake occured 5 min after intraventricular (i.v.t.) administration of the δ opiate receptor agonist. The most pronounced 2-DG uptake at this time interval can be observed in the subiculum, including the CA1 hippocampal area, frontal cortex and central amygdala. A general decrease of glucose consumption, compared to control values, is observed after 10 min, in all regions, with exception of the subiculum. Since functional activity and 2-DG uptake are correlated, we suggest that the subiculum and/or CA1 area, are probably the brain regions most involved in the enkephalin-induced epileptic phenomena.

Opiate receptors and cardiovascular control in conscious SHR and WKY rats.

This study examined the cardiovascular, respiratory, and sympathetic effects of selective mu and delta opioid agonists microinjected into the hypothalamic nucleus preopticus medialis (POM) of conscious SHR and WKY rats. The mu receptor agonist D-Ala2-MePhe4-Gly5-ol-enkephalin (DAGO) at a dose of 0.6 or 6.0 nanomoles (Nmol) increased the blood pressure and heart rate in WKY rats. In SHR rats, the lower dose of DAGO similarly had a pressor effect whereas the higher dose was depressor; heart rat was increased only by the 6.0 nmol dose in these animals. In both SHR and WKY rats, this opioid caused respiratory acidosis and elevation of plasma norepinephrine (NE) and epinephrine (E); plasma vasopressin was reduced by the higher dose of DAGO. All of these effects of the mu agonist were reversed by the opiate receptor antagonist naloxone (0.5 mg/kg, i.a.). The delta opiate-receptor agonist D-Ala2-D-leu5-eukephalin at a dose of 6.0 or 20.0 nmol increased blood pressure and heart rate in both SHR and WKY rats without affecting respiratory variables. Plasma NE and EPI were elevated at the peak of the pressor period. These studies suggest that the anteroventral hypothalamic region may be an important site in central autonomic regulation by opioid peptides. The mu-receptor agonist was more potent than the delta agonist in eliciting cardiovascular and respiratory effects and associated sympatho-adrenomedullary activation.(ABSTRACT TRUNCATED AT 250 WORDS)

D-Ala2,D-Leu5-enkephalin generalizes to a discriminative stimulus produced by fentanyl but not ethylketocyclazocine.

Male Sprague-Dawley rats were trained to discriminate between the effects of saline and either fentanyl (0.04 mg/kg) or ethylketocyclazocine (0.32 mg/kg) by responding on a FR 10 schedule of food reinforcement with a lever on one side of a food cup following a subcutaneous saline injection and responding with a lever on the alternate side following the subcutaneous injection of one of those drugs. The effects of an intracerebroventricular injection of either fentanyl (2.89-14.45 nmol) or D-Ala2,D-Leu5-enkephalin (0.172-1.72 nmol) dose-dependently generalized to the discriminative stimulus produced by fentanyl injected subcutaneously. Intracerebroventricular injection of ethylketocyclazocine (15.7-125.8 nmol) but not D-Ala2,D-Leu5-enkephalin (1.72-13.76 nmol) dose-dependently generalized to the discriminative stimulus produced by ethylketocyclazocine injected subcutaneously. These data demonstrate similarities in the discriminative stimulus properties of proposed micron and delta but not kappa and delta opiate receptor agonists.

Delta opiate receptors are involved in the endopioid-induced myoclonic contractions

Morphine, the prototype mu opiate receptor agonist, decreased the spontaneous and [D-Ala 2]-Met-enkephalinamide (DALA)-induced myoclonic contractions (MC) of submandibular muscles in the anaesthetized rat. The proposed kappa receptor agonists ketocyclazocine, ethylketocyclazocine and bremazocine failed to induce MC. In addition, bremazocine inhibited the spontaneous and DALA induced MC. Cy-clazocine, the so-called sigma opiate receptor agonist, had a weak potency in generation of MC, but without step dose response tendency. The most potent opioid peptide in inducing the MC and electrocortical (ECoG) epileptic pattern was the delta opiate receptor agonist [D-Ala 2,D-Leu 5]-enkephalin (DADL). All drugs were administered intraventricularly. The results indicate that myoclonic phenomena induced by DADL and probably by other endopioids are mediated by delta opiate receptors in the rat brain. It is suggested that the combined ECoG and EMG method used in this study offers an opportunity to define further the biological role of opiate receptors and to identify the potential delta opiate receptor acting drugs, which might provide a new approach to the therapy of some seizure disorders.

Differential effects of potassium on the potency of different opioids in the mouse vas deferens.

The effect of potassium on the potency of different opioids to inhibit electrically evoked twitches of the mouse vas deferens has been studied. In general, opioids lose activity as the concentration of potassium increases. Distinct differences, however, were observed between specific opiate receptor agonists. Least sensitive to the effect of potassium proved mu- and delta-opiate receptor agonists, showing only a 2-fold increase in the concentration required to cause a half-maximal inhibition at 14 mM K+. In contrast, the supposed dynorphin receptor/kappa-receptor agonists exhibited at this concentration up to an 8-fold loss of potency. Dynorphin1-13 was found to be intermediate with a 5-fold loss of inhibitory activity. These data suggest a modulatory action of potassium for dynorphin- and kappa-receptors.