Delta Opioid Receptor and Peptide: A Dynamic Therapy for Stroke and Other Neurological Disorders.

Research of the opioid system and its composite receptors and ligands has revealed its promise as a potential therapy for neurodegenerative diseases such as stroke and Parkinson's Disease. In particular, delta opioid receptors (DORs) have been elucidated as a therapeutically distinguished subset of opioid receptors and a compelling target for novel intervention techniques. Research is progressively shedding light on the underlying mechanism of DORs and has revealed two mechanisms of DOR neuroprotection; DORs function to maintain ionic homeostasis and also to trigger endogenous neuroprotective pathways. Delta opioid agonists such as (D-Ala2, D-Leu5) enkephalin (DADLE) have been shown to promote neuronal survival and decrease apoptosis, resulting in a substantial amount of research for its application as a neurological therapeutic. Most notably, DADLE has demonstrated significant potential to reduce cell death following ischemic events. Current research is working to reveal the complex mechanisms of DADLE's neuroprotective properties. Ultimately, our knowledge of the DOR receptors and agonists has made the opioid system a promising target for therapeutic intervention in many neurological disorders.

[The experimental clinical substantiation of treatment of patients with odontogenic phlegmon of maxillofacial area using Dаlargin in complex therapy.]

The patients with odontogenic phlegmon of maxillofacial area suffer from immune depression at the surgical stage of treatment that can unfavorably affect their rehabilitation. The study analyzes possibility of application of medication Dalargin in complex treatment of patients during post-operation period. The experimental study established components of immune system affected by medication. Thereupon, Dalargin was applied in clinical practice of treatment of patients with course of disease of average severity. The study proved immunomodulatory characteristics of Dalargin effecting various fractions of sub-populations of lymphocytes and manifesting by way of decreasing of initially high indices and increasing of initially low indices that is of great importance during treatment of patients with odontogenic hormones, especially in case of severe course of disease.

Effect of Peripheral µ-, δ-, and κ-Opioid Ligands on the Development of Tolerance to Ethanol-Induced Analgesia.

We studied the rate of development of tolerance to the ethanol-induced analgesia under the effect of µ-, δ-, and κ-opioid agonists and antagonists not crossing the blood-brain barrier and rapidly inactivated by gastric and duodenal proteolytic enzymes. Activation of gastric κ-opioid receptors eliminated the analgesic effect of ethanol and accelerated the development of tolerance to ethanol-induced analgesia. In contrast, activation of gastric µ-opioid receptors decelerated the development of this tolerance. Activation of gastric δ-opioid receptors produced no effect on examined tolerance. µ-Opioid receptor antagonist decelerated and δ-opioid receptor antagonist accelerated the development of tolerance to ethanol-induced analgesia. Thus, the state of gastric opioid receptors affects the manifestation of ethanol-induced analgesia and the development of tolerance to this effect.

[Comparison of pharmacological renal preconditioning with dalargin and lithium ions in the model of gentamycin-induced acute renal failure].

PURPOSE: To examine the efficacy of renal preconditioning effect of dalargin and lithium ions by observing the model of gentamycin-induced acute renalfailure. MATERIALS AND METHODS: The experiments were performed on white rats, male. The influence of dalargin and lithium ions on the development of gentamycin-induced acute renalfailure was studied in vivo. On the first 24 hours after dalargin injections were terminated, the rats were euthanized humanly. After this we took the blood for a biochemistry study and a renal culture for biochemical test and also for the test of gsk-3ß activity. Concentrations of creatinine and urea were studied in serum. The culture samples of renal tubular epithelium before insertion of gentamycin were incubated in dalargin or lithium ions in different concentrations. After that the substratum was immediately changed to gentamycin in different concentrations also and the incubated for 24 hours. After all the standards MTT-test was performed (based on the ability of living cells to reduce the unpainted form by 3-4,5-dimethylthiazol-2-yl-2,5-difenilterarazola to blue crystalline farmazan). RESULTS: Lithium precondition leads to the 250% increase of gsk-3ß concentration (p = 0.035). The same results were observed after injection of dalargin in 50 mcg/kg concentration. Concentration of creatinine was 44% lower in the dalargin group than in the control group (p = 0.022). Concentration of creatinine was 32% lower in the lithium group than in the control group (p = 0.030). Concentration of urea was 27% lower in the lithium group than in the control group (p = 0.049). Morphological inflammatory changes in the control group were more significant also. In vitro studies showed the maximum efficacy in the lithium group. The most effective dalargin concentration was 5 mg/ml. CONCLUSION: Lithium and dalargine preconditioning lowers the signs of gentamycine induced acute renal failure and damage rate of renal parenchyma in vivo and in vitro.

Delta opioid receptor and its peptide: a receptor-ligand neuroprotection.

In pursuit of neurological therapies, the opioid system, specifically delta opioid receptors and delta opioid peptides, demonstrates promising therapeutic potential for stroke, Parkinson's disease, and other degenerative neurological conditions. Recent studies offer strong evidence in support of the therapeutic use of delta opioid receptors, and provide insights into the underlying mechanisms of action. Delta opioid receptors have been shown to confer protective effects by mediating ionic homeostasis and activating endogenous neuroprotective pathways. Additionally, delta opioid agonists such as (D-Ala 2, D-Leu 5) enkephalin (DADLE) have been shown to decrease apoptosis and promote neuronal survival. In its entirety, the delta opioid system represents a promising target for neural therapies.

Delayed administration of D-Ala2-D-Leu5-enkephalin, a delta-opioid receptor agonist, improves survival in a rat model of sepsis.

Sepsis is the major cause of death in intensive care units, despite enormous efforts in the development of antimicrobial therapies. Sepsis is mediated by early [e.g., tumor necrosis factor (TNF)-α and interleukin (IL)-1ß] and late [e.g., high-mobility group box 1 protein (HMGB1)] proinflammatory cytokines. HMGB1, which is secreted into extracellular milieu by activated macrophages or passively released by destroyed macrophages, stimulates intensive inflammatory responses. D-Ala2-D-Leu5-enkephalin (DADLE), a synthetic δ-opioid receptor agonist, has been shown to protect rats from sepsis. Here we elucidated the mechanism for protective effect of DADLE against sepsis. Sepsis was established in Sprague-Dawley rats by means of cecal ligation and puncture (CLP). In this model, the serum levels of TNF-α and IL-1ß were increased after 2-3 h, while those of HMGB1 were increased after 18 h. Administration of DADLE (5 mg/kg) concurrently with CLP improved survival, which was associated with the decreases in the serum levels of TNF-α, IL-1ß and HMGB1. Importantly, DADLE administrated 4 h after CLP showed comparable protective effect as the concurrent administration, with decreased serum HMGB1 levels. Moreover, peritoneal macrophages isolated from rats were challenged with lipopolysaccharide (LPS). Concurrent or delayed DADLE administration at 10(-6) M suppressed the LPS-induced cell death. DADLE also suppressed the release of HMGB1 from macrophages that was induced by LPS, TNF-α or interferon-γ. In conclusion, DADLE protects rats from sepsis probably by decreasing the serum level of HMGB1. We propose DADLE as a candidate for septic shock therapy, even if it is administered after the onset of sepsis.

[Pancreatic functional status after wedge resection of the duodenal wall and para-pancreatic micro-irrigation].

RESEARCH OBJECTIVE: To study influence parapancreatic microirrigation on morphological and functional condition of a pancreas and transformations of enzymatic activity of blood serum and enzymatic activity of lymph of a chest lymphatic channel after an operative trauma of a duodenum. MATERIAL AND METHODS: Research is executed on 140 not purebred dogs which have been divided into six groups and united in two series. In the first series (30 dogs) were studied changes pancreatic exosecretion in the postoperative period of resection of duodenum (group 1.1), in the postoperative period of resection of duodenum with preliminary infiltration of a parapancreatic tissue of 0.5% by a solution of Novocain (group 1.2) and after resection of duodenum with application parapancreatic microirrigation (group 1.3). In the second series (110 dogs) were studied frequency of development of acute pancreatitis, enzymatic activity of blood serum and enzymatic activity of lymph of thoracal lymphatic duct after resection of duodenum (group 2.1) and in the postoperative period of resection of duodenum with preliminary infiltration of a parapancreatic tissue of 0.5% by a solution of Novocain (group 2.2) and after resection of duodenum with application parapancreatic microirrigation (group 2.3). RESULTS: Application parapancreatic microirrigation does not lead to oppression pancreatic exosecretion at the first o'clock after duodenotomy, and substantially reduces the pancreatic hypersecretion observed in the postoperative period of resection of a duodenum. In addition, application parapancreatic microirrigation reduces frequency of development of acute pancreatitis and promotes less expressed increase enzymatic activity of blood serum and enzymatic activity of lymph thoracal lymphatic duct at development of the given complication after operational trauma of duodenum in comparison with resection of duodenum and after a resection of a duodenum executed against infiltration of a parapancreatic tissue of 0.5% by a solution of Novocain.

Hibernation-like state induced by an opioid peptide protects against experimental stroke.

BACKGROUND: Delta opioid peptide [D-ala2,D-leU5]enkephalin (DADLE) induces hibernation in summer ground squirrels, and enhances preservation and survival of isolated or transplanted lungs and hearts. In the present study, we investigated the protective effect of DADLE in the central nervous system. RESULTS: Adult Sprague-Dawley rats were pretreated with DADLE (4 mg/kg every 2 h x 4 injections, i.p.) or saline prior to unilateral occlusion of the middle cerebral artery (MCA). Daily behavioral tests revealed that ischemic animals treated with DADLE did not show any significant behavioral dysfunctions compared with saline-treated ischemic animals. Opioid antagonists only transiently inhibited the protective effect of DADLE, indicating the participation of non-opioid mechanisms in DADLE neuroprotection. Histological examination using triphenyltetrazolium chloride (TTC) revealed that brains from ischemic animals treated with DADLE, either alone or with adjuvant opioid blockers, exhibited almost completely intact striata. In contrast, brains from ischemic animals that received saline showed significant infarction in the lateral striatum. Analyses of apoptotic cell death revealed a significant increase in the p-53 mRNA expression in the striatum of ischemic animals that received saline, while those that received DADLE exhibited near normal striatal p-53 expression. This protective effect was accompanied by significant increments in protein levels of glial cell line-derived neurotrophic factor in the striatum of DADLE-treated ischemic animals. CONCLUSION: These results indicate that DADLE protected against necrotic and apoptotic cell death processes associated with ischemia-reperfusion injury. The present study demonstrates that delta opioids are crucially involved in stroke, suggesting that the opioid system is important in the study of brain injury and protection.

Effects of D­Ala2, D­Leu5­Enkephalin pre­ and post­conditioning in a rabbit model of spinal cord ischemia and reperfusion injury.

It has recently been revealed that during the aorta­clamped period, D­Ala2, D­Leu5­Enkephalin (DADLE) infusion can protect the spinal cord against ischemia and reperfusion (I/R) injury. However, the protective effects of DADLE administration prior to ischemia or at the time of early reperfusion have not yet been investigated. Drug pre­ or post­conditioning can serve as a more valuable clinical strategy. Therefore, the present study was designed to investigate the neuroprotective effect of DADLE infusion at different time intervals in order to determine the optimum time point for ischemic spinal cord protection. A total of 40 New Zealand white rabbits were randomly divided into 5 groups: Sham­operated (Sham), normal saline pre­conditioning (NS), DADLE per­conditioning (Dper), DADLE pre­conditioning (Dpre) and DADLE post­conditioning (Dpost). All animals were subjected to spinal cord ischemia for 30 min followed by 48 h reperfusion. Hind limb motor functions were assessed according to the Tarlov criterion when the animals regained consciousness, 6, 24 and 48 h after reperfusion. Histological analysis and the number of viable α­motor neurons were also used to assess the extent of spinal cord injury. Compared with the NS group, the Tarlov scores and the number of normal neurons were significantly higher in the Dper group (P<0.05), which were consistent with the results of a previous study. In addition, the paraplegia rate and loss of normal motor neurons were lower in the DADLE per­ and post­conditioning groups compared with the DADLE pre­conditioning; however, these were not statistically significant. DADLE 0.05 mg/kg administration at three time points all mitigated normal motor neuron injury in the anterior horn and decreased the paraplegia rates in rabbits. The therapeutic benefits appeared best in the post­conditioning group with DADLE, and worst in the pre­conditioning group.

[Cardiovascular effects of D-ALA2, LEU5, ARG6-enkephalin (dalargin) are mediated by peripheral mu-opioid receptor activation].

It has been established that intravenous administration of dalargin at a dose of 0.1 mg/kg induced hypotensive, positive inotropic, and positive chronotropic response in patients with myocardial infarction, while not producing the "steal syndrome." The positive chronotropic effect of dalargin was mediated by peripheral mu-opioid receptors. Increase in the heart rate induced by dalargin had a reflex nature. Direct action of dalargin on the heart was accompanied by a decrease in the heart rate and a delay in the cardiac conductance in the atrioventricular junction region.

Multifaceted Effects of Delta Opioid Receptors and DADLE in Diseases of the Nervous System.

BACKGROUND: The opioid system is considered a potential therapeutic target in a variety of neurological disorders. Delta opioid receptors (DORs) are broadly expressed in the brain, and their activation protects cells from hypoxic/ischemic insults by counteracting disruptions of ionic homeostasis and initiating neuroprotective pathways. The DOR agonist D-Ala2-D-Leu2-Enkephalin (DADLE) promotes neuronal survival, mitigates apoptotic pathways, and protects neurons and glial cells from ischemia-induced cell death, thus making DADLE a promising therapeutic option for stroke. The significant amount of research regarding DORs and DADLE in the last decades also suggests their potential in treating other neurological disorders. METHODS: This review compiled relevant literature detailing the role of DORs and agonists in central nervous system function and neuropathologies. RESULTS: Several studies demonstrate potential mechanisms implicating a key interaction between DORs and DADLE in conferring neuroprotective benefits. A better understanding of DOR function in disease-specific contexts is critical to transitioning DOR agonists into the clinic as a therapy for stroke and other neurological diseases. CONCLUSION: Evidence-based studies support the potential of the delta-opioid family of receptors and its ligands in developing novel therapeutic strategies for stroke and other brain disorders.

Delta opioid receptors stimulation with [D-Ala2, D-Leu5] enkephalin does not provide neuroprotection in the hippocampus in rats subjected to forebrain ischemia.

It has been reported that delta opioid agonists can have neuroprotective efficacy in the central nervous system. This study was conducted to test the hypothesis that a delta opioid receptor (DOR) agonist, [D-Ala2, D-Leu5] enkephalin (DADLE), can improve neuron survival against experimental forebrain ischemia in rats. Using male rats (n=125), intraperitoneal injection of DADLE (0, 0.25, 1, 4, 16 mg kg-1) was performed 30 min before ischemia. Ten minutes interval forebrain ischemia was provided by the bilateral carotid occlusion combined with hypotension (35 mm Hg) under isoflurane (1.5%) anesthesia. All animals were neurologically and histologically evaluated after a recovery period of 1 week. As histological evaluation, percentages of ischemic neurons in the CA1, CA3, dentate gyrus (DG) were measured. During the recovery period, 27 rats died because of apparent upper airway obstruction, seizure, or unidentified causes. There were no differences in the motor activity score among the groups. Ten minutes forebrain ischemia induced approximately 75, 20, and 10% neuronal death in the CA1, CA3, and DG, respectively. Any doses of DADLE did not attenuate neuronal injury in the hippocampus after ischemia. Pre-ischemic treatment of DORs agonism with DADLE did not provide any neuroprotection to the hippocampus in rats subjected to forebrain ischemia.

[Endocrine homeostasis and its correction with stress protectors in children with severe burn injury].

The use of stress protection with dalargin, clofelin, and pentamine in the treatment of children with severe burn injury was ascertained to result in a reduction in the magnitude of abnormal changes in the endocrine system and in the prevention of depletion of its compensatory capacities. This treatment will assist in reducing the severity of endotoxicosis, as well as the frequency and severity of toxic and pyoseptic complications.

Effect of delta opioid receptor activation on spatial cognition and neurogenesis in cerebral ischemic rats.

This study aimed to investigate whether a selective delta opioid receptor agonist, [D-Ala2, D-Leu5]-Enkephalin (DADLE), regulates neurogenesis in the hippocampus of ischemic rats. Using an intracerebral cannula, rats were subjected to cerebral ischemia using the standard four-vessel occlusion. DADLE (2.5nmol), DADLE (2.5nmol) with naltrindole (NAL) (2.5nmol), or vehicle was administered at the onset of reperfusion. Bromodeoxyuridine (BrdU, 100mg/kg, intraperitoneal) was used to label newly formed cells from days 1 to 7 after ischemia. Immunohistochemistry was used to evaluate cell proliferation and apoptosis and differentiation 7days 28 days, respectively, after ischemia. Morris water maze test was conducted to test spatial learning and memory 23-27 days after ischemia. We found that DADLE treatment improved performance in the Morris water maze test, promoted proliferation and differentiation of newly formed neurons, and inhibited differentiation into astrocytes in a rat model of cerebral ischemia. Furthermore, the protective effects of DADLE were significantly reversed by co-administration of NAL (P<0.05), a highly potent and selective delta opioid receptor antagonist. Our findings suggest that DADLE promotes spatial cognitive function recovery and regulates neurogenesis after ischemia, which may provide a promising therapeutic strategy for cerebral ischemia.

[Transcranial electrostimulation combined with dalargin ultraphonophoresis in the treatment of patients with chronic idiopathic eczema].

General condition and local status were analysed in patients with chronic idiopathic eczema before the conventional treatment and combined therapy including sessions of transcranial electrostimulation and dalargin phonophoresis and after these treatments. The latter combination improved the patients' quality of life and promoted their faster recovery.

Protective effect of delta opioid agonist [D-Ala2, D-Leu5] enkephalin on spinal cord ischemia reperfusion injury by regional perfusion into abdominal aorta in rabbits.

[D-Ala(2), D-Leu(5)] enkephalin (DADLE) has been reported to exhibit protective effects against hypoxic or ischemic induced brain insult. However its efficacy on the spinal cord ischemia-reperfusion injury remains unclear. Here we investigate whether DADLE could attenuate ischemia and reperfusion induced neural injury in the rabbit spinal cord. New Zealand white rabbits were subjected to spinal cord ischemia by infrarenal aortic occlusion for 30 min. In the period of spinal cord ischemia, DADLE 0.5 mg/kg or NS were infused continuously into the distal clamped abdominal aorta. The heart rate, blood pressure, and core temperature were monitored continuously during the whole experimental procedure. Then the neurological behavioral function was assessed with Tarlov scale system at 1h, 6h, 24h, 48 h after reperfusion, and neuronal injury evaluation in the ventral horn of gray matter was measured by counting the normal motor neurons at 48 h after reperfusion. Comparing with the control group, the Tarlov scores were significantly higher and the incidences of paraplegia were significantly lower in the DADLE group at four time-point recorded. In addition, the normal neurons numbers in the DADLE group were significant more than those in the control group at 48 h after reperfusion. These results suggested that DADLE infused into the abdominal aorta during ischemia period could attenuate behavioral retardation and the loss of normal motor neuron induced by ischemia-reperfusion in rabbits.

Squirreling away at Parkinson's.

A compound that triggers hibernation in ground squirrels can also protect brain cells from the lack of oxygen following a stroke.

Analysis of the role of delta opioid receptors in gastroprotection in the rat.

The effect of delta opioid agonists - [D-Ala2, D-Leu5]-enkephalin (DADLE), [D-Pen2, D-Pen5]-enkephalin (DPDPE) and deltorphin II - on acidified ethanol induced gastric mucosal lesions was studied in the rat compared with that of morphine. It was found that DADLE, DPDPE, deltorphin II and morphine exerted a dose-dependent inhibition on the mucosal lesions injected subcutaneously, their ID50 values were 0.037, 1.8, 3.5 and 0.35 micromoles/kg, respectively. Naltrindole (10 mg/kg sc.), the selective delta opioid receptor antagonist, inhibited the gastroprotective effect of DADLE, DPDPE and deltorphin II, but it failed to antagonise the effect of morphine. Our results suggest that 1. delta receptors are involved in opioid-mediated gastroprotection, 2. ethanol-induced gastric mucosal damage in the rat may be a quick, simple in vivo model for screening opioid delta receptor agonists and antagonists in the periphery.

The anti-arrhythmic effect of D-Ala 2, Leu 5, Arg 6-enkephalin and its possible mechanism.

We studied antiarrhythmic action of D-Ala 2, Leu 5, Arg 6-enkephalin (dalargin) in experiments on male rats. Dalargin is reported to prevent heart rhythm disturbance and heart electrical stability decrease in experimental coronary occlusion, postinfarction, cardiosclerosis and emotional stress. Dalargin prevents acute myocardial ischaemia-induced increase of cAMP content in blood serum and cardiac muscle, as an indirect feature of its antiadrenergic activity. D-Ala 2, Leu 5, Arg 6-enkephalin leads to a decrease of cAMP content in myocardium and blood plasma, which presumably indicates a decrease of sympathetic tone. The data strongly suggest that cGMP content increase and somatostatin level decrease in cardiac muscle play a significant role in antiarrhythmic action of dalargin.

Effect of a delta receptor agonist on duration of survival during hemorrhagic shock.

OBJECTIVES: Selective delta receptor agonists have been shown to stabilize membrane physiologic processes, reduce metabolic rates, and provide protection against ischemic insults through K(ATP) channel opening in a variety of organ beds. However, their potential for affecting outcomes in states of generalized ischemia has not been explored. The authors examined the effect of the nonselective delta receptor agonist, DADLE (D-Ala2-Leu5-enkephalin), on hemodynamic stability and duration of survival in an animal model of severe hemorrhagic shock. METHODS: Conscious Sprague Dawley rats with indwelling catheters were hemorrhaged at a rate of 3.25 mL/100 grams over 20 minutes after half of the group received 1% DADLE (1 mg/kg IV). Following the hemorrhage, all rats were continuously monitored for heart rate (HR), mean arterial pressure (MAP), and life signs for up to three hours (death defined as apnea, systolic blood pressure < 30 mm Hg without pulsations, and electroencephalographic silence). Survival rates and hemodynamic trends were compared between the control and DADLE-treated groups. RESULTS: In the 14 rats studied (8 DADLE; 6 controls), initial hemorrhage resulted in similar hemodynamic shock (average MAP fall: 118 to 59 vs 119 to 55 mm Hg). Analysis of survival at 3.5 hours revealed statistically significant differences between the control and DADLE groups. While 50% of the DADLE group survived past the three hours, no control animals were still alive at the end of the experimental period. The MAP trended downward and the HR increased for the control group, but all hemodynamic parameters stabilized in the rats treated with DADLE. CONCLUSIONS: Most current strategies for treating shock focus on the supply side of resuscitation. The coordinated various actions of DADLE have the potential to work in concert in the intact organism to improve overall survival during severe hemorrhagic shock. In an animal model of severe hemorrhagic shock, there was improvement in hemodynamic stability and a prolonged survival with DADLE treatment. Physiologic manipulation with DADLE appears to be a way to improve survival during shock with possible clinical implications.