Comparative Analysis of Infarct Size Limiting Activity of δ-Opioid Receptor Agonists in Reperfused Heart In Vivo.

The study examined the effects of δ-opioid receptor (OR) agonists on infarct size on cardiac ischemia (45 min) and reperfusion (120 min) in vivo model in rats narcotized with α-chloralose. The OR agonists were injected intravenously 5 min prior to reperfusion, OR antagonists were administered 10 min before reperfusion. A selective δ-OR agonist BW373U86 (1 mg/kg) reduced the infarct size/area at risk ratio. A selective δ1-OR agonist DPDPE injected in the doses of 0.1 or 0.969 mg/kg produced no effect on infarct size. The selective δ2-OR agonist deltorphin II (0.12 mg/kg) reduced infarct size/area at risk ratio by 2 times. The δ-OR agonist p-Cl-Phe-DPDPE (1 mg/kg) reduced infarct size/area at risk ratio by 40%. Naltrexone and naloxone methiodide, the peripheral OR antagonists, and selective δ2-OR antagonist naltriben prevented the infarct size limiting effect of deltorphin II. Therefore, activation of peripheral δ2-OR enhanced cardiac resistance against toxic action of reperfusion. During reperfusion, deltorphin II demonstrated the most pronounced cardioprotective activity.

Evaluation of the effects of specific opioid receptor agonists in a rodent model of spinal cord injury.

OBJECTIVE: The current study aimed to evaluate the contribution(s) of specific opioid receptor systems to the analgesic and detrimental effects of morphine, observed after spinal cord injury in prior studies. STUDY DESIGN: We used specific opioid receptor agonists to assess the effects of µ- (DAMGO), δ- (DPDPE) and κ- (GR89696) opioid receptor activation on locomotor (Basso, Beattie and Bresnahan scale, tapered beam and ladder tests) and sensory (girdle, tactile and tail-flick tests) recovery in a rodent contusion model (T12). We also tested the contribution of non-classic opioid binding using [+]- morphine. METHODS: First, a dose-response curve for analgesic efficacy was generated for each opioid agonist. Baseline locomotor and sensory reactivity was assessed 24 h after injury. Subjects were then treated with an intrathecal dose of a specific agonist and re-tested after 30 min. To evaluate the effects on recovery, subjects were treated with a single dose of an agonist and both locomotor and sensory function were monitored for 21 days. RESULTS: All agonists for the classic opioid receptors, but not the [+]- morphine enantiomer, produced antinociception at a concentration equivalent to a dose of morphine previously shown to produce strong analgesic effects (0.32 µmol). DAMGO and [+]- morphine did not affect long-term recovery. GR89696, however, significantly undermined the recovery of locomotor function at all doses tested. CONCLUSIONS: On the basis of these data, we hypothesize that the analgesic efficacy of morphine is primarily mediated by binding to the classic µ-opioid receptor. Conversely, the adverse effects of morphine may be linked to activation of the κ-opioid receptor. Ultimately, elucidating the molecular mechanisms underlying the effects of morphine is imperative to develop safe and effective pharmacological interventions in a clinical setting. SETTING: USA. SPONSORSHIP: Grant DA31197 to MA Hook and the NIDA Drug Supply Program.

The antinociceptive effects of a δ-opioid receptor agonist in mice with painful diabetic neuropathy: Involvement of heme oxygenase 1.

Diabetic neuropathy is poorly controlled by classical analgesics and the research of new therapeutic alternatives is indispensable. Our aim is to investigate if treatment with a carbon monoxide-releasing molecule (tricarbonyldichlororuthenium(II) dimer; CORM-2) or an inducible heme oxygenase (HO-1) inducer (cobalt protoporphyrin IX; CoPP) could enhance the antinociceptive effects produced by a δ-opioid receptor (DOR) agonist in mice with painful diabetic neuropathy. In diabetic mice induced by streptozotocin (STZ) injection, the antiallodynic and antihyperalgesic effects produced by the subcutaneous administration of a DOR agonist ([d-Pen(2),d-Pen(5)]-Enkephalin; DPDPE) and the reversion of its effects with the administration of an HO-1 inhibitor (tin protoporphyrin IX; SnPP) were evaluated. Moreover, the antinociceptive effects produced by the intraperitoneal administration of 10mg/kg of CORM-2 or CoPP, alone or combined, with a subanalgesic dose of DPDPE were also assessed. Our results demonstrated that the subcutaneous administration of DPDPE inhibited the mechanical and thermal allodynia as well as the thermal hyperalgesia induced by diabetes in a dose-dependent manner. Moreover, while the antinociceptive effects produced by a low dose of DPDPE were enhanced by CORM-2 or CoPP co-treatments, the inhibitory effects produced by a high dose of DPDPE were completely reversed by the administration of an HO-1 inhibitor, SnPP, indicating the involvement of HO-1 in the antinociceptive effects produced by this DOR agonist during diabetic neuropathic pain in mice. In conclusion, this study shows that the administration of CORM-2 or CoPP combined with a DOR agonist could be an interesting strategy for the treatment of painful diabetic neuropathy.

In vivo profiling of seven common opioids for antinociception, constipation and respiratory depression: no two opioids have the same profile.

BACKGROUND AND PURPOSE: For patients experiencing inadequate analgesia and intolerable opioid-related side effects on one strong opioid analgesic, pain relief with acceptable tolerability is often achieved by rotation to a second strong opioid. These observations suggest subtle pharmacodynamic differences between opioids in vivo. This study in rats was designed to assess differences between opioids in their in vivo profiles. EXPERIMENTAL APPROACH: Male Sprague Dawley rats were given single i.c.v. bolus doses of morphine, morphine-6-glucuronide (M6G), fentanyl, oxycodone, buprenorphine, DPDPE ([D-penicillamine(2,5) ]-enkephalin) or U69,593. Antinociception, constipation and respiratory depression were assessed using the warm water tail-flick test, the castor oil-induced diarrhoea test and whole body plethysmography respectively. KEY RESULTS: These opioid agonists produced dose-dependent antinociception, constipation and respiratory depression. For antinociception, morphine, fentanyl and oxycodone were full agonists, buprenorphine and M6G were partial agonists, whereas DPDPE and U69,593 had low potency. For constipation, M6G, fentanyl and buprenorphine were full agonists, oxycodone was a partial agonist, morphine produced a bell-shaped dose-response curve, whereas DPDPE and U69,593 were inactive. For respiratory depression, morphine, M6G, fentanyl and buprenorphine were full agonists, oxycodone was a partial agonist, whereas DPDPE and U69,593 were inactive. The respiratory depressant effects of fentanyl and oxycodone were of short duration, whereas morphine, M6G and buprenorphine evoked prolonged respiratory depression. CONCLUSION AND IMPLICATIONS: For the seven opioids we assessed, no two had the same profile for evoking antinociception, constipation and respiratory depression, suggesting that these effects are differentially regulated. Our findings may explain the clinical success of 'opioid rotation'. LINKED ARTICLES: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.

Enfermedad de Wilson: espectro clínico de la enfermedad hepática / No disponible

La enfermedad de Wilson es un trastorno hereditario autosómico recesivo del metabolismo del cobre (gen ATP7B), que se caracteriza por la acumulación del mismo en diferentes órganos, principalmente el hígado y el cerebro. Es una enfermedad poco frecuente, difícil de diagnosticar en muchas ocasiones y con un espectro clínico muy amplio y, por lo tanto, debemos sospecharla siempre en un paciente con hepatopatía de causa no clara. En el siguiente artículo presentamos 2 pacientes con diferentes formas de manifestación de la enfermedad hepática, uno de ellos requirió trasplante hepático urgente por fallo hepático fulminante y el otro recibió tratamiento médico. El objetivo de esta observación clínica es analizar el diagnóstico de la enfermedad de Wilson en 2 pacientes en los que se inició de forma diferente y, por tanto, el amplio espectro clínico de la enfermedad y su tratamiento (AU)

Wilson’s disease is a hereditary autosomal recessive disorder of copper metabolism, characterized by copper accumulation in the liver and brain. This rare entity, which has abroad clinical spectrum, is often difficult to diagnose and should therefore always be suspected in patients with liver disease of unclear cause. We describe two types of manifestation of liver disease in two patients; the first developed fulminant hepatic failure requiring urgent liver transplantation and the second showed advanced chronic liver disease and received standard medical treatment. The objective of this clinical observation is to analyze the diagnosis of Wilson’s disease in two patients with distinct onset, illustrating the broad clinical spectrum of the disease, and its treatment (AU)

Treatment with carbon monoxide-releasing molecules and an HO-1 inducer enhances the effects and expression of µ-opioid receptors during neuropathic pain.

BACKGROUND: The administration of µ-opioid receptors (MOR) and δ-opioid receptors (DOR) as well as cannabinoid-2 receptor (CB2R) agonists attenuates neuropathic pain. We investigated if treatment with two carbon monoxide-releasing molecules (CORM-2 and CORM-3) or an inducible heme oxygenase inducer (cobalt protoporphyrin IX, CoPP) could modulate the local and systemic effects and expression of MOR, DOR, and CB2R during neuropathic pain. METHODS: In C57BL/6 mice, at 10 days after the chronic constriction of sciatic nerve, we evaluated the effects of the intraperitoneal administration of 10 mg/kg of CORM-2, CORM-3, or CoPP on the antiallodynic and antihyperalgesic actions of a locally or systemically administered MOR (morphine), DOR ([d-Pen(2),d-Pen(5)]-enkephalin) or CB2R ((2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone ) agonist. The effects of CORM-2 and CoPP treatments on the expression of MOR, DOR, CB2R, inducible and constitutive heme oxygenases, microglia activation marker (CD11b/c), and neuronal and inducible nitric oxide synthases were also assessed. RESULTS: Treatments with CO-RMs and CoPP reduced the mechanical and thermal hypersensitivity induced by sciatic nerve injury, increased the local, but not systemic, antinociceptive effects of morphine, and decreased those produced by DPDPE and JWH-015. Both CORM-2 and CoPP treatments enhanced MOR and inducible heme oxygenase expression, unaltered DOR and constitutive heme oxygenase expression, and decreased the overexpression of CB2R, CD11b/c, and neuronal and inducible nitric oxide synthases induced by sciatic nerve injury. CONCLUSIONS: This study shows that CO-RMs and CoPP treatments increase the local antinociceptive effects of morphine through enhancing MOR peripheral expression and inhibiting spinal microglial activation and overexpression of neuronal/inducible nitric oxide synthases.

Activation of peripheral delta-opioid receptors leads to anti-hyperalgesic responses in the masseter muscle of male and female rats.

In this project, we examined peripheral δ-opioid receptor (DOR)-mediated anti-hyperalgesic responses in the context of an acute orofacial muscle pain condition in both male and female rats. We also investigated whether the ATP-sensitive K+ channel (KATP), a downstream target of OR signaling, contributes to DOR-mediated anti-hyperalgesic responses. Local pretreatment of the masseter with a DOR agonist, [D-Pen², D-Pen6]-enkephalin (DPDPE), dose-dependently attenuated capsaicin-induced mechanical hypersensitivity in both male and female rats. However, there were sex differences in the potency of local DPDPE in that a 10-fold higher dose of DPDPE was required in female rats to produce the level of anti-hyperalgesia achieved in male rats. The sex differences in the DPDPE effect may not be fully explained by DOR expression level since there was no significant sex difference in DOR mRNA levels in trigeminal ganglia (TG). Finally, pretreatment of the masseter with the KATP antagonist, glibenclamide, significantly blocked the effects of DPDPE in male rats suggesting that the peripheral DOR effect is mediated by the KATP. These studies revealed novel information about sex differences with regards to peripherally localized DOR-mediated anti-hyperalgesia under an orofacial muscle pain condition.

Doença de Wilson em crianças e adolescentes: como fazer diagnóstico precoce / Wilson's disease in children and adolescent: a key to an early diagnosis

A doença de Wilson é uma desordem autossômica recessiva do metabolismo do cobre, que leva à impregnação desse metal em diversos tecidos como o fígado, cérebro, córnea e rins. Tem prevalência de 1:40.000 e evolui de forma progressiva e fatal se não tratada. Seu diagnóstico depende de suspeição clínica e exames laboratoriais, podendo ser difícil nos pacientes assintomáticos ou com insuficiência hepática grave. A tríade clássica de apresentação é hepática, neurológica e oftalmológica. Na criança, a forma de apresentação mais comum é a hepática (aguda ou crônica). Os critérios diagnósticos são baseados na presença de ceruloplasmina baixa, cobre em urina de 24 horas e cobre livre elevados e avaliação oftalmológica à procura do anel de Kayser-Fleischer. O tratamento medicamentoso deve ser instituído o quanto antes, de forma a evitaremse as lesões teciduais do excesso de cobre, daí a grande importância do diagnóstico precoce. A droga de escolha é a D-penicilamina, mas é necessário o monitoramento de seus possíveis efeitos colaterais e eventuais pioras do quadro neuropsiquiátrico. Existem outras drogas, como a trientina, tetratiomolibdato e o zinco, que também têm efeito na redução do cobre orgânico. (AU)

Wilson disease is an authossomal recessive disorder of copper metabolism that leads to the impregnation of the metal in different tissues such as the liver, brain, cornea and kidneys. There is a prevalence of 1:40,000 and evolution is progressive and fatal if untreated. The diagnosis depends on clinical suspicion and laboratory tests, and may be difficult in situations such as the asymptomatic patients or with severe liver insufficiency. The classic triad presentation is the hepatic, neurological and ophthalmologic disease. In children, the most common is the hepatic (acute or chronic). The diagnosis criteria are based on the presence of low ceruloplasmine, elevated copper in 24-hour urine and high seric copper and ophthalmologic evaluation in search of Kayser Fleischer ring. The medication treatment must be established as soon as possible so as to prevent tissue lesions due to copper excess, hence the great importance of early diagnosis. The drug choice is the D-penicilamin, with careful monitoring of side effects and attention for occasional worsening of the neuropsychiatric state. There are other drugs as trientine, tetratiomolibdato and zinc that also have an effect on the reduction of organic copper. (AU)

[Intracellular mechanisms of opioidergic regulation of the myocardial function during normoxia and postischemic reperfusion].

Cardioprotective and inotropic effects of selective agonists of delta1- and k1-opioid receptors (OR): DPDPE (0.1 microM/L) and U-50.488 (0.1 microM/L) were studied during 45 min global ischemia and 30 min reperfusion of the rat isolated perfused heart. Activation of both OR types promoted a 2-fold reduction in reperfusion leakage of creatine kinase. Cardioprotective effect of U-50.488 was accompanied by a 2-fold decrease in cAMP levels in myocardium. The selective delta1-agonist DPDPE had no effect on the cAMP content. Cardioprotective effect of DPDPE was not demonstrated after inhibition of Ca2+-ATPase in sarcoplasmic reticulum (SR) by cyclopiazonic acid. Stimulation of myocardial delta1- and K1-OR decreased the heart rate and force of contraction both before ischemia and during reperfusion. In summary, cardioprotective effect of U-50.488 depends on the reduction in myocardial cAMP levels whereas cytoprotective effect of DPDPE is mediated via opioidergic alteration in Ca2+-transport at SR level. Decrease in pump function of heart in response to OR activation does not depend upon alteration in cAMP levels in the myocardium.

Effects of opioid subtypes on detrusor overactivity in rats with cerebral infarction.

AIM: In order to determine the influence of different opioid receptor subtypes on detrusor overactivity after left middle cerebral artery (MCA) occlusion, cystometric recordings were obtained in conscious rats. METHODS: Female Sprague-Dawley rats were used in this study. Control cystometrography was followed by left MCA occlusion. The sham-operated (SO) rats underwent the same procedures except for MCA occlusion. [D-Ala(2), Phe(4), Gly(5)]-enkephalin (DAGO; mu-opioid agonist), [D-Pen(2,5)]-enkephalin (DPDPE; delta1-opioid agonist), deltorpin II (delta2-opioid agonist), and U-50488 (kappa-opioid agonist) were administered intracerebroventricularly at graded doses. The bladder capacity, residual volume, micturition threshold pressure, and bladder contraction pressure were determined. Finally, the volume of the infarction was measured. RESULTS: The intracerebroventricular administration of DAGO and DPDPE significantly increased the bladder capacity in the cerebrally infarcted (CI) and SO rats, but differences in the changes in bladder capacity between the CI and SO rats were not significant. Deltorpin II did not produce any changes in the bladder capacity in the CI or SO rats at any dose examined. However, the intracerebroventricular administration of U-50488 significantly increased the bladder capacity in the CI rats but not in the SO rats. None of the drugs affected the residual volume, micturition threshold pressure or bladder contraction pressure at any dosage examined. The mean infarcted volumes were not significantly different from those in the vehicle-treated rats. CONCLUSION: These results suggest that the opioid receptor subtypes, mu and delta1 in the brain, are related to the micturition reflex. Furthermore, the kappa opioid agonist might be useful for the suppression of detrusor overactivity caused by cerebral infarction.

Selective delta-opioid receptor antagonist N,N(CH3)2-Dmt-Tic-OH does not reduce ethanol intake in alcohol-preferring AA rats.

We studied the effect of a novel delta-opioid receptor antagonist N,N(CH(3))(2)Dmt-Tic-OH (Me(2)-Dmt-Tic-OH) on voluntary ethanol intake in an alcohol-preferring AA (Alko, Alcohol) rat line using a 4-hour limited access paradigm. Acute injections of Me(2)-Dmt-Tic-OH (10 and 30 mg/kg, i.p.) did not reduce 1-hour or 4-hour ethanol intake. Subtype non-selective opioid receptor antagonist naltrexone [0.1 and 0.3 mg/kg, subcutaneously (s.c.)] significantly reduced 1-hour ethanol drinking but had no effect on 4-hour ethanol consumption. Locomotor stimulation induced by the delta-opioid receptor agonist Tyr-D-Pen-Gly-Phe-D-Pen (DPDPE; 15 microg, intracerebroventricularly) was significantly attenuated by Me(2)-Dmt-Tic-OH (10 and 30 mg/kg, i.p.), which confirmed its efficacy as a delta-opioid receptor antagonist in rat brain. Our results support the idea that delta-opioid receptors do not mediate alcohol reward in AA rats.

Role of delta-opioid receptor agonists on infarct size reduction in swine.

Opioids are involved in cardiac ischemic preconditioning. Important species differences in cellular signaling mechanisms, antiarrhythmic, and antistunning effects have been described. The role of the delta-opioid receptor activation in swine remains unknown. Forty minutes before a 45-min occlusion and 180-min reperfusion of the left anterior descending coronary artery, open-chest, pentobarbital-anesthetized swine received either 1) saline (controls); 2) [D-Ala(2),D-Leu(5)]enkephalin (DADLE); 3) [D-Pen(2,5)]enkephalin (DPDPE); 4) deltorphin-D, a novel delta(2)-opioid agonist; or 5) ischemic preconditioning (IP). Assessed were 1) infarct size to area at risk (IS, triphenyltetrazolium staining), 2) regional and global myocardial function (sonomicrometry, ventricular pressure catheters), and 3) arrhythmias (electrocardiogram analyses). It was found that DPDPE and deltorphin-D pretreatment reduced IS from 64.7 +/- 5 to 36.5 +/- 6% and 27.4 +/- 11% (P < 0.01), respectively, whereas DADLE had no effect (66.8 +/- 3%). Both IP and DADLE had a proarrhythmic effect (P < 0.01). However, no differences in global or regional myocardial function or arrhythmia scores were observed between groups. This suggests that delta-receptor-specific opioids provide cardioprotection in swine.

Opioids confer myocardial tolerance to ischemia: interaction of delta opioid agonists and antagonists.

BACKGROUND: Mammalian hibernation biology is now known to be mediated by delta opioids. The altered myocellular physiology of hibernation closely parallels that of hypothermic ischemia used to protect the heart for cardiac surgery. METHODS AND RESULTS: The present study examined the interaction of delta opioid agonists and antagonists on myocardial tolerance to ischemia. By means of a nonhibernating isolated rabbit heart model, functional and metabolic myocardial parameters were assessed during nonischemic baseline and postischemic recovery periods. Control hearts with standard cardioplegic protection alone were compared with those with cardioplegia plus preperfusion with a delta opioid agonist, a delta opioid antagonist, or both. All hearts were then subjected to 2 hours of global ischemia. Compared with cardioplegia alone, postischemic left ventricular developed pressure, coronary flows, and myocardial oxygen consumption were all increased with administration of delta opioid agonists and decreased below baseline with delta opioid antagonists. Functional recovery of left ventricular developed pressure was improved with opioids (control hearts: 36 +/- 3 mm Hg vs hearts with cardioplegia plus delta opioid agonist: 65 +/- 5 mm Hg, P <.01) and inhibited with antagonists (control hearts: 36 +/- 3 mm Hg vs hearts with cardioplegia plus delta opioid antagonist: 17 +/- 5 mm Hg, P <.05), and true to form, the protective opioid effect was negated when combined with an antagonist (control hearts: 36 +/- 3 mm Hg vs hearts with cardioplegia plus delta opioid agonist and delta opioid antagonist: 42 +/- 4 mm Hg, P = not significant). CONCLUSIONS: This study demonstrates that cardiac tolerance to ischemia may be mediated by delta opioids.