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Delta-opioid receptors (δ-ORs) are known to be involved in associative learning and modulating motivational states. We wanted to study if they were also involved in naturally-occurring reinforcement learning behaviors such as vocal learning, using the zebra finch model system. Zebra finches learn to vocalize early in development and song learning in males is affected by factors such as the social environment and internal reward, both of which are modulated by endogenous opioids. Pairs of juvenile male siblings (35-day-old) were systemically administered a δ-OR-selective antagonist naltrindole or vehicle (controls) for a period of 10 days. The acoustic structure of songs differed across treated and control groups at adulthood (120 days). Naltrindole-treated birds had a significantly lower pitch, mean frequency, and frequency modulation than controls, whereas there was no difference in the number of songs in naltrindole-treated and control siblings. Since the opioid and dopaminergic systems interact, we decided to study whether blocking δ-ORs during the sensitive period led to changes in dopaminoceptive neurons in Area X, a song control nucleus in the basal ganglia. Interestingly, compared with controls, naltrindole-treated birds had higher numbers of DARPP-32-positive medium spiny neurons and potentially excitatory synapses in Area X. We show that manipulating δ-OR signaling during the learning phase resulted in alterations in the acoustic features of song and had long term effects on dopaminergic targets within the basal ganglia in adulthood. Our results suggest that endogenous opioids regulate the development of cognitive processes and the underlying neural circuitry during the sensitive period for learning. [ABSTRACT FROM AUTHOR]

There is some evidence that delta-opioid receptors may be involved in the brain processes related to neuroprotection. The aim of the present studies was to test the hypothesis that endogenous opioid peptides acting via delta-opioid receptors can protect against stress-induced changes in factors related to brain plasticity and stress hormone release. Forty male adult Wistar rats were used. Half of the animals were exposed to sustained partial restraint stress (hypokinesis) lasting 48 h. Rats were treated with vehicle (isotonic saline) or the delta-opioid receptor antagonist naltrindole (3 mg/kg/ml, s.c.) six times a day. The stressfulness of the model was confirmed by increased plasma concentrations of corticosterone and prolactin, the increase in anxiety behavior in the open field test, as well as the reduction of BrdU incorporation into newly formed DNA in the hippocampus. Treatment with naltrindole potentiated the stress-induced rise in aldosterone concentrations. The blockade of delta-opioid receptors resulted in a decrease in hippocampal BDNF gene expression independently of control or stress conditions. Treatment with naltrindole enhanced plasma concentrations of copeptin, a stable precursor of vasopressin. In conclusion, these results suggest that endogenous opioid peptides might play an inhibitory role in aldosterone release under stress conditions and in the control of vasopressin release independently of stress exposure. Endogenous opioids might stimulate hippocampal gene expression of the important neurotrophic factor BDNF via delta-opioid receptors. [ABSTRACT FROM AUTHOR]

Background/aim: Physical exercise is a state of physiological stress that requires adaptation of the organism to physical activity. Glycogen is an important and essential energy source for muscle contraction. Skeletal muscle and liver are two important glycogen stores, and the energy required to maintain exercise in rodents are provided by destruction of this glycogen depot. In this study, the effects of endogenous opioid peptide antagonism at the central nervous system level on tissue glycogen content after exhaustive exercise were investigated. Materials and methods: Rats had intracerebroventricularly (icv) received nonspecific opioid peptide receptor antagonist, naloxone (50 μg/10 μL in saline) and δ-opioid receptor-selective antagonist naltrindole (50 μg/10 μL in saline) and then exercised till exhaustion. After exhaustion, skeletal muscle, heart, and liver were excised immediately. Results: Both opioid peptide antagonists decreased glycogen levels in skeletal muscle. Although, in soleus muscle, this decrease was not statistically significant (p > 0.05), in gastrocnemius muscle, it was significant in the icv naloxone administered group compared with control (p < 0.05). Heart glycogen levels increased significantly in both naloxone and naltrindole groups compared to control and sham-operated groups (p < 0.05). Heart glycogen levels were higher in the naloxone group than naltrindole (p < 0.05). Liver glycogen levels were elevated significantly with icv naloxone administration compared with the control group (p < 0.05). Glycogen levels in the naloxone group was also significantly higher than the naltrindole group (p < 0.05). Conclusion: Our findings indicate that icv administered opioid peptide antagonists may play a role in glycogen metabolism in peripheral tissues such as skeletal muscle, heart, and liver. [ABSTRACT FROM AUTHOR]

Meeting the metabolic demands of donor livers using normothermic ex vivo liver perfusion (NEVLP) preservation technology is challenging. The delta opioid agonist [D-Ala2, D-Leu5] enkephalin (DADLE) has been reported to decrease the metabolic demand in models of ischemia and cold preservation. We evaluated the therapeutic potential of DADLE by investigating its ability to protect against oxidative stress and hepatic injury during normothermic perfusion. Primary rat hepatocytes were used in an in vitro model of oxidative stress to determine the minimum dose of DADLE needed to induce protection and the mechanisms associated with protection. NEVLP was then used to induce injury in rat livers and determine the effectiveness of DADLE in preventing liver injury. In hepatocytes, DADLE was protective against oxidative stress and led to a decrease in phosphorylation of JNK and p38. Naltrindole, a δ-opioid receptor antagonist, blocked this effect. DADLE also activated the PI3K/Akt signaling pathway, and PI3K/Akt inhibition decreased the protective effects of DADLE treatment. In addition, DADLE treatment during NEVLP resulted in lower perfusate alanine aminotransferase and tissue malondialdehyde and better tissue adenosine triphosphate and glutathione. Furthermore, perfusion with DADLE compared with perfusate alone preserved tissue architecture. DADLE confers protection against oxidative stress in hepatocytes and during NEVLP. These data suggest that the mechanism of protection involved the prevention of mitochondrial dysfunction by opioid receptor signaling and subsequent increased expression of prosurvival/antiapoptotic signaling pathways. Altogether, data suggest that opioid receptor agonism may serve as therapeutic target for improved liver protection during NEVLP. [ABSTRACT FROM AUTHOR]

Abstract Oxycodone, a widely prescribed and very potent oral opioid analgesic agent, is highly addictive and has many side effects, including troublesome constipation. Our studies in mice indicated that pretreatment of naltrindole did not significantly affect the analgesic efficacy of oxycodone but attenuated the tolerance and withdrawal induced by chronic oxycodone administration. Naltrindole also attenuated the oxycodone-induced rewarding and re-instatement behaviors, as shown by the conditioned place preference test. Further, oxycodone-induced decrease in intestinal transit (i.e., constipation) was reduced by naltrindole. However, naltrindole did not block the respiratory depression produced by oxycodone. Taken together, these data suggest that naltrindole can attenuate some major side effects while retaining the analgesic efficacy of oxycodone in mice. Naltrindole and oxycodone may have the potential to be a potent analgesic combination with much lower levels of oxycodone's side effects of addictive liability and constipation. [ABSTRACT FROM AUTHOR]

Background: The use of aroma oils dates back to at least 3000 B.C., where it was applied to mummify corpses and treat the wounds of soldiers. Since the 1920s, the term "aromatherapy" has been used for fragrance therapy with essential oils. The purpose of this study was to determine whether the essential oil of Eucalyptus (EOE) affects pain pathways in various pain conditions and motor coordination. Methods: Mice were subjected to inhalation or intraperitoneal injection of EOE, and its analgesic effects were assessed by conducting formalin, thermal plantar, and acetic acid tests; the effects of EOE on motor coordination were evaluated using a rotarod test. To determine the analgesic mechanism, 5'-guanidinonaltrindole (k-opioid antagonist, 0.3 mg/kg), naltrindole (d-opioid antagonist, 5 mg/kg), glibenclamide (d-opioid antagonist, 2 mg/kg), and naloxone (m-opioid antagonist, 4, 8, 12 mg/kg) were injected intraperitoneally. Results: EOE showed an analgesic effect against visceral pain caused by acetic acid (EOE, 45 mg/kg); however, no analgesic effect was observed against thermal nociceptive pain. Moreover, it was demonstrated that EOE did not have an effect on motor coordination. In addition, an anti-inflammatory effect was observed during the formalin test. Conclusions: EOE, which is associated with the μ-opioid pain pathway, showed potential effects against somatic, inflammatory, and visceral pain and could be a potential therapeutic agent for pain. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Inula britannica L. is a predominant medicinal plant traditionally utilized in the treatments of arthritis and back pain in Iranian folk medicine. Aim of the study The purpose of this research was to evaluate the antinociceptive effects of Inula britannica L. flower essential oil (IBLEO) and one of its major constituents, Patuletin (Pn), in male mice. Materials and methods In this study, we used pain assessment tests including acetic acid-induced writhing, tail-flick (TF), formalin induced paw licking (FIPL) model, and glutamate-induced paw licking (GPL). For understanding the supposed antinociceptive mechanisms of IBLEO, opioid and L -arginine/NO/cGMP/ KATP pathways were examined. Results In the TF, writhing, GPL, and FIPL tests, a dosage of 100 mg/kg of IBLEO showed noteworthy antinociceptive effects in comparison with control (p < 0.05). In writhing test, administration of selective opioid antagonists (naltrindole, nor-binaltorphimine, and naloxonazine) attenuated the antinociceptive effect of IBLEO in comparison with control (p < 0.001). Both methylene blue and glibenclamide blocked the antinociceptive effect of IBLEO (p < 0.05), but the administration of L-arginine or sodium nitroprusside fundamentally potentiated the antinociception induced by IBLEO in phase II of the FIPL (p < 0.05). Additionally, patuletin showed significant antinociceptive effects in writhing, FIPL, and GPL tests (p < 0.01). Conclusion The results of this examination showed that IBLEO and Pn have antinociceptive effects. The modulation of glutamatergic systems by opioid receptors could be involved, at least in part, in these effects. Our data also suggest the activation of the L -arginine/NO/cGMP/KATP pathway in IBLEO antinociceptive effects. [ABSTRACT FROM AUTHOR]

Abstract: It has been recently demonstrated that predictive learning induces a persistent accumulation of delta‐opioid receptors (DOPrs) at the somatic membrane of cholinergic interneurons (CINs) in the nucleus accumbens shell (Nac‐S). This accumulation is required for predictive learning to influence subsequent choice between goal‐directed actions. The current experiments investigated the local neurochemical events responsible for this translocation. We found that (1) local administration of substance P into multiple striatal sub‐territories induced DOPr translocation and (2) that this effect was mediated by the NK1 receptor, likely through its expression on CINs. Interestingly, whereas intrastriatal infusion of the D1 agonist chloro‐APB reduced the DOPr translocation on CINs and infusion of the D2 agonist quinpirole had no effect, co‐administration of both agonists again generated DOPr translocation, suggesting the effect of the D1 agonist alone was due to receptor internalisation. In support of this, local administration of cocaine was found to increase DOPr translocation as was chloro‐APB when co‐administered with the DOPr antagonist naltrindole. These studies provide the first evidence of delta‐opioid receptor translocation in striatal cholinergic interneurons outside of the accumbens shell and suggest that, despite differences in local striatal neurochemical microenvironments, a similar molecular mechanism – involving an interaction between dopamine and SP signalling via NK1R – regulates DOPr translocation in multiple striatal regions. To our knowledge, this represents a novel mechanism by which DOPr distribution is regulated that may be particularly relevant to learning‐induced DOPr trafficking. [ABSTRACT FROM AUTHOR]

Agonists selectively acting at NOP, MOP, DOP and KOP receptors as well as mixed opioid receptor agonists are known to exert anti-hypersensitive efficacy in the rat spinal nerve ligation (SNL) model of neuropathic pain. To investigate the relative contribution of individual opioid receptor activation to the overall efficacy of mixed opioid receptor agonists, selective doses of respective opioid receptor antagonists have to be employed. In order to identify such selective antagonist doses, doses of the selective NOP, MOP, DOP and KOP receptor agonists Ro65–6570, morphine, SNC-80 and U50488H, that produced maximum efficacy without apparent side effects, were challenged by each of the receptor antagonists J-113397 (NOP receptor), naloxone (MOP receptor), naltrindole (DOP receptor) and nor-binaltorphimine (KOP receptor). J-113397, naloxone, naltrindole and nor-binaltorphimine at intraperitoneal doses of 4.64, 1, 10, and 10 mg/kg, respectively, inhibited anti-hypersensitive effects mediated by the corresponding cognate NOP, MOP, DOP and KOP receptor selective agonists. Selectivity could be demonstrated for MOP, DOP and NOP receptor antagonists, as they did not attenuate effects mediated by agonists acting on non-cognate receptors, whereas the KOP receptor antagonist nor-BNI demonstrated partial cross-antagonism of the DOP receptor agonist SNC-80. Thus, specific doses of opioid receptor antagonists that completely but still selectively attenuate full anti-hypersensitive efficacy of corresponding opioid receptor agonists were identified in the rat SNL model. [ABSTRACT FROM AUTHOR]

Background Intermittent hypoxia training (IHT) produces robust myocardial protection against ischemia-reperfusion induced infarction and arrhythmias. Blockade of this cardioprotection by antagonism of either β 1 -adrenergic or δ-opioid receptors (δ-OR) suggests autonomic and/or opioidergic adaptations. Purpose To test the hypothesis that IHT shifts cardiac autonomic balance toward greater cholinergic and opioidergic influence. Methods Mongrel dogs completed 20 d IHT, non-hypoxic sham training, or IHT with the δ-OR antagonist naltrindole (200 μg/kg sc ). The vagolytic effect of the δ-OR agonist met-enkephalin-arg-phe delivered by sinoatrial microdialysis was evaluated following IHT. Sinoatrial, atrial and left ventricular biopsies were analyzed for changes in δ-OR, the neurotrophic monosialoganglioside, GM-1, and cholinergic and adrenergic markers. Results IHT enhanced vagal bradycardia vs. sham dogs ( P < 0.05), and blunted the δ 2 -OR mediated vagolytic effect of met-enkephalin-arg-phe. The GM-1 labeled fibers overlapped strongly with cholinergic markers, and IHT increased the intensity of both signals ( P < 0.05). IHT increased low and high intensity vesicular acetylcholine transporter labeling of sinoatrial nodal fibers ( P < 0.05) suggesting an increase in parasympathetic arborization. IHT reduced select δ-OR labeled fibers in both the atria and sinoatrial node ( P < 0.05) consistent with moderation of the vagolytic δ 2 -OR signaling described above. Furthermore, blockade of δ-OR signaling with naltrindole during IHT increased the protein content of δ-OR (atria and ventricle) and vesicular acetylcholine transporter (atria) vs. sham and untreated IHT groups. IHT also reduced the sympathetic marker, tyrosine hydroxylase in ventricle ( P < 0.05). Summary IHT shifts cardiac autonomic balance in favor of parasympathetic control via adaptations in opioidergic, ganglioside, and adrenergic systems. [ABSTRACT FROM AUTHOR]

Intermittent, normobaric hypoxia confers robust cardioprotection against ischemia-induced myocardial infarction and lethal ventricular arrhythmias. δ-Opioid receptor (DOR) signaling and reactive oxygen species (ROS) have been implicated in cardioprotective phenomena, but their roles in intermittent hypoxia are unknown. This study examined the contributions of DOR and ROS in mediating intermittent hypoxia-induced cardioprotection. Mongrel dogs completed a 20 day program consisting of 5–8 daily, 5–10 min cycles of moderate, normobaric hypoxia (FIO2 0.095–0.10), with intervening 4 min room air exposures. Subsets of dogs received the DOR antagonist naltrindole (200 μg/kg, sc) or antioxidant N-acetylcysteine (250 mg/kg, po) before each hypoxia session. Twenty-four hours after the last session, the left anterior descending coronary artery was occluded for 60 min and then reperfused for 5 h. Arrhythmias detected by electrocardiography were scored according to the Lambeth II conventions. Left ventricles were sectioned and stained with 2,3,5-triphenyl-tetrazolium-chloride, and infarct sizes were expressed as percentages of the area at risk (IS/AAR). Intermittent hypoxia sharply decreased IS/AAR from 41 ± 5 % (n = 12) to 1.8 ± 0.9 % (n = 9; P < 0.001) and arrhythmia score from 4.1 ± 0.3 to 0.7 ± 0.2 (P < 0.001) vs. non-hypoxic controls. Naltrindole (n = 6) abrogated the cardioprotection with IS/AAR 35 ± 5 % and arrhythmia score 3.7 ± 0.7 (P < 0.001 vs. untreated intermittent hypoxia). N-acetylcysteine (n = 6) interfered to a similar degree, with IS/AAR 42 ± 3 % and arrhythmia score 4.7 ± 0.3 (P < 0.001 vs. untreated intermittent hypoxia). Without the intervening reoxygenations, hypoxia (n = 4) was not cardioprotective (IS/AAR 50 ± 8 %; arrhythmia score 4.5 ± 0.5; P < 0.001 vs. intermittent hypoxia). Thus DOR, ROS and cyclic reoxygenation were obligatory participants in the gradually evolving cardioprotection produced by intermittent hypoxia. [ABSTRACT FROM AUTHOR]

Background and Purpose: Stimuli that predict rewarding events can control choice between future actions, and this control could be mediated by δ-opioid receptors in the nucleus accumbens shell (NAc-S). Stimuli predicting the absence of important events can also guide choice, although it remains unknown whether they do so via changes in an accumbal δ-opioid receptor-related process.Experimental Approach: δ-opioid receptor-eGFP mice were trained to perform two instrumental actions that delivered different food outcomes. Choice between the two actions was then tested in the presence of stimuli paired with either the delivery or the non-delivery of each of the two outcomes. Bilateral infusions of the δ-opioid receptor antagonist naltrindole into the NAc-S were used to determine the role of these receptors at the time of choice and δ-opioid receptor expression in the NAc-S used to assess functional activity.Key Results: A stimulus predicting a specific outcome biased choice performance towards the action previously earning that same outcome. In contrast, a stimulus signalling the absence of that outcome biased performance away from the action that delivered that outcome towards actions associated with the absence of that outcome. Both effects were associated with increased δ-opioid receptor expression on the membrane of cholinergic interneurons within the NAc-S. Furthermore, both effects were blocked by naltrindole infused into the NAc-S.Conclusions and Implications: These findings suggest that δ-opioid receptors in the NAc-S were involved in the effects of predictive learning on choice between actions, whether those predictions involve the presence or absence of specific rewarding events.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. [ABSTRACT FROM AUTHOR]

The endogenous opioid system has been implicated in mediating the reinforcing effects of ethanol (EtOH). Naltrexone (NTX), an opioid antagonist with concentration-dependent selectivity for the mu receptor, naltrindole (NTI), a selective delta receptor antagonist, and U50,488H, a selective kappa receptor agonist were examined in both alcohol-preferring (P) and nonselected (Long Evans (LE)) rats to determine whether they differentially affected the seeking and consumption of EtOH and sucrose. Using the sipper-tube model, rats reinforced with either 2 % sucrose or 10 % EtOH were injected with vehicle and either NTI (2.5, 5.0, or 10.0 mg/kg), U50 (2.5, 5.0, or 10.0 mg/kg), low-dose NTX (0.1, 0.3, or 1.0 mg/kg), or high-dose NTX (1.0, 3.0, or 10.0 mg/kg). Subsequent intakes (consummatory) or lever responses (seeking) were assessed. Overall, NTI, U50, and NTX attenuated intake and responding for sucrose and EtOH, with EtOH-reinforced P rats being the most sensitive to the effects of NTI on intake and seeking. U50 treatment decreased intake and seeking in both P and LE rats but did not selectively reduce EtOH intake or seeking in either line. P rats were more sensitive than LE rats to lower doses of NTX, and these doses more selectively attenuated responding for EtOH than sucrose. Higher doses of NTX suppressed intake and responding across both lines and reinforcers. These results suggest that drugs selective for the opioid receptors may be good pharmacotherapeutic targets, particularly in those with an underlying genetic predisposition for greater EtOH preference/intake. [ABSTRACT FROM AUTHOR]

Highlights: [•] We examined the role of delta-opioid receptors in the VP in ingestive behaviour. [•] We used the delta-opioid receptor antagonist naltrindole. [•] Naltrindole injection increased the consumption of a saccharin solution. [•] Naltrindole injection elevated perceived palatability for the saccharin solution. [•] Naltrindole injection caused no changes in aversion to saccharin CS in CTA. [ABSTRACT FROM AUTHOR]

Highlights: [•] We identified a dengue virus inhibitor in a library of drug-like small molecules. [•] This inhibitor, SDM25N, restricts replication of the viral genome. [•] Amino acid substitutions in the viral NS4B protein confer resistance to SDM25N. [•] Our data establish NS4B as a target for antiviral therapies. [Copyright &y& Elsevier]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the AβPP/PS1 transgenic mouse model is a commonly used experimental model to mimic the pathological and cognitive impairments in AD. As a classic method to evaluate spatial learning and memory, the Morris water maze is widely applied to study the cognitive deficits in rodent AD models. However, the assay procedure is relatively complicated and requires a properly equipped environment. The novel object recognition test is a relatively simple and straightforward method to test working memory in rodents. However, whether the latter can be used as a common tool for evaluating the therapeutic effects of drugs in the AβPP/PS1 transgenic AD mouse model remains unclear. In the present study, we assessed the cognitive impairment of AβPP/PS1 AD mice with the novel object recognition test. In parallel, Morris water maze was performed and compared with the novel object recognition study. Both assays worked equally well in evaluating the cognitive defect of AβPP/PS1 mice. Furthermore, we drew similar conclusions from the novel object recognition assay as from the Morris water maze in assessing the therapeutic effects of two previously reported compounds, donepezil and naltrindole, on AD. We found the novel object recognition to be a facile assay with almost no stress to mice and think it could be used as an ideal primary screening assay to evaluate drug effects on AβPP/PS1 AD model. [ABSTRACT FROM AUTHOR]

Physical exercise increases the level of endogenous opiates that possibly play a major role for integration of hormonal and metabolic responses to exercise. Increased endogenous opioids in response to physical activity may enhance the performance through decreasing pain perception. However, what possible effect the opioid peptides have on physical exercise at the level of central nervous system remains to be elucidated. In this study, naloxone (N=6), and naltrindole (N=8) were administered intracerebroventrically to rats. A physiologic saline group (N=10) and a control group (N=8) were also included in the study. All groups were then subjected to exhaustive exercise on a treadmill. Besides recording the exhaustion time, blood glucose and lactate levels were measured before and after exercise. Treatments with naloxone and naltrindole had no effect on the exhaustion time. In comparison with pre-exercise period, lactate levels increased, while glucose levels decreased significantly in the blood of all animals during post-exercise period. However, decreased level of glucose in the post-exercise period was statistically significant only in those treated with naltrindole, compared with the other groups. Our findings indicate that the central endogenous opioid peptides may have a role in the regulation of glucose metabolism during exhaustive exercise. This effect can be mediated via delta opioid receptors, although they exert no effect on the performance, namely, on the exhaustion time. [ABSTRACT FROM AUTHOR]

Abstract: Food intake is significantly increased following administration of agonists of GABA and opioid receptors into the nucleus accumbens shell (NACs) and ventral tegmental area (VTA). GABA-A or GABA-B receptor antagonist pretreatment within the VTA or NACs differentially affects mu-opioid agonist-induced feeding elicited from the same site. Correspondingly, general or selective opioid receptor antagonist pretreatment within the VTA or NACs differentially affects GABA agonist-induced feeding elicited from the same site. Regional interactions have been evaluated in feeding studies by administering antagonists in one site prior to agonist administration in a second site. Thus, opioid antagonist–opioid agonist and GABA antagonist–GABA agonist feeding interactions have been identified between the VTA and NACs. However, pretreatment with GABA-A or GABA-B receptor antagonists in the VTA failed to affect mu opioid agonist-induced feeding elicited from the NACs, and correspondingly, these antagonists administered in the NACs failed to affect mu opioid-induced feeding elicited from the VTA. To evaluate whether regional and reciprocal VTA and NACs feeding interactions occur for opioid receptor modulation of GABA agonist-mediated feeding, the present study examined whether feeding elicited by the GABA-B agonist, baclofen microinjected into the NACs was dose-dependently blocked by pretreatment with general (naltrexone: NTX), mu (beta-funaltrexamine: BFNA), kappa (nor-binaltorphamine: NBNI) or delta (naltrindole: NTI) opioid antagonists in the VTA, and correspondingly, whether VTA baclofen-induced feeding was dose-dependently blocked by NACs pretreatment with NTX, BFNA, NBNI or NTI in rats. Bilateral pairs of cannulae aimed at the VTA and NACs were stereotaxically implanted in rats, and their food intakes were assessed following vehicle and baclofen (200ng) in each site. Baclofen produced similar magnitudes of increased food intake following VTA and NACs treatment. Baclofen administration in the VTA or NACs was also preceded by administration of NTX (0.1, 1, 5μg, 0.5h), BFNA (0.4, 4μg, 24h), NBNI (0.6, 6μg, 0.5h) or NTI (0.4, 4μg, 0.5h) into the other site with intake measured 1, 2 and 4h after agonist treatment. VTA NTX significantly reduced NACs baclofen-induced feeding. Correspondingly, NACs NTX significantly reduced VTA baclofen-induced feeding, indicating a robust and bidirectional general opioid and GABA-B receptor feeding interaction. Whereas the high, but not low VTA BFNA dose reduced NACs baclofen-induced feeding, NACs BFNA failed to affect VTA baclofen-induced feeding, indicating a unidirectional mu opioid and GABA-B receptor feeding interaction. Whereas VTA NBNI at both doses reduced NACs baclofen-induced feeding, the high, but not low NACs NBNI dose significantly reduced VTA baclofen-induced feeding, indicating a bidirectional kappa opioid and GABA-B receptor feeding interaction. Whereas VTA NTI only transiently reduced NACs baclofen-induced feeding, NACs NTI failed to affect VTA baclofen-induced feeding, indicating a weak unidirectional delta opioid and GABA-B receptor interaction. Whereas administration of NTX or BFNA into the NACs or VTA marginally reduced spontaneous food intake, NBNI or NTI into the same sites failed to alter food intake alone. Therefore, the present study suggests that GABA employs a distributed brain network in mediating its ingestive effects that is dependent upon intact opioid receptor signaling with kappa opioid receptors more involved than mu and delta opioid receptors underlying these regional effects. An alternative hypothesis to be considered is that these effects could be the sum of two independent drug effects (opioid antagonists decreasing and baclofen increasing food intake). [Copyright &y& Elsevier]

Rationale: Compounds acting on delta opioid receptors (DOR) modulate anxiety-like behaviors, yet the site of action underlying this effect is unknown. DOR mRNA and protein are expressed in the central nucleus of the amygdala, a region that plays an important role in processing fear, stress, and anxiety. We hypothesized that this brain region may contribute to the modulation of anxiety by DOR drugs. Objective: The present study investigated the role of DOR in the central amygdala in anxiety-like behaviors. Methods: The selective DOR agonist [D-Pen 2,5]-enkephalin (DPDPE) or antagonist naltrindole was bilaterally microinjected into the central nucleus of the amygdala of adult male Sprague Dawley rats and anxiety-like behaviors were assessed using the elevated plus maze. The effects of DOR agonists on heightened anxiety produced by stress were also investigated. Results: Rats injected with DPDPE into the central nucleus of the amygdala demonstrated less anxiety-like behavior, as evidenced by significantly greater number of open-arm entries and time spent in the open arms than controls. Naltrindole administered alone did not affect the duration or number of entries onto the open arms; however, naltrindole pre-treatment blocked the anxiolytic effects produced by DPDPE. Systemic administration of the selective DOR agonist, SNC80, or microinjection of DPDPE into the central amygdala prior to a swim stress blocked the anxiogenic effect produced by the swim stress. Conclusions: These findings provide direct evidence that activation of DOR in the central amygdala reduces anxiety-like behavior and suggest that DOR in this area are important for regulating anxious states. [ABSTRACT FROM AUTHOR]

Abstract: The present study aimed to characterize the ability of the novel delta opioid peptide (DOP) receptor agonist H-Dmt-Tic-NH-CH(CH2–COOH)-Bid (UFP-512) to attenuate motor deficits in 6-hydroxydopamine (6-OHDA) hemilesioned rats. Lower doses (0.1–10 μg/kg) of UFP-512 administered systemically (i.p.) stimulated stepping activity in the drag test and overall gait abilities in the rotarod test whereas higher doses (100–1000 μg/kg) were ineffective or even worsened Parkinsonism. Microdialysis coupled to an akinesia test (bar test) was then used to determine the circuitry involved in the motor actions of UFP-512. An antiakinetic dose of UFP-512 (10 μg/kg) decreased GABA in globus pallidus (GP) as well as GABA and glutamate (GLU) release in substantia nigra reticulata (SNr). On the other hand, a pro-akinetic dose (1000 μg/kg) of UFP-512 increased pallidal GABA, simultaneously producing a decrease in GABA and an increase in nigral GLU release. Moreover, to test the hypothesis that changes in motor behavior were associated with changes in nigro–thalamic transmission, amino acid release in ventromedial thalamus (VMTh, a target of nigro–thalamic GABAergic projections) was also measured. The anti-akinetic dose of UFP-512 reduced GABA and increased thalamic GLU release while the pro-akinetic dose increased GABA without affecting thalamic GLU release. Finally, regional microinjections were performed to investigate the brain areas involved in motor actions of UFP-512. UFP-512 microinjections into GP increased akinesia whereas UFP-512 microinjections into SNr reduced akinesia. Furthermore, the selective DOP receptor antagonist naltrindole (NTD) increased akinesia when injected into either area, GP being more sensitive. We conclude that UFP-512, depending on dose, improves or worsens motor activity in hemiparkinsonian rats by acting differentially as a DOP receptor agonist in SNr and a DOP receptor antagonist in GP, ultimately decreasing or increasing the activity of nigro–thalamic GABAergc output neurons, respectively. [Copyright &y& Elsevier]

Abstract: Previous research has shown that opioid blockage enhances consummatory successive negative contrast (cSNC)—a suppression of consummatory behavior following a downshift from 32% to 4% sucrose solution. In Experiment 1, administration of the nonselective opioid receptor antagonist naloxone (2mg/kg, ip) distorted the comparison between expected and received incentives. The results of Experiment 2 discarded the alternative that naloxone enhances cSNC by inducing a conditioned taste aversion. The results of Experiments 3a–3c provided no evidence that opioid administration after the first downshift trial modulated subsequent consummatory performance. The opioids tested included naloxone (2mg/kg, ip), the δ-opioid receptor selective antagonist naltrindole (1mg/kg, ip), and the δ-opioid receptor selective agonist DPDPE (24μg/kg, ip). The selected doses have proven in earlier experiments to be effective when administered before training. Experiments 4–5 failed to uncover any effects of posttraining opioid blockage with naloxone in an appetitive extinction task (autoshaping with lever-food pairings). These results add to our previous understanding of opioid function in situations involving incentive downshifts, suggesting a role in the comparison process that triggers cSNC, but no apparent function in memory consolidation related to the downshift event. [Copyright &y& Elsevier]

Abstract: Evidence indicates that endogenous opioids play a role in body temperature (Tb) regulation in mammals but no data exist about the involvement of the specific opioid receptors, mu, kappa and delta, in the reduction of Tb induced by hypoxia. Thus, we investigated the participation of these opioid receptors in the anteroventral preoptic region (AVPO) in hypoxic decrease of Tb. To this end, Tb of unanesthetized Wistar rats was monitored by temperature data loggers before and after intra-AVPO microinjection of the selective kappa-opioid receptor antagonist nor-binaltorphimine dihydrochloride (nor-BNI; 0.1 and 1.0 μg/100 nL/animal), the selective mu-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 cyclic (CTAP; 0.1 and 1.0 μg/100 nL/animal), and the selective delta-opioid receptor antagonist Naltrindole (0.06 and 0.6 μg/100 nL/animal) or saline (vehicle, 100 nL/animal), during normoxia and hypoxia (7% inspired O2). Under normoxia, no effect of opioid antagonists on Tb was observed. Hypoxia induced Tb to reduce in vehicle group, a response that was inhibited by the microinjection intra-AVPO of nor-BNI. In contrast, CTAP and Naltrindole did not change Tb during hypoxia but caused a longer latency for the return of Tb to the normoxic values just after low O2 exposure. Our results indicate the kappa-opioid receptor in the AVPO is important for the reduction of Tb during hypoxia while the mu and delta receptors are involved in the increase of Tb during normoxia post-hypoxia. [Copyright &y& Elsevier]

Abstract: It has been difficult to find conditioned preference for tactile cues paired with ethanol intoxication in rats. Toward understanding the ontogeny of ethanol reinforcement, we aimed at establishing a simple and reliable procedure for (1) assessing primary appetitive conditioning to ethanol in infant rats and (2) discerning the role the opioid system plays in ethanol-mediated conditioning at this age. Experiment 1 determined the parameters (i.e., dose, interval of conditioning) for assessing ethanol-mediated conditioning. Pups were then trained with differential Pavlovian conditioning (Experiments 2 and 3) in which ethanol intoxication (1.0–2.0g/kg, intragastrically or intraperitoneally delivered) was paired with a tactile stimulus (sandpaper) while an alternative texture signaled the absence of ethanol''s effects. Unpaired control conditions were also used. Tactile preferences were assessed after two conditioning sessions. Paired rats spent significantly more time on sandpaper than unpaired controls, an effect that was greater after intragastric administration of 1.0 than 2.0g/kg ethanol. This effect was replicated in Experiments 4a and 4c and found to be inhibited by pretreatment with general (naloxone [NAL]) or specific (d-Pen-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH2 [CTOP] and naltrindole) opioid antagonists. Blood ethanol levels at conditioning were not altered by NAL (Experiment 4b). The study outlines a procedure that reveals appetitive conditioning to ethanol by infant rats. The results are discussed in terms of a potential ethanol-induced activation of the endogenous opioid system during the onset of the intoxication process. [Copyright &y& Elsevier]

The characterization of the discriminative stimulus properties of naloxone has focused primarily on its actions at the mu opioid receptor, although naloxone also displays an affinity for delta and kappa receptor subtypes. The present study extends this characterization of the naloxone cue by investigating if relatively specific antagonists for the mu (naltrexone: 0.10–0.56 mg/kg), delta (naltrindole: 1–18 mg/kg), and kappa (MR2266: 1.8–10 mg/kg) opioid receptor subtypes will substitute for naloxone in animals trained to discriminate naloxone from its vehicle. The temporal nature of the naloxone cue was examined by varying pretreatment time points (15, 30, 45, 60 min). Finally, various doses of naltrexone methobromide (1–18 mg/kg) were assessed to determine peripheral mediation of the cue. Female Long–Evans rats ( N = 30) received an injection of naloxone (1 mg/kg; i.p.) 15 min prior to a pairing of saccharin (20-min access) and the emetic LiCl (1.8 mEq; i.p.; n = 16, group NL) or vehicle ( n = 14, group NW); on other days, they were injected with saline prior to saccharin alone. Substitution tests with compounds with various receptor affinities and selective CNS and PNS actions were then assessed. Only naloxone and naltrexone produced dose-dependent decreases in saccharin consumption. Naloxone administered at 15 and 30 min before saccharin produced decreases in consumption similar to that displayed on training days. Naltrexone methobromide substituted only at the highest dose tested (18 mg/kg). Naloxone’s stimulus effects appear to be mediated centrally via activity at the mu opioid receptor. [ABSTRACT FROM AUTHOR]

Background: Functional interactions between μ- and δ-opioid receptors (MOPr and DOPr, respectively) are implicated in morphine tolerance and dependence. The contribution of DOPr to the conditioned rewarding effects of morphine and the enhanced conditioned response that occurs after repeated morphine administration is unknown. This issue was addressed with the conditioned place preference procedure (CPP). Methods: Rats received home cage injections of saline or morphine (5.0 mg/kg/day × 5 days) before conditioning. For sensitization studies, DOPr antagonists (DOPr1/2: naltrindole, DOPr2: naltriben, DOPr1: 7-benzylidenenaltrexone) were administered before morphine injections. Conditioning sessions (2 morphine; 2 saline) commenced 3 days later. To assess the influence of acute DOPr blockade on the conditioning of morphine reward in naïve animals, 3 morphine and 3 saline conditioning sessions were employed. Antagonists were administered before morphine conditioning sessions. Results: Morphine was ineffective as a conditioning stimulus after two conditioning sessions in naïve rats. However, doses ≥ 3.0 mg/kg produced significant CPP in morphine pre-exposed rats, confirming that sensitization develops to the conditioned rewarding effects of morphine. In animals that received morphine pre-exposure with naltrindole or naltriben but not 7-benzylidenenaltrexone, sensitization was prevented. No attenuation of morphine CPP was observed in animals that received DOPr antagonists acutely, before conditioning sessions. Conclusions: These data indicate a critical role of DOPr systems in mediating sensitization to the conditioned rewarding effects of morphine. The efficacy of naltrindole and naltriben in preventing the enhanced response to morphine suggest the specific involvement of DOPr2 in the sensitization process. [Copyright &y& Elsevier]

The delta opioid peptide (DOP) receptor has been proposed as a target in the symptomatic therapy of Parkinson’s disease. However, the circuitry underlying the antiparkinsonian action of DOP receptor agonists and their site of action have never been adequately investigated. Systemic administration of the DOP receptor agonist (+)-4-[(αR)-α-(2 S,5 R)-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl]- N-N-diethylbenzamide (SNC-80) attenuated akinesia/bradykinesia and improved motor activity in 6-hydroxydopamine hemilesioned rats. Opposite effects were produced by the selective DOP receptor antagonist naltrindole (NTD), suggesting that endogenous enkephalins tonically sustain movement under parkinsonian conditions. Microdialysis revealed that SNC-80 reduced GABA release in globus pallidus (GP) while NTD elevated it. Moreover, SNC-80 reduced GABA and glutamate release in substantia nigra reticulata (SNr) whereas NTD reduced GABA without affecting glutamate release. The bar test coupled to microdialysis showed that perfusion with NTD in SNr but not GP or striatum prevented the antiakinetic effect of systemic SNC-80 and its neurochemical correlates. Consistently, microinjections of SNC-80 into SNr or bicuculline in GP attenuated parkinsonian-like symptoms while SNC-80 microinjections in GP or striatum were ineffective. This study demonstrates that nigral DOP receptors mediate antiparkinsonian actions of SNC-80 and challenges the common view that DOP receptor agonists solely attenuate parkinsonism via pallidal mechanisms. [ABSTRACT FROM AUTHOR]

Abstract: The highly selective delta opioid agonist, SNC80, elicits dopamine-related behaviors including locomotor stimulation and conditioned place-preference. In contrast, it has been reported that SNC80 fails to promote dopamine efflux from the striatum of freely moving rats. However, SNC80 does enhance behavioral responses to the stimulants, amphetamine and cocaine, suggesting an interaction between delta opioids and psychostimulants. Since the increase in locomotor activity elicited by amphetamine and related stimulants acting at the dopamine transporter is associated with increases in extracellular concentrations of dopamine within the striatum, we hypothesized that SNC80 enhances this activity by potentiating the overflow of dopamine through the transporter. To test this hypothesis, striatal preparations from Sprague Dawley rats were assayed for dopamine efflux in response to amphetamine challenge. SNC80 was given either in vivo or in vitro directly to rat striatal tissue, prior to in vitro amphetamine challenge. Both in vivo and in vitro administration of SNC80 enhanced amphetamine-mediated dopamine efflux in a concentration- and time-dependent manner. However, SNC80 in either treatment paradigm produced no stimulation of dopamine efflux in the absence of amphetamine. The effect of SNC80 on amphetamine-mediated dopamine overflow, but not the effect of amphetamine alone, was blocked by the delta selective antagonist, naltrindole and was also observed with other delta agonists. The results of this study demonstrate that even though SNC80 does not stimulate dopamine efflux alone, it is able to augment amphetamine-mediated dopamine efflux through a delta opioid receptor mediated action locally in the striatum. [Copyright &y& Elsevier]

Abstract: We have previously reported on antitussive effect of (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5′,6′-dihydro-3-methoxy-4′H-pyrrolo[3,2,1-ij]quinolino[2′,1′:6,7]morphinan-14-ol(1b) methanesulfonate (TRK-850), a selective δ opioid receptor antagonist which markedly reduced the number of coughs in a rat cough model. We designed TRK-850 based on naltrindole (NTI), a typical δ opioid receptor antagonist, to improve its permeability through the blood–brain barrier by introducing hydrophobic moieties to NTI. The ED50 values of NTI and compound 1b by intraperitoneal injections were 104μg/kg and 2.07 μg/kg, respectively. This increased antitussive potency probably resulted from the improved brain exposure of compound 1b. However, 1b was extremely unstable toward metabolism by cytochrome P450. In this study, we designed and synthesized compound 1b derivatives to improve the metabolic instability, which resulted in affording highly potent and metabolically stable oral antitussive agent (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-8′-fluoro-5′,6′-dihydro-4′H-pyrrolo[3,2,1-ij]quinolino[2′,1′:6,7]morphinan-3,14-diol (1c) methanesulfonate (TRK-851). [Copyright &y& Elsevier]

Abstract: The purpose of this study was to assess the antinociceptive and antiallodynic effect of melatonin as well as its possible mechanism of action in diabetic rats. Streptozotocin (50 mg/kg) injection caused hyperglycemia within 1 week. Formalin-evoked flinching was increased in diabetic rats as compared to non-diabetic rats. Oral administration of melatonin (10–300 mg/kg) dose-dependently reduced flinching behavior in diabetic rats. In addition, K-185 (a melatonin MT2 receptor antagonist, 0.2–2 mg/kg, s.c.) completely blocked the melatonin-induced antinociception in diabetic rats, whereas that naltrexone (a non-selective opioid receptor antagonist, 1 mg/kg, s.c.) and naltrindole (a selective δ opioid receptor antagonist, 0.5 mg/kg, s.c.), but not 5′-guanidinonaltrindole (a selective κ opioid receptor antagonist, 1 mg/kg, s.c.), partially reduced the antinociceptive effect of melatonin. Given alone K-185, naltrexone, naltrindole or 5′-guanidinonaltrindole did not modify formalin-induced nociception in diabetic rats. Four to 8 weeks after diabetes induction, tactile allodynia was observed in the streptozotocin-injected rats. On this condition, oral administration of melatonin (75–300 mg/kg) dose-dependently reduced tactile allodynia in diabetic rats. Both antinociceptive and antiallodynic effects were not related to motor changes as melatonin did not modify number of falls in the rotarod test. Results indicate that melatonin is able to reduce formalin-induced nociception and tactile allodynia in streptozotocin-injected rats. In addition, data suggest that melatonin MT2 and δ opioid receptors may play an important role in these effects. [Copyright &y& Elsevier]

Background and Purpose: Ultralow doses of naltrexone, a non-selective opioid antagonist, have previously been found to augment acute morphine analgesia and block the development of tolerance to this effect. Since morphine tolerance is dependent on the activity of micro and delta receptors, the present study investigated the effects of ultralow doses of antagonists selective for these receptor types on morphine analgesia and tolerance in tests of thermal and mechanical nociception.Experimental Approach: Effects of intrathecal administration of mu-receptor antagonists, CTOP (0.01 ng) or CTAP (0.001 ng), or a delta-receptor antagonist, naltrindole (0.01 ng), on spinal morphine analgesia and tolerance were evaluated using the tail-flick and paw-pressure tests in rats.Key Results: Both micro and delta antagonists augmented analgesia produced by a sub-maximal (5 microg) or maximal (15 microg) dose of morphine. Administration of the antagonists with morphine (15 microg) for 5 days inhibited the progressive decline of analgesia and prevented the loss of morphine potency. In animals exhibiting tolerance to morphine, administration of the antagonists with morphine produced a recovery of the analgesic response and restored morphine potency.Conclusions and Implications: Combining ultralow doses of micro- or delta-receptor antagonists with spinal morphine augmented the acute analgesic effects, inhibited the induction of chronic tolerance and reversed established tolerance. The remarkably similar effects of micro- and delta-opioid receptor antagonists on morphine analgesia and tolerance are interpreted in terms of blockade of the latent excitatory effects of the agonist that limit expression of its full activity. [ABSTRACT FROM AUTHOR]

Abstract: The present study examined the effects of NIH 11082 ((−)-(1R,5R,9R)-5,9-dimethyl-2′-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride), a benzomorphan analogue, in the mouse tail-suspension, an assay used to detect anti-depressant agents. NIH 11082 significantly decreased immobility time during tail-suspension, with a comparable magnitude as the tricyclic anti-depressant desipramine. Importantly, NIH 11082 failed to elicit convulsions or other overt behavioral signs of toxicity. The delta-opioid receptor antagonist naltrindole (AD50 =2.0 mg/kg), but not the non-selective mu-opioid receptor antagonist naltrexone or the kappa-opioid receptor antagonist nor-BNI, blocked the effects of NIH 11082 in the tail-suspension test. These results reinforce the notion that delta-opioid receptor agonists can produce significant effects in a behavioral model used to screen anti-depressant drugs. [Copyright &y& Elsevier]