Effects Of Opioid Antagonists Research Articles

A single exposure to the predator odor 2,4,5-trimethylthiazoline causes long-lasting affective behavioral changes in female mice: Modulation by kappa opioid receptor signaling

The volatile compound 2,4,5-trimethylthiazoline (TMT, a synthetic predator scent) triggers fear, anxiety, and defensive responses in rodents that can outlast the encounter. The receptor systems underlying the development and persistence of TMT-induced behavioral changes remain poorly characterized, especially in females. Kappa opioid receptors regulate threat generalization and fear conditioning and alter basal anxiety, but their role in unconditioned fear responses in females has not been examined. Here, we investigated the effects of the long-lasting kappa opioid receptor antagonist, nor-binalthorphinmine dihydrochloride (nor-BNI; 10mg/kg), on TMT-induced freezing and conditioned place aversion in female mice. We also measured anxiety-like behavior in the elevated plus maze three days after TMT and freezing behavior when returned to the TMT-paired context ten days after the single exposure. We found that 35μl of 10% TMT elicited a robust freezing response during a five-minute exposure in female mice. TMT evoked persistent fear as measured by conditioned place aversion, reduced entries into the open arm of the elevated plus maze, and increased general freezing behavior long after TMT exposure. In line with the known role of kappa-opioid receptors in threat generalization, we found that kappa-opioid receptor antagonism increased basal freezing but reduced freezing during TMT presentation. Together, these findings indicate that a single exposure to TMT causes long-lasting changes in fear-related behavioral responses in female mice and highlights the modulatory role of kappa-opioid receptor signaling on fear-related behavioral patterns in females.

The Role of Opioid Receptor Antagonists in Regulation of Blood Pressure and T-Cell Activation in Mice Selected for High Analgesia Induced by Swim Stress.

Opioid peptides and their G protein-coupled receptors are important regulators within the cardiovascular system, implicated in the modulation of both heart and vascular functions. It is known that naloxone-an opioid antagonist-may exert a hypertensive effect. Recent experimental and clinical evidence supports the important role of inflammatory mechanisms in hypertension. Since opioids may play a role in the regulation of both blood pressure and immune response, we studied these two processes in our model. We aimed to evaluate the effect of selective and non-selective opioid receptor antagonists on blood pressure and T-cell activation in a mouse model of high swim stress-induced analgesia. Blood pressure was measured before and during the infusion of opioid receptor antagonists using a non-invasive tail-cuff measurement system. To assess the activation of T-cells, flow cytometry was used. We discovered that the non-selective antagonism of the opioid system by naloxone caused a significant elevation of blood pressure. The selective antagonism of μ and κ but not δ opioid receptors significantly increased systolic blood pressure. Subsequently, a brief characterization of T-cell subsets was performed. We found that the blockade of μ and δ receptors is associated with the increased expression of CD69 on CD4 T-cells. Moreover, we observed an increase in the central memory CD4 and central memory CD8 T-cell populations after the δ opioid receptor blockade. The antagonism of the μ opioid receptor increased the CD8 effector and central memory T-cell populations.

Opioid receptor antagonism and neural response to monetary rewards: Pilot studies in light and heavy alcohol users.

Alcohol use disorder (AUD) is a prevalent condition associated with high degree of comorbidity and mortality. Among the few approved pharmacotherapies for AUD, two involve opioid receptor antagonism. Naltrexone and nalmefene are thought to act via opioid receptor blockage to reduce neural response to alcohol and drug-associated cues and consumption, but there have been limited efforts to characterize these effects in humans. In these studies, we sought to test the magnitude of opioid antagonism effects on neural response to monetary rewards in two groups: light drinkers (for the naltrexone study) and heavy drinkers (for the nalmefene study). We conducted double-blind, randomized, crossover pilot studies of reward activation in the brain following acute administration of opioid antagonist and placebo in 11 light and 9 heavy alcohol users. We used a monetary incentive delay task during functional MRI. We found a main effect of cue type on BOLD activation in the nucleus accumbens, demonstrating a neural reward response. The effect of opioid antagonism, relative to placebo, was small and nonsignificant for reward activation in the accumbens for both light and heavy alcohol users. Based on the results of two pilot studies, opioid antagonist medications do not appear to decrease neural activation to monetary rewards in the nucleus accumbens relative to placebo.

What are the effects of antidepressants and opioid antagonists for the treatment of disordered and problem gambling?

What are the effects of antidepressants and opioid antagonists for the treatment of disordered and problem gambling?

Opioid Receptor-Mediated and Non-Opioid Receptor-Mediated Roles of Opioids in Tumour Growth and Metastasis.

Opioids are administered to cancer patients in the period surrounding tumour excision, and in the management of cancer-associated pain. The effects of opioids on tumour growth and metastasis, and their consequences on disease outcome, continue to be the object of polarised, discrepant literature. It is becoming clear that opioids contribute a range of direct and indirect effects to the biology of solid tumours, to the anticancer immune response, inflammation, angiogenesis and importantly, to the tumour-promoting effects of pain. A common misconception in the literature is that the effect of opioid agonists equates the effect of the mu-opioid receptor, the major target of the analgesic effect of this class of drugs. We review the evidence on opioid receptor expression in cancer, opioid receptor polymorphisms and cancer outcome, the effect of opioid antagonists, especially the peripheral antagonist methylnaltrexone, and lastly, the evidence available of a role for opioids through non-opioid receptor mediated actions.

Sodium chloride injection to treat opioid overdose; Does it work? A preclinical study

Opioid overdoses (ODs) are increasing in Mexico's northern border. Because naloxone is usually not available, witnesses inject common salt (NaCl) into a vein of OD victims in an attempt to help them regain consciousness. Despite this widespread practice, no preclinical studies have addressed the efficacy of NaCl as an opioid antidote. Here we tested saline solutions at different concentrations. Because the highest (31.6 %) caused tail necrosis, we selected 17.7 % as a hypertonic saline solution (HSS) to determine if it could prevent the lethal effect of morphine (Mor), fentanyl (Fen), or Mor + Fen in adult Wistar male rats. We also evaluated if NaCl could modify the opioid antagonist effect of naloxone. Our results show that HSS: a) sensitizes animals to thermal but not mechanical stimuli; b) does not prevent mortality caused by high morphine or fentanyl doses; c) decreases the latency to recovery from the sedative effects caused by low doses of morphine or fentanyl; and d) increases naloxone's efficacy to prevent the lethality produced by Mor or Fen, but not by Mor + Fen. These results suggest that HSS is marginally effective in shortening the recovery time from nonfatal opioid ODs and increases naloxone's efficacy to counteract opioid-induced ODs.

Left-Right Side-Specific Neuropeptide Mechanism Mediates Contralateral Responses to a Unilateral Brain Injury.

Neuropeptides are implicated in control of lateralized processes in the brain. A unilateral brain injury (UBI) causes the contralesional sensorimotor deficits. To examine whether opioid neuropeptides mediate UBI induced asymmetric processes we compared effects of opioid antagonists on the contralesional and ipsilesional hindlimb responses to the left-sided and right-sided injury in rats. UBI induced hindlimb postural asymmetry (HL-PA) with the contralesional hindlimb flexion, and activated contralesional withdrawal reflex of extensor digitorum longus (EDL) evoked by electrical stimulation and recorded with EMG technique. No effects on the interossei (Int) and peroneaus longus (PL) were evident. The general opioid antagonist naloxone blocked postural effects, did not change EDL asymmetry while uncovered cryptic asymmetry in the PL and Int reflexes induced by UBI. Thus, the spinal opioid system may either mediate or counteract the injury effects. Strikingly, effects of selective opioid antagonists were the injury side-specific. The μ-antagonist β-funaltrexamine (FNA) and κ-antagonist nor-binaltorphimine (BNI) reduced postural asymmetry after the right but not left UBI. In contrast, the δ-antagonist naltrindole (NTI) inhibited HL-PA after the left but not right-side brain injury. The opioid gene expression and opioid peptides were lateralized in the lumbar spinal cord, and coordination between expression of the opioid and neuroplasticity-related genes was impaired by UBI that together may underlie the side-specific effects of the antagonists. We suggest that mirror-symmetric neural circuits that mediate effects of left and right brain injury on the contralesional hindlimbs are differentially controlled by the lateralized opioid system.

Characterization of opioidergic mechanisms related to the anti-migraine effect of vagus nerve stimulation

Vagus nerve stimulation (VNS) is a promising neuromodulation approach used in the treatment of migraine, whose therapeutic mechanism is largely unknown. Previous studies suggest that VNS's anti-nociceptive effects may, in part, involve engaging opioidergic mechanisms. We used a validated preclinical model of head pain, with good translational outcomes in migraine, acute intracranial-dural stimulation, which has responded to invasive VNS.We tested the effects of μ (MOR), δ (DOR) and κ (KOR) opioid receptor agonists in this model, and subsequently the effects of opioid receptor antagonists against VNS-mediated neuronal inhibition. MOR, DOR, and KOR agonists all inhibited dural-evoked trigeminocervical neuronal responses. Both DOR and KOR agonists also inhibited ongoing spontaneous firing of dural responsive neurons. Both DOR and KOR agonists were more efficacious than the MOR agonist in this model. We confirm the inhibitory effect of invasive VNS and demonstrate that this effect was prevented by a broad-spectrum opioid receptor antagonist, and by a highly selective DOR antagonist. Our data confirm the role of MOR in dural-trigeminovascular neurotransmission and additionally provide evidence of a role of both DOR and KOR in dural-nociceptive transmission of trigeminocervical neurons. Further, the results here provide evidence of engagement of opioidergic mechanisms in the therapeutic action of VNS in headache, specifically the DOR. These studies provide further support for the important role of the DOR in headache mechanisms, and as a potential therapeutic target. The data begin to dissect the mode of action of the analgesic effects of VNS in the treatment of primary headache disorders.

Differential effects of novel kappa opioid receptor antagonists on dopamine neurons using acute brain slice electrophysiology.

Activation of the kappa opioid receptor (KOR) contributes to the aversive properties of stress, and modulates key neuronal circuits underlying many neurobehavioral disorders. KOR agonists directly inhibit ventral tegmental area (VTA) dopaminergic neurons, contributing to aversive responses (Margolis et al. 2003, 2006); therefore, selective KOR antagonists represent a novel therapeutic approach to restore circuit function. We used whole cell electrophysiology in acute rat midbrain slices to evaluate pharmacological properties of four novel KOR antagonists: BTRX-335140, BTRX-395750, PF-04455242, and JNJ-67953964. Each compound concentration-dependently reduced the outward current induced by the KOR selective agonist U-69,593. BTRX-335140 and BTRX-395750 fully blocked U-69,593 currents (IC50 = 1.2 ± 0.9 and 1.2 ± 1.3 nM, respectively). JNJ-67953964 showed an IC50 of 3.0 ± 4.6 nM. PF-04455242 exhibited partial antagonist activity asymptoting at 55% blockade (IC50 = 6.7 ± 15.1 nM). In 3/8 of neurons, 1 μM PF-04455242 generated an outward current independent of KOR activation. BTRX-335140 (10 nM) did not affect responses to saturating concentrations of the mu opioid receptor (MOR) agonist DAMGO or the delta opioid receptor (DOR) agonist DPDPE, while JNJ-67953964 (10 nM) partially blocked DAMGO and DPDPE responses. Importantly, BTRX-335140 (10 nM) rapidly washed out with complete recovery of U-69,593 responses within 10 min. Collectively, we show electrophysiological evidence of key differences amongst KOR antagonists that could impact their therapeutic potential and have not been observed using recombinant systems. The results of this study demonstrate the value of characterizing compounds in native neuronal tissue and within circuits implicated in the neurobehavioral disorders of interest.

Opioids in Post-stroke Pain: A Systematic Review and Meta-Analysis.

Background: Post-stroke pain is one of the most common sequelae of stroke, which stands among the leading causes of death and adult-acquired disability worldwide. The role and clinical efficacy of opioids in post-stroke pain syndromes is still debated. Objectives: Due to the important gap in knowledge on the management of post-stroke pain, this systematic review aimed at assessing the efficacy of opioids in post-stroke pain syndromes. Methods: A literature search was conducted on databases relevant for medical scientific literature, i.e. PubMed/MEDLINE, Scopus, Web of Science and Cochrane Library databases from databases inception until August 31st, 2020 for clinical trials assessing the effects of opioids and opioid antagonists on pain reduction and pain related symptoms in patients with post-stroke pain syndromes. Studies assessing the effects of other medications (e.g., tricyclic antidepressant, pregabalin) or non - pharmacological management strategies (e.g., neurostimulation techniques) were excluded. The selected studies have been subjected to examination of the risk of bias. Results: The literature search retrieved 83,435 results. After duplicates removal, 34,285 articles were title and abstract screened. 25 full texts were assessed and 8 articles were identified to be eligible for inclusion in the qualitative summary and narrative analysis, of which three were placebo-controlled and two were dose-response. Among placebo-controlled studies, two evaluated the analgesic effect of morphine and one assessed the effects of the opioid antagonist naloxone on patients with central post-stroke pain. With regard to dose-response studies, both were on patients with central post-stroke pain, one assessing the efficacy of levorphanol, and the other on naloxone. Seven out of eight included studies showed an overall slight analgesic effect of opioids, with less consistent effects on other pain-related symptoms (e.g., mood, quality of life). The randomized controlled trials were subjected to meta-analysis and rating of the quality of evidence for the two outcomes considered according to GRADE (Grading of Recommendations, Assessment, Development and Evaluations) system. The overall results are inconclusive because of the small number of studies and of patients. Conclusions: The limited number of the included studies and their heterogeneity in terms of study design do not support the efficacy of opioids in post-stroke pain and in pain-related outcomes. Large double-blind randomized clinical trials with objective assessment of pain and related symptoms are needed to further investigate this topic.

Research advances in mechanisms about the effect of pretreatment with low-dose opioid antagonist on opioid-induced side effects

Opioid drugs, acting with the opioid receptors, are commonly used in clinical anesthesia and analgesia, but there is no effective preventive strategies for its side effects such as respiratory depression, hyperalgesia, and opioid tolerance. Naloxone and Nalmefene , these two drugs are mainly used for postoperative snooze and respiratory depression relieve. In recent years, it has been reported that preadministration of ultralow-dose opioid receptor antagonists can significantly alleviate postoperative opioid tolerance and hyperalgesia. This review summarized research advances of the effect and potential mechanism of ultralow-dose opioid receptor antagonist on adverse reactions induced by opioid receptor agonists. With further study of opioid agonists combined with ultralow-dose antagonists, new ideas will be generated for prevention of side effects caused by opioid drugs. Key words: Naloxone; Nalmefene; Hyperalgesia; Opioid tolerance

Activation of Kappa Opioid Receptor Regulates the Hypothermic Response to Calorie Restriction and Limits Body Weight Loss.

Mammals maintain a nearly constant core body temperature (Tb) by balancing heat production and heat dissipation. This comes at a high metabolic cost that is sustainable if adequate calorie intake is maintained. When nutrients are scarce or experimentally reduced such as during calorie restriction (CR), endotherms can reduce energy expenditure by lowering Tb [1-6]. This adaptive response conserves energy, limiting the loss of body weight due to low calorie intake [7-10]. Here we show that this response is regulated by the kappa opioid receptor (KOR). CR is associated with increased hypothalamic levels of the endogenous opioid Leu-enkephalin, which is derived from the KOR agonist precursor dynorphin [11]. Pharmacological inhibition of KOR, but not of the delta or the mu opioid receptor subtypes, fully blocked CR-induced hypothermia and increased weight loss during CR independent of calorie intake. Similar results were seen with DIO mice subjected to CR. In contrast, inhibiting KOR did not change Tb in animals fed ad libitum (AL). Chemogenetic inhibition of KOR neurons in the hypothalamic preoptic area reduced the CR-induced hypothermia, whereas chemogenetic activation of prodynorphin-expressing neurons in the arcuate or the parabrachial nucleus lowered Tb. These data indicate that KOR signaling is a pivotal regulator of energy homeostasis and can affect body weight during dieting by modulating Tb and energy expenditure.

Behavioral Pharmacology of Novel Kappa Opioid Receptor Antagonists in Rats.

BackgroundNew treatments for stress-related disorders including depression, anxiety, and substance use disorder are greatly needed. Kappa opioid receptors are expressed in the central nervous system, including areas implicated in analgesia and affective state. Although kappa opioid receptor agonists share the antinociceptive effects of mu opioid receptor agonists, they also tend to produce negative affective states. In contrast, selective kappa opioid receptor antagonists have antidepressant- and anxiolytic-like effects, stimulating interest in their therapeutic potential. The prototypical kappa opioid receptor antagonists (e.g., norBNI, JDTic) have an exceptionally long duration of action that complicates their use in humans, particularly in tests to establish safety. This study was designed to test dose- and time-course effects of novel kappa opioid receptor antagonists with the goal of identifying short-acting lead compounds for future medication development.MethodsWe screened 2 novel, highly selective kappa opioid receptor antagonists (CYM-52220 and CYM-52288) with oral efficacy in the warm water tail flick assay in rats to determine initial dose and time course effects. For comparison, we tested existing kappa opioid receptor antagonists JDTic and LY-2456302 (also known as CERC-501 or JNJ-67953964).ResultsIn the tail flick assay, the rank order of duration of action for the antagonists was LY-2456302 < CYM-52288 < CYM-52220 << JDTic. Furthermore, LY-2456302 blocked the depressive (anhedonia-producing) effects of the kappa opioid receptor agonist U50,488 in the intracranial self-stimulation paradigm, albeit at a higher dose than that needed for analgesic blockade in the tail flick assay.ConclusionsThese results suggest that structurally diverse kappa opioid receptor antagonists can have short-acting effects and that LY-2456302 reduces anhedonia as measured in the intracranial self-stimulation test.

Opioid Antagonists for Pharmacological Treatment of Gambling Disorder: Are they Relevant?

Background: To date, no drugs have been approved for gambling disorder. Numerous publications have described the value of opioid antagonists. Indeed, the mesocorticolimbic dopaminergic pathway has been suggested as the underlying cause of reward-seeking behaviour, and it is modulated by the opioid system.Objective: This study aims to evaluate the relevance of opioid antagonists for treating GD.Method: A systematic literature review was conducted. A search of the PubMed electronic database, PsycINFO and the Cochrane Systematic Review Database without any limits was performed.Results: There is little information concerning the effects of opioid antagonists on GD. The total search with “nalmefene and gambling” without any limits revealed only 11 articles. The search with “naltrexone and gambling” without any limits gener-ated 47 articles. Nevertheless, the best available data support the use of opioid antagonists, particularly in individuals with a history of alcohol use disorder or strong gambling urges.Conclusion: Future trials are still needed. Indeed, opioid antagonists effectiveness has been investigated in only a limited number of patients, clinical trials do not reflect the heterogeneity of GD and there is little knowledge of the predictive factors of response to treatments. Moreover, differential affinity to nalmefene for kappa receptors may be associated with a particular effect in a yet to be defined addiction phenotype. Head to head comparisons between naltrexone and nalmefene would be helpful in combining other medication or psychotherapy. The identification of subgroups of patients that are more likely to benefit from opioid antagonists should be a goal

Effects of Local Opioid Antagonist on Diabetic Fracture Rat Model

Category: Diabetes Introduction/Purpose: Complications associated with the diabetes include increased incidence of fracture healing, delayed fracture healing, delayed osteoblasts cell replication, decreased angiogenesis, migration and/or osteoblast cell differentiation. The cellular events involved in bone healing are adversely affected by diabetes; however, can be modulated by the Opioid Growth Factor (OGF)–OGF receptor (OGFr) is an inhibitory peptide that downregulates DNA synthesis in a tissue nonspecific manner. Diabetes is associated with elevated serum levels of OGF and dysregulation of the OGFr leading to multiple complications related to healing, sensitivity, and regeneration. This study explores the presence and function of the OGF-OGFr axis in bone tissue from type 1 diabetic rats examining intact and fractured femurs during early phases of the repair process Methods: Seven-week-old Sprague Dawley rats were injected with streptozotocin (40mg/kg i.p.) to induce T1D; other rats received buffer only and served as controls. After one month, hyperglycemia rats underwent surgery to produce a fracture at the distal third of the femur. Four diabetic rats received opioid antagoinist (naltrexone) and calcium sulfate and all remaining rats received calcium sulfate with water only. X-rays were taken immediately after surgery and after rats were euthanized on post-surgery; femur and tibia were collected for protein isolation, western blot analysis along with frozen or paraffin-embedded for histological analysis Results: Immunofluorescence indicated approximately 90% increase in opioid growth factor receptor expression in diabetic femurs compared to age-matched normal femurs. Western Blotting also suggested an increase in the receptor protein in diabetic bones relative to normal bone. TRAP staining for osteoclasts was greater in control and opioid antagonist-treated diabetic fractures when compared to the number of osteoclasts in vehicle-treated diabetic fractured femurs. Safranin O stained sections revealed approximately more bone in opioid growth receptor antagonist-treated diabetic bone fractures than in vehicle-treated bone fractures Conclusion: These data support our hypothesis that expression levels of OGFr are dysregulated in the bone of diabetic patients leading to complications in bone healing. Moreover, modulation of the OGF-OGFr pathway with receptor antagonists restored some aspects of bone healing. With further study, these preliminary results support the role of the OGF-OGFr axis in treatment of diabetic bone healing. New therapies to target dysregulation of the OGF-OGFr regulatory pathway in diabetes would provide a safe and effective disease-modifying treatment for delayed bone healing.

Effects of Chronic, Intermittent Sucrose Consumption on the Discriminative Stimulus Effects of Dopamine or Opioid Antagonists

Chronic, intermittent sucrose access has been shown to induce neurochemical changes in the brain, including increasing the levels of dopamine and D3‐receptor mRNA, decreasing the levels of D2‐receptor mRNA, and increasing μ‐opioid receptor binding. We wondered if chronic, intermittent sucrose consumption would alter the ability of rats to discriminate drugs that affect endorphin and dopamine functioning. We successfully trained rats with chronic, intermittent sucrose access to discriminate various naltrexone training doses (ranging from 0.32 – 3.2 mg/kg) from saline. In the present series of studies, we sought to determine if chronic, intermittent sucrose consumption alters the ability of haloperidol to serve as a discriminative stimulus. Sprague‐Dawley rats were trained to discriminate between haloperidol [0.018–0.56 mg/kg, 30 min pretreatment (PT)] and vehicle in a two‐lever, operant choice procedure. Most subjects reached the discrimination criteria (80% or greater condition‐appropriate responding for 8 of 10 consecutive sessions). Among subjects that acquired the discrimination, there were no significant differences in acquisition between subjects with chronic, intermittent sucrose access and subjects with 24‐hr water access. Haloperidol (0.032 – 0.056 mg/kg) produced significant rate suppression. Increasing the PT to 60 minutes increased rates of lever pressing and reinforcers earned, but did not alter haloperidol generalization functions. Taken together, chronic sucrose consumption enhanced naltrexone's ability to function as a discriminative stimulus, but did not affect the discriminative stimulus effects of haloperidol.Support or Funding InformationUniversity of Wisconsin‐Eau Claire Office of Research and Sponsored ProgramsThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The effects of recurrent hypoglycaemia and opioid antagonists on the adrenal catecholamine synthetic capacity in a rat model of HAAF.

In this study, we investigated the effects of recurrent hypoglycaemia on the adrenal catecholamine synthetic enzymes in a rat model of hypoglycaemia-associated autonomic failure (HAAF). We found that plasma adrenaline was significantly reduced by about 50% in response to recurrent hypoglycaemia versus single hypoglycaemia. However, tyrosine hydroxylase (TH) protein and phosphorylation at Ser31 and Ser40 were increased in HAAF; similarly, aromatic aminoacid decarboxylase protein was also increased indicating a likely increase in catecholamine synthesis in the adrenal gland. Opioid antagonists, naloxone and methylnaltrexone did not restore plasma adrenaline in HAAF; however, naloxone increased TH phosphorylation at Ser31 and Ser40.

Profiling molecular factors associated with pyknosis and developmental arrest induced by an opioid receptor antagonist and dihydroartemisinin in Plasmodium falciparum.

Malaria continues to be a devastating disease, largely caused by Plasmodium falciparum infection. We investigated the effects of opioid and cannabinoid receptor antagonists on the growth of intraerythrocytic P. falciparum. The delta opioid receptor antagonist 7-benzylidenenaltrexone (BNTX) and the cannabinoid receptor antagonists rimonaband and SR144528 caused growth arrest of the parasite. Notably BNTX and the established antimalarial drug dihydroartemisinin induced prominent pyknosis in parasite cells after a short period of incubation. We compared genome-wide transcriptome profiles in P. falciparum with different degrees of pyknosis in response to drug treatment, and identified 11 transcripts potentially associated with the evoking of pyknosis, of which three, including glutathione reductase (PfGR), triose phosphate transporter (PfoTPT), and a conserved Plasmodium membrane protein, showed markedly different gene expression levels in accordance with the degree of pyknosis. Furthermore, the use of specific inhibitors confirmed PfGR but not PfoTPT as a possible factor contributing to the development of pyknosis. A reduction in total glutathione levels was also detected in association with increased pyknosis. These results further our understanding of the mechanisms responsible for P. falciparum development and the antimalarial activity of dihydroartemisinin, and provide useful information for the development of novel antimalarial agents.

Effect of Topical Opioid Antagonist on Diabetic Wound Healing in Rat Model

Category: Basic Sciences/Biologics, Diabetes Introduction/Purpose: Approximately 50% of the 170 million people worldwide with diabetes experience complications associated with delayed cutaneous wound healing. The current widely used treatment for DFU is topical platelet-derived growth factor (PDGF); however, it has significant side-effects. Preclinical studies have shown that a small molecular weight opioid receptor antagonist, blocks the interactions between the growth inhibitory peptide Opioid Growth Factor (OGF) and its receptor OGFr and accelerates cell proliferation and enhances angiogenesis and wound closure. The hypothesis of this research is that the topical formulation of opioid receptor antagonist is an effective therapy for healing of cutaneous wounds in diabetic rats, with healing times comparable to the standard care and will promote enhanced cell replication and accelerated angiogenesis. Methods: Fourteen diabetic rats per group with four excisional cutaneous wounds were positioned dorsally on type 1 diabetic rats and randomly treated topically with an opioid receptor antagonist (0.03% Naltrexone), topical platelet derived growth factor (Regranex®), or placebo moisturizing cream alone. Wound closure, DNA synthesis (bromodeoxyuridine incorporation-BrdU labeling), and production of the cytokines PDGF and vascular endothelial growth factor (VEGF) were monitored. Results: Naltrexone and Regranex® treatment resulted in more than 65% closure on days 8 and 10 respectively. On day 12, only one Naltrexone- and two Regranex-treated wounds remained (~1%), whereas the control group had 50% visible wounds. DNA synthesis in Regranex® treated wounds was 21% in comparison to vehicle-treated wounds at 28%; Naltrexone-treated diabetic wounds had 42% BrdU labeling comparable to the normal vehicle treated wounds. Naltrexone treatment significantly increased cell replication in comparison to Regranex treatment and to vehicle-only treated wounds (p&lt;0.001). Tissue immunostained at 1, 2, and 4 days after surgery with anti-PDGF antibodies indicated that both Regranex® and Naltrexone increase PDGF+ labeling at 1 day, with Naltrexone treatment (but not Regranex®) continuing to enhance PDGF production at 4 days Conclusion: Topical opioid receptor antagonist has been shown to enhance wound healing by increasing cell replication, accelerating angiogenesis, and matrix formation and targets an underlying pathophysiology of diabetes and enhances cell replication at all stages of wound remodeling. Topical opioid receptor antagonist is safe and effectively targets the disease-modifying pathways in this comparison study of topical platelet derived growth factor for wound closure in Type 1 diabetic rats.These data suggest that blockade of the OGF-OGFr axis, utilizing 0.03% Naltrexone is a safe and effective alternative for treatment for diabetic wounds by targeting several phases of wound repair.

Opioid antagonists with minimal sedation for opioid withdrawal.

Managed withdrawal is a necessary step prior to drug-free treatment or as the endpoint of long-term substitution treatment. To assess the effects of opioid antagonists plus minimal sedation for opioid withdrawal. Comparators were placebo as well as more established approaches to detoxification, such as tapered doses of methadone, adrenergic agonists, buprenorphine and symptomatic medications. We updated our searches of the following databases to December 2016: CENTRAL, MEDLINE, Embase, PsycINFO and Web of Science. We also searched two trials registers and checked the reference lists of included studies for further references to relevant studies. We included randomised and quasi-randomised controlled clinical trials along with prospective controlled cohort studies comparing opioid antagonists plus minimal sedation versus other approaches or different opioid antagonist regimens for withdrawal in opioid-dependent participants. We used standard methodological procedures expected by Cochrane. Ten studies (6 randomised controlled trials and 4 prospective cohort studies, involving 955 participants) met the inclusion criteria for the review. We considered 7 of the 10 studies to be at high risk of bias in at least one of the domains we assessed.Nine studies compared an opioid antagonist-adrenergic agonist combination versus a treatment regimen based primarily on an alpha2-adrenergic agonist (clonidine or lofexidine). Other comparisons (placebo, tapered doses of methadone, buprenorphine) made by included studies were too diverse for any meaningful analysis. This review therefore focuses on the nine studies comparing an opioid antagonist (naltrexone or naloxone) plus clonidine or lofexidine versus treatment primarily based on clonidine or lofexidine.Five studies took place in an inpatient setting, two studies were in outpatients with day care, two used day care only for the first day of opioid antagonist administration, and one study described the setting as outpatient without indicating the level of care provided.The included studies were heterogeneous in terms of the type of opioid antagonist treatment regimen, the comparator, the outcome measures assessed, and the means of assessing outcomes. As a result, the validity of any estimates of overall effect is doubtful, therefore we did not calculate pooled results for any of the analyses.The quality of the evidence for treatment with an opioid antagonist-adrenergic agonist combination versus an alpha2-adrenergic agonist is very low. Two studies reported data on peak withdrawal severity, and four studies reported data on the average severity over the period of withdrawal. Peak withdrawal induced by opioid antagonists in combination with an adrenergic agonist appears to be more severe than withdrawal managed with clonidine or lofexidine alone, but the average severity over the withdrawal period is less. In some situations antagonist-induced withdrawal may be associated with significantly higher rates of treatment completion compared to withdrawal managed with adrenergic agonists. However, this result was not consistent across studies, and the extent of any benefit is highly uncertain.We could not extract any data on the occurrence of adverse events, but two studies reported delirium or confusion following the first dose of naltrexone. Delirium may be more likely with higher initial doses and with naltrexone rather than naloxone (which has a shorter half-life), but we could not confirm this from the available evidence.Insufficient data were available to make any conclusions on the best duration of treatment. Using opioid antagonists plus alpha2-adrenergic agonists is a feasible approach for managing opioid withdrawal. However, it is unclear whether this approach reduces the duration of withdrawal or facilitates transfer to naltrexone treatment to a greater extent than withdrawal managed primarily with an adrenergic agonist.A high level of monitoring and support is desirable for several hours following administration of opioid antagonists because of the possibility of vomiting, diarrhoea and delirium.Using opioid antagonists to induce and accelerate opioid withdrawal is not currently an active area of research or clinical practice, and the research community should give greater priority to investigating approaches, such as those based on buprenorphine, that facilitate the transition to sustained-release preparations of naltrexone.