Delta-opioid Receptor Agonist Research Articles

Levorphanol for Treatment of Intractable Neuropathic Pain in Cancer Patients.

Neuropathic pain in cancer patients is often difficult to treat, requiring a combination of several different pharmacological therapies. We describe two patients with complex neuropathic pain syndromes in the form of phantom limb pain and Brown-Sequard syndrome who did not respond to conventional treatments but responded dramatically to the addition of levorphanol. Levorphanol is a synthetic strong opioid that is a potent N-methyl-d-aspartate receptor antagonist, mu, kappa, and delta opioid receptor agonist, and reuptake inhibitor of serotonin and norepinephrine. It bypasses hepatic first-pass metabolism and thereby not subjected to numerous drug interactions. Levorphanol's unique profile makes it a potentially attractive opioid in cancer pain management.

Modulation of the central opioid system as an antidepressant target in rodent models.

There has been a resurgence in interest in the central opioid system as a target in the treatment of depression. Using a range of laboratory rodent tests, potential antidepressant properties have been most associated with kappa opioid receptor antagonists, delta opioid receptor agonists, and nociceptin/orphanin FQ receptor antagonists. Although most studies to date have assessed acute behavioral effects, more elaborate investigations have demonstrated activity following repeated administration. Concerns over adverse effects have meant that opioid candidates need to be examined for their abuse potential, locomotor stimulant, and other adverse effects that might reside by activating a certain receptor subtype. The interplay between the central opioid and monoaminergic systems has been established with many clinically used antidepressants exhibiting affinity for opioid receptors that could contribute to their therapeutic effect. Similarly currently marketed opioid drugs such as tramadol possess antidepressant properties. More recent investigations have begun to examine combining of opioid agents, conferring unique profiles. This approach acknowledges that targeting a single opioid receptor may not be sufficient to produce the balanced profile of therapeutic effects, while minimizing adverse effects. As these compounds begin to reach the clinical stage, hopefully they will represent an important addition to the armamentarium to treat depression.

SNC80 and naltrindole modulate voltage-dependent sodium, potassium and calcium channels via a putatively delta opioid receptor-independent mechanism.

SNC80 was designed as a highly selective nonpeptide delta opioid receptor (DOR) agonist. Antidepressant-like and antinociceptive effects of this compound were demonstrated in animal models. Naltrindole was synthetized as a highly selective DOR antagonist. Its antitussive and antinociceptive effects were reported. Observed effects of SNC80 and naltrindole may be accompanied by changes in neuronal excitability including modulation of voltage-dependent ion channels. We investigated possible DOR-independent modulation of neuronal sodium, calcium and potassium currents by both agents. NG108-15 cells lacking expression of DOR protein were used as model of neuronal cells. Cells were differentiated into neuronal phenotype by exposure to dibutyryl cyclic-AMP (dbcAMP). Lack of DORs expression in NG108-15 cells and the presence of DOR expression in brain and neuronal cultures were demonstrated by Western blot analysis. Both SNC80 and naltrindole exerted low to moderate modulatory effects on voltage-dependent ion currents. SNC80 weakly inhibited sodium current, potentiated calcium current, and did not act on potassium channels. Naltrindole inhibited sodium current, did not act on calcium current and inhibited potassium current at a high concentration. Such effects should be taken into account when these compounds are used for investigation of DOR-mediated signaling pathways.

DPI-289, a novel mixed delta opioid agonist / mu opioid antagonist (DAMA), has L-DOPA-sparing potential in Parkinson's disease.

L-DOPA-induced dyskinesia (LID) remains a significant problem in the management of Parkinson's disease (PD). In rodent and macaque models of PD, delta opioid receptor agonists have anti-parkinsonian actions while mu opioid antagonists can reduce the expression of LID. DPI-289 is a novel molecule with a unique combination of opioid receptor DAMA actions: delta agonist (Ki: 0.73 nM); mu antagonist (Ki: 12 nM). We demonstrated that DPI-289 has oral bioavailability and established its pharmacokinetic profile in both rat and primate. We hypothesised that these combined DAMA actions would provide an enhancement of L-DOPA effect without an associated increase in dyskinesia. In parkinsonian 6-OHDA lesioned rats and MPTP-lesioned macaques, DPI-289 provided anti-parkinsonian actions as monotherapy and an enhancement of L-DOPA benefit. Thus, acute administration of DPI-289 (3 mg/kg, p.o.) to 6-OHDA-lesioned rats produced a significant reduction in forelimb asymmetry (by 48%) that was maintained throughout the fifteen-day repeat-treatment period. Importantly, and in contrast to L-DOPA administration (6 mg/kg, i.p.), these benefits were not compromised by the development of abnormal involuntary movements. In the macaque, as monotherapy, DPI-289 (10 and 20 mg/kg) had significant, though incomplete, anti-parkinsonian actions lasting approximately 4 h. These benefits were not associated with dyskinesia. In fact, over the 6 h period of observation, DPI-289 (20 mg/kg) decreased parkinsonism by 19% and increased activity by 67% compared to vehicle treatment. By contrast, while high-dose L-DOPA (LDh) alone alleviated parkinsonism (for 3 h) this benefit was accompanied by significant dyskinesia that was disabling in nature. LDh provided a 50% reduction in parkinsonism over 6 h and 151% increase in activity. The combination of DPI-289 (20 mg/kg) and a low-dose of L-DOPA (LDl) provided anti-parkinsonian benefits greater than LDl alone without eliciting any significant dyskinesia. Treatment with LDl alone provided only transient statistically significant anti-parkinsonian benefit. However, the combination of LDl and DPI-289 reduced parkinsonism for 6 h (duration of monitoring), with parkinsonism being reduced by 35% and activity increased by 90% but with no increase in dyskinesia over that observed with LDl alone. Thus, DPI-289 has potential to improve the benefits of dopaminergic therapy in Parkinson's disease.

Effects of the delta opioid receptor agonist KNT-127 on electroencephalographic activity in mice.

We previously reported that the novel selective delta opioid receptor (DOP) agonist KNT-127 did not cause convulsions in mice, whereas the prototype DOP agonist SNC80 did. Previous studies have reported that SNC80 caused electroencephalographic (EEG) disturbances in rodents. However, whether KNT-127 affects EEG responses is unknown. Therefore, the present study aimed to compare the effect of KNT-127 on EEG responses with that of SNC80 in mice. For behavioral experiments, male C57BL6/J mice were injected intraperitoneally with either KNT-127 (30 mg/kg) or SNC80 (30 mg/kg) and monitored for convulsions and subsequent catalepsy-like behavior for 10 min immediately after drug treatment. For EEG recording experiments, EEG electrodes were implanted into the right hemisphere. EEG signals exceeding twice the baseline amplitude were defined as seizure spikes. KNT-127 did not induce convulsive or catalepsy-like behaviors in mice and did not result in seizure spikes, while significantly higher EEG power density was observed at 2 Hz. In contrast, SNC80 administration resulted in convulsive behaviors, seizure spikes, and significantly higher EEG power density between 2 and 10 Hz in mice. In this study, we clearly demonstrated that KNT-127 administration induces neither convulsive effects nor seizure spikes in mice. We propose that KNT-127 should be considered a candidate compound for the development of improved DOP-based psychotropic drug that lack the convulsive properties.

Stimulation of accumbal GABAA receptors inhibits delta2-, but not delta1-, opioid receptor-mediated dopamine efflux in the nucleus accumbens of freely moving rats

The nucleus accumbens contains delta-opioid receptors that may reduce inhibitory neurotransmission. Reduction in GABAA receptor-mediated inhibition of accumbal dopamine release due to delta-opioid receptor activation should be suppressed by stimulating accumbal GABAA receptors. As delta-opioid receptors are divided into delta2- and delta1-opioid receptors, we analysed the effects of the GABAA receptor agonist muscimol on delta2- and delta1-opioid receptor-mediated accumbal dopamine efflux in freely moving rats using in vivo microdialysis. Drugs were administered intracerebrally through the dialysis probe. Doses of compounds indicate total amount administered (mol) during 25–50min infusions. The delta2-opioid receptor agonist deltorphin II (25.0nmol)- and delta1-opioid receptor agonist DPDPE (5.0nmol)-induced increases in dopamine efflux were inhibited by the delta2-opioid receptor antagonist naltriben (1.5nmol) and the delta1-opioid receptor antagonist BNTX (150.0pmol), respectively. Muscimol (250.0pmol) inhibited deltorphin II (25.0nmol)-induced dopamine efflux. The GABAA receptor antagonist bicuculline (50.0pmol), which failed to affect deltorphin II (25.0nmol)-induced dopamine efflux, counteracted the inhibitory effect of muscimol on deltorphin II-induced dopamine efflux. Neither muscimol (250.0pmol) nor bicuculline (50.0 and 500.0pmol) altered DPDPE (5.0nmol)-induced dopamine efflux. The present results show that reduction in accumbal GABAA receptor-mediated inhibition of dopaminergic activity is necessary to produce delta2-opioid receptor-induced increase in accumbal dopamine efflux. This study indicates that activation of delta2- but not delta1-opioid receptors on the cell bodies and/or terminals of accumbal GABAergic interneurons inhibits GABA release and, accordingly, decreases GABAA receptor-mediated inhibition of dopaminergic terminals, resulting in enhanced accumbal dopamine efflux.

The delta opioid receptor agonist KNT-127 in the prelimbic medial prefrontal cortex attenuates veratrine-induced anxiety-like behaviors in mice

We previously reported that systemic administration of the selective delta opioid receptor (DOP) agonist KNT-127 produces potent anxiolytic-like effects in rats. Although a higher distribution pattern of DOPs was reported in the prelimbic medial prefrontal cortex (PL-PFC) of rodents, the role of DOPs in PL-PFC and in anxiolytic-like effects have not been well examined. Recently, we demonstrated that activation of PL-PFC with the sodium channel activator veratrine increases glutamatergic neurotransmission and produces anxiety-like behaviors in mice. Therefore, we investigated the effects of co-perfusion with KNT-127 in PL-PFC on veratrine-induced anxiety-like behaviors in mice. We also simultaneously measured extracellular glutamate and GABA levels. In addition, we assessed the effect of KNT-127 on the expression of c-Fos in sub-regions of the amygdala.Extracellular glutamate levels were measured in seven-week-old male C57BL/6N mice using an in vivo microdialysis-HPLC/ECD system, and behaviors were assessed simultaneously in an open field test. Basal levels of glutamate were measured by collecting samples every 10min for 60min. The drug-containing medium was perfused for 30min, and the open field test was performed during the last 10min of drug perfusion. After drug treatments, the perfusion was switched from drug-containing medium to control medium without drugs and samples were collected for another 90min.KNT-127 co-perfusion completely diminished veratrine-induced anxiety-like behaviors and attenuated the veratrine-induced increase in extracellular glutamate levels in PL-PFC. Interestingly, KNT-127 perfusion alone in PL-PFC did not affect anxiety-like behaviors. Local perfusion of veratrine in PL-PFC induced c-Fos immunoreactivity in sub-regions of amygdala. Co-perfusion of KNT-127 diminished c-Fos expression.Here we demonstrate that the DOP agonist KNT-127 in PL-PFC attenuates veratrine-induced anxiety-like behaviors in mice. These effects may be caused by the presynaptic suppression of activated glutamatergic transmission in PL-PFC, which projects to sub-regions of the amygdala. We propose that compounds like KNT-127, which inhibit glutamatergic transmission in PL-PFC, are candidates for novel anxiolytics.

Promising Therapeutic Agents: Delta Opioid Receptor Agonists

Adequate characterization of the endogenous opioid system’s peptides and receptors; in addition to, the development of highly selective ligands, have improved research approaches and understanding the roles of this system. Delta-Opioid Receptor (DOR) was found to exhibit distinctive pharmacological profile and tissue distribution compared to other opioid receptors. Hence, DOR has been extensively investigated in the last decade as a potential target in the treatment of various disorders. Research findings indicate high potential of DOR agonists in the modulation of brain as well as cardiovascular system functions. DOR activation was found to display cytoprotective effects against ischemia/reperfusion injury in neurons and cardiomyocytes. DOR affects cellular functions on the level of gene expression, ion channels, enzymatic activity and membrane-receptors functions through multiple signaling pathways and second messenger systems. Moreover, DOR has been implicated in mood disorders; in vivo administration of DOR agonists and enkephalinase inhibitors had significant anxiolytic and antidepressant effects. More recent research findings have shown consistent and statistically significant results on DOR activation beneficial effects in cardiac conditioning, neural ischemia protection, anxiety and depression management. Further advances in research would potentially reveal the exact molecular mechanisms underlying DOR functions in relation to receptor subtypes and signaling pathways.

Utilizing Delta Opioid Receptors and Peptides for Cytoprotection: Implications in Stroke and Other Neurological Disorders.

The opioid system has been elucidated as a potential target for therapy in a variety of neurological disorders including stroke. Delta opioid receptors have been revealed to pose an especially compelling biological function for new neuroprotective therapies. Two distinct therapeutic mechanisms have been characterized for delta opioid receptors, namely, these receptors aid in maintaining ionic homeostasis and initiate endogenous neuroprotective pathways. Specific agonists of delta opioid receptors, such as (D-Ala2, D-Leu5) enkephalin (DADLE), have displayed the ability to promote neuronal survival and mitigate apoptotic pathways. These findings have led to a significant amount of research on this molecule's potential as a neurotherapeutic. At the forefront of these efforts has been investigation into DADLE's ability to protect neurons and glial cells following ischemia. Additionally, current research is attempting to reveal the dynamic neuroprotective mechanisms that mediate DADLE's therapeutic benefits. This review article discusses the scientific evidence supporting the use of delta opioid family of receptors and ligands as a promising target for therapeutic intervention in neurological disorders, with emphasis on stroke.

Alterations in opioid inhibition cause widespread nociception but do not affect anxiety-like behavior in oral cancer mice

Widespread pain and anxiety are commonly reported in cancer patients. We hypothesize that cancer is accompanied by attenuation of endogenous opioid-mediated inhibition, which subsequently causes widespread pain and anxiety. To test this hypothesis we used a mouse model of oral squamous cell carcinoma (SCC) in the tongue. We found that mice with tongue SCC exhibited widespread nociceptive behaviors in addition to behaviors associated with local nociception that we reported previously. Tongue SCC mice exhibited a pattern of reduced opioid receptor expression in the spinal cord; intrathecal administration of respective mu (MOR), delta (DOR), and kappa (KOR) opioid receptor agonists reduced widespread nociception in mice, except for the fail flick assay following administration of the MOR agonist. We infer from these findings that opioid receptors contribute to widespread nociception in oral cancer mice. Despite significant nociception, mice with tongue SCC did not differ from sham mice in anxiety-like behaviors as measured by the open field assay and elevated maze. No significant differences in c-Fos staining were found in anxiety-associated brain regions in cancer relative to control mice. No correlation was found between nociceptive and anxiety-like behaviors. Moreover, opioid receptor agonists did not yield a statistically significant effect on behaviors measured in the open field and elevated maze in cancer mice. Lastly, we used an acute cancer pain model (injection of cancer supernatant into the mouse tongue) to test whether adaptation to chronic pain is responsible for the absence of greater anxiety-like behavior in cancer mice. No changes in anxiety-like behavior were observed in mice with acute cancer pain.

Delta opioid receptor agonist attenuates lipopolysaccharide-induced myocardial injury by regulating autophagy

BackgroundPrevious studies have described the protective effects of DADLE on myocardial injury in sepsis. Recently, autophagy has been shown to be an innate defense mechanism in sepsis-related myocardial injury. However, whether DADLE has an pro-autophagic effect is yet to be elucidated. The present study aimed to investigate the effect of DADLE on the regulation of autophagy during sepsis. MethodsMale mice were subjected to LPS or vehicle intraperitoneal injection. After LPS injection, mice received either DADLE, Naltrindole or vehicle. ELISA and JC-1 were used to evaluate the level cTnI and Mitochondrial membrane potential. Cardiac ultrastructural and autophagosomes were visualized by transmission electron microscopy. The relative protein levels were analyzed by Western blot. ResultsThe results showed that treatment with DADLE both immediately or 4 h after LPS intraperitoneal injection could improve the survival rate of mice with endotoxemic. DADLE could ease myocardium ultrastructure injury induced by LPS, this cardioprotective effect was also seen in increased MMP levels, and decreased cTnI levels. Through observation of transmission electron microscopy and Western blot we have discovered that the amount of autophagosome and the expression of autophagy related protein LC3II, Beclin1 were significantly increased with DADLE treatment. DADLE promoted LPS-induced autophagosome maturation as indicated by the increased LAMP-1 protein level and decreased SQSTM1/p62 protein level. The selective δ-opioid receptor antagonist Naltrindole play an opposite effects. ConclusionsDADLE could improve the survival and protect myocardial dysfunction in mice with LPS-induced endotoxemia. This effect was related to the increase of autophagy.

D-Alanine 2, Leucine 5 Enkephaline (DADLE)-mediated DOR activation augments human hUCB-BFs viability subjected to oxidative stress via attenuation of the UPR

Human mesenchymal stem cells (hMSCs) although being potent in repairing injured or ischemic tissues, their success regarding tissue-regenerative approaches are hindered by the paucity in their viability. The elevated levels of reactive oxygen species (ROS) in damaged sites provoke the pernicious effects of donor MSC survival. In the present study, the effect of delta-opioid receptor (DOR) activation on human umbilical cord-blood borne fibroblasts (hUCB-BFs) survival under oxidative stress (H2O2) was evaluated. Oxidative stress which is known to trigger pathological conditions of the unfolded protein response (UPR) leads to endoplasmic reticulum stress. Upon its activation by D-Alanine 2, Leucine 5 Enkephaline (DADLE, selective DOR agonist) in hUCB-BFs under oxidative stress, a significant down regulation (~2 folds) of key UPR genes was observed as determined by qPCR, Thioflavin-T protein aggregation assay and western blot analysis. Concomitantly, the oxidative stress-mediated cell-death was ameliorated and the viable-cells' percentage was enhanced following DOR activation. The intracellular ROS production upon H2O2 treatment as determined by CM-H2DCFDA staining was repressed, the anti-apoptotic marker Bcl-2 was upregulated along with a significant suppression in the expression levels of pro-apoptotic proteins Bax and Bad upon DOR activation. Upon subsequent treatment with naltrindole, the effects of DADLE-induced cytoprotection were reverted significantly. These results propound the role of DADLE-mediated DOR-activation on improvement of the viability, which might succour successful hUCB-BFs transplants and greatly absolve the inefficacy of tissue-specific engineered transplants.

Novel delta opioid receptor agonists with oxazatricyclodecane structure showing potent agonistic activities

We recently reported oxazatricyclodecane derivatives 1 as δ opioid receptor (DOR) agonists having a novel chemotype, but their DOR agonistic activities were relatively low. Based on the working hypothesis that the dioxamethylene moiety in 1 may be an accessory site and that it may interfere with the sufficient conformational change of the receptor required for exerting the full agonistic responses, we designed and synthesized new oxazatricyclodecane derivatives 2–4 lacking the dioxamethylene moiety. As we expected, the designed compounds 2–4 showed pronouncedly improved agonistic activities for the DOR. Compound 2a with the 17-cyclopropylmethyl substituent was a potent agonist with the highest selectivity for the DOR and was expected to be a lead compound for novel and selective DOR agonists.

Mu-opioid receptor and delta-opioid receptor differentially regulate microglial inflammatory response to control proopiomelanocortin neuronal apoptosis in the hypothalamus: effects of neonatal alcohol

BackgroundOpioid receptors are known to control neurotransmission of various peptidergic neurons, but their potential role in regulation of microglia and neuronal cell communications is unknown. We investigated the role of mu-opioid receptors (MOR) and delta-opioid receptors (DOR) on microglia in the regulation of apoptosis in proopiomelanocortin (POMC) neurons induced by neonatal ethanol in the hypothalamus.MethodsNeonatal rat pups were fed a milk formula containing ethanol or control diets between postnatal days 2–6. Some of the alcohol-fed rats additionally received pretreatment of a microglia activation blocker minocycline. Two hours after the last feeding, some of the pups were sacrificed and processed for histochemical detection of microglial cell functions or confocal microscopy for detection of cellular physical interaction or used for gene and protein expression analysis. The rest of the pups were dissected for microglia separation by differential gradient centrifugation and characterization by measuring production of various activation markers and cytokines. In addition, primary cultures of microglial cells were prepared using hypothalamic tissues of neonatal rats and used for determination of cytokine production/secretion and apoptotic activity of neurons.ResultsIn the hypothalamus, neonatal alcohol feeding elevated cytokine receptor levels, increased the number of microglial cells with amoeboid-type circularity, enhanced POMC and microglial cell physical interaction, and decreased POMC cell numbers. Minocycline reversed these cellular effects of alcohol. Alcohol feeding also increased levels of microglia MOR protein and pro-inflammatory signaling molecules in the hypothalamus, and MOR receptor antagonist naltrexone prevented these effects of alcohol. In primary cultures of hypothalamic microglia, both MOR agonist [D-Ala 2, N-MePhe 4, Gly-ol]-enkephalin (DAMGO) and ethanol increased microglial cellular levels and secretion of pro-inflammatory cell signaling proteins. However, a DOR agonist [D-Pen2,5]enkephalin (DPDPE) increased microglial secretion of anti-inflammatory cytokines and suppressed ethanol’s ability to increase microglial production of inflammatory signaling proteins and secretion of pro-inflammatory cytokines. In addition, MOR-activated inflammation promoted while DOR-suppressed inflammation inhibited the apoptotic effect of ethanol on POMC neurons.ConclusionsThese results suggest that ethanol’s neurotoxic action on POMC neurons results from MOR-activated neuroinflammatory signaling. Additionally, these results identify a protective effect of a DOR agonist against the pro-inflammatory and neurotoxic action of ethanol.

Delta Opioid Receptors and Modulation of Mood and Emotion.

Depression is a pervasive and debilitating mental disorder that is inadequately treated by current pharmacotherapies in a majority of patients. Although opioids have long been known to regulate mood states, the use of opioids to treat depression is rarely discussed. This chapter explores the preclinical and clinical evidence supporting the antidepressant-like effects of opioid ligands, and in particular, delta opioid receptor (DOR) agonists. DOR agonists have been shown to produce antidepressant-like effects in a number of animal models. Some DOR agonists also produce convulsions which has limited their clinical utility. However, DOR agonists that generate antidepressant-like effects without convulsions have recently been developed and these drugs are beginning to be evaluated in humans. Work investigating potential mechanisms of action for the antidepressant-like effects of DOR agonists is also explored. Understanding mechanisms that give rise to DOR-mediated behaviors is critical for the development of DOR drugs with improved safety and clinical utility, and future work should be devoted to elucidating these pathways.

The Delta Opioid Receptor in Pain Control.

Nowadays, the delta opioid receptor (DOPr) represents a promising target for the treatment of chronic pain and emotional disorders. Despite the fact that they produce limited antinociceptive effects in healthy animals and in most acute pain models, DOPr agonists have shown efficacy in various chronic pain models. In this chapter, we review the progresses that have been made over the last decades in understanding the role played by DOPr in the control of pain. More specifically, the distribution of DOPr within the central nervous system and along pain pathways is presented. We also summarize the literature supporting a role for DOPr in acute, tonic, and chronic pain models, as well as the mechanisms regulating its activity under specific conditions. Finally, novel compounds that have make their way to clinical trials are discussed.

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

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

Delta Opioid Receptor Expression and Function in Primary Afferent Somatosensory Neurons.

The functional diversity of primary afferent neurons of the dorsal root ganglia (DRG) generates a variety of qualitatively and quantitatively distinct somatosensory experiences, from shooting pain to pleasant touch. In recent years, the identification of dozens of genetic markers specifically expressed by subpopulations of DRG neurons has dramatically improved our understanding of this diversity and provided the tools to manipulate their activity and uncover their molecular identity and function. Opioid receptors have long been known to be expressed by discrete populations of DRG neurons, in which they regulate cell excitability and neurotransmitter release. We review recent insights into the identity of the DRG neurons that express the delta opioid receptor (DOR) and the ion channel mechanisms that DOR engages in these cells to regulate sensory input. We highlight recent findings derived from DORGFP reporter mice and from in situ hybridization and RNA sequencing studies in wild-type mice that revealed DOR presence in cutaneous mechanosensory afferents eliciting touch and implicated in tactile allodynia. Mechanistically, we describe how DOR modulates opening of voltage-gated calcium channels (VGCCs) to control glutamatergic neurotransmission between somatosensory neurons and postsynaptic neurons in the spinal cord dorsal horn. We additionally discuss other potential signaling mechanisms, including those involving potassium channels, which DOR may engage to fine tune somatosensation. We conclude by discussing how this knowledge may explain the analgesic properties of DOR agonists against mechanical pain and uncovers an unanticipated specialized function for DOR in cutaneous mechanosensation.

Effects of repeated treatment with a delta opioid receptor agonist KNT-127 on hyperemotionality in olfactory-bulbectomized rats

We previously demonstrated that a single treatment of a non-peptidic delta opioid receptor agonist, KNT-127, has an antidepressant-like effect in rodents in the forced swim test. Here we evaluated the effect of repeated administration of the potential antidepressant KNT-127 in an olfactory-bulbectomized (OBX) rat model. Male Wistar rats (8–12 weeks old) underwent olfactory bulbectomy. From 14days after surgery each was weighed and administered either KNT-127 (3mgkg−1/day), the selective serotonin reuptake inhibitor (SSRI) fluoxetine (10mgkg−1/day), or vehicle, daily for 14 days. Hyperemotionality was measured on days 3, 5, 7, 10, and 14. Repeated administration of KNT-127 significantly decreased total and individual hyperemotionality scores (attack, startle, struggle and fight) over the entire period. Conversely, fluoxetine did not show any significant effect on days 3, 5, 7, or 14 but significantly reduced the total score on day 10. The inhibitory effects of KNT-127 were greater than those of fluoxetine. The KNT-127 and control groups both gained weight, while the fluoxetine group lost weight. Our results suggest that KNT-127 is a potential lead compound for antidepressant therapy, with high efficacy, a relatively rapid onset of therapeutic effect, and without the possible adverse effects of weight loss caused by SSRIs.

The Delta-Opioid Receptor Agonist D-Ala2-D-Leu2-Enkephalin Enhances Hypoxic Depression of Excitatory Synaptic Transmission and Improves Recovery of Rat Cortical Neurons from Hypoxia in vitro

We investigated the influence of the delta-opioid receptor-preferring agonist D-Ala2-D-Leu2-enkephalin (DADLE) in vitro during long- and short-term hypoxia on the single cortical neuron membrane currents, the postsynaptic currents (PSCs), and the postsynaptic potentials (PSPs) in rats. Rat cortical pyramidal neurons showed 2 distinct and prognostically relevant responses to hypoxia. Type A neurons that responded to hypoxia by an inward current, followed by a steady outward current, were shown to recover during subsequent reoxygenation. In contrast, type B neurons that responded by a steady inward current, indicative of gradual anoxic depolarisation, suffered irreversible membrane dysfunction and did not recover completely during reoxygenation. Pre-treatment with 1 µmol/l DADLE attenuated the hypoxic inward current and favored complete recovery of holding current and input resistance during reoxygenation, even when neurons were challenged by a second exposure to hypoxia. DADLE enhanced the inhibitory effect of hypoxia on PSPs and PSCs. We assume that this neuroprotective effect is transmitted by the additive effects of DADLE on the hypoxic PSP/PSC suppression, thereby inhibiting presynaptic glutamate release.