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Many patients with chronic pain conditions suffer from depression. The mechanisms underlying pain-induced depression are still unclear. There are critical links of medial prefrontal cortex (mPFC) synaptic function to depression, with signaling through the endocannabinoid (eCB) system as an important contributor. We hypothesized that afferent noxious inputs after injury compromise activity-dependent eCB signaling in the mPFC, resulting in depression. Depression-like behaviors were tested in male and female rats with traumatic neuropathy [spared nerve injury (SNI)], and neuronal activity in the mPFC was monitored using the immediate early gene c-fos and in vivo electrophysiological recordings. mPFC eCB Concentrations were determined using mass spectrometry, and behavioral and electrophysiological experiments were used to evaluate the role of alterations in eCB signaling in depression after pain. SNI-induced pain induced the development of depression phenotypes in both male and female rats. Pyramidal neurons in mPFC showed increased excitability followed by reduced excitability in the onset and prolonged phases of pain, respectively. Concentrations of the eCBs, 2-arachidonoylglycerol (2-AG) in the mPFC, were elevated initially after SNI, and our results indicate that this resulted in a loss of CB1R function on GABAergic interneurons in the mPFC. These data suggest that excessive release of 2-AG as a result of noxious stimuli triggers use-dependent loss of function of eCB signaling leading to excessive GABA release in the mPFC, with the final result being behavioral depression. SIGNIFICANCE STATEMENT Pain has both somatosensory and affective components, so the complexity of mechanisms underlying chronic pain is best represented by a biopsychosocial model that includes widespread CNS dysfunction. Many patients with chronic pain conditions develop depression. The mechanism by which pain causes depression is unclear. Although manipulation of the eCB signaling system as an avenue for providing analgesia per se has not shown much promise in previous studies. An important limitation of past research has been inadequate consideration of the dynamic nature of the connection between pain and depression as they develop. Here, we show that activity-dependent synthesis of eCBs during the initial onset of persistent pain is the critical link leading to depression when pain is persistent.

A major hurdle preventing effective interventions for patients with mild traumatic brain injury (mTBI) is the lack of known mechanisms for the long-term cognitive impairment that follows mTBI. The closed head impact model of repeated engineered rotational acceleration (rCHIMERA), a non-surgical animal model of repeated mTBI (rmTBI), mimics key features of rmTBI in humans. Using the rCHIMERA in rats, this study was designed to characterize rmTBI-induced behavioral disruption, underlying electrophysiological changes in the medial prefrontal cortex (mPFC), and associated mitochondrial dysfunction. Rats received 6 closed-head impacts over 2 days at 2 Joules of energy. Behavioral testing included automated analysis of behavior in open field and home-cage environments, rotarod test for motor skills, novel object recognition, and fear conditioning. Following rmTBI, rats spent less time grooming and less time in the center of the open field arena. Rats in their home cage had reduced inactivity time 1 week after mTBI and increased exploration time 1 month after injury. Impaired associative fear learning and memory in fear conditioning test, and reduced short-term memory in novel object recognition test were found 4 weeks after rmTBI. Single-unit in vivo recordings showed increased neuronal activity in the mPFC after rmTBI, partially attributable to neuronal disinhibition from reduced inhibitory synaptic transmission, possibly secondary to impaired mitochondrial function. These findings help validate this rat rmTBI model as replicating clinical features, and point to impaired mitochondrial functions after injury as causing imbalanced synaptic transmission and consequent impaired long-term cognitive dysfunction.

Neonatal hypoxic-ischemic encephalopathy (HIE) causes serious neurological disability; there are, however, currently few promising therapies for it. We have recently shown that δ-opioid receptor (DOR) is neuroprotective by downregulating TNF-α. Since hypoxia-ischemia (HI) triggers a robust inflammatory response, which exacerbates HI brain damage, we investigated, in this study, whether DOR activation could regulate inflammatory cytokine expression, thereby playing a protective effect on the neonatal brain under HI. Twenty-five neonatal rats were randomly divided into five groups: (1) control (control); (2) HI; (3) HI with saline (HI + NS); (4) DOR activation with UFP-512 (a potent and specific DOR agonist) under HI conditions (HI + U); and (5) DOR inhibition using NT treatment under HI conditions (HI + NT). The rats were sacrificed by decapitation at 24 h after HI, and their brains were rapidly removed for measurements. The protein expression of TNF-α, IL-6, ICAM-1, IL-10, IL-18, NQO-1, Nrf-2, and HO-1 was measured using Western blot. In the hemispheres exposed to HI, DOR activation significantly decreased the expressions of TNF-α, IL-6, and ICAM-1 in the cortex, while it significantly increased IL-10 and had no effect on IL-18 in the same region. In contrast, DOR had no appreciable effect on inflammatory cytokine expression in non-cortical tissues including hippocampal, subcortical, and cerebellar tissues. Moreover, HI stress triggered an upregulation of Nrf-2 nuclear protein as well as some of its downstream anti-inflammatory genes such as HO-1 and NQO-1 in the cortex, while DOR activation further augmented such a protective reaction against HI injury. DOR plays an important role in protecting against HI by regulating the expression of inflammatory and anti-inflammatory cytokines in the cortex, which is likely mediated by the Nrf-2/HO-1/NQO-1 signaling.

Dorsal root ganglion field stimulation (GFS) relieves evoked and spontaneous neuropathic pain by use-dependent blockade of impulse trains through the sensory neuron T-junction, which becomes complete within less than 1 minute for C-type units, also with partial blockade of Aδ units. We used this tool in the spinal nerve ligation (SNL) rat model to selectively block sensory neuron spontaneous activity (SA) of axotomized neurons at the fifth lumbar (L5) level vs blockade of units at the L4 level that remain uninjured but exposed to inflammation. In vivo dorsal root single-unit recordings after SNL showed increased SA in L5 units but not L4 units. Ganglion field stimulation blocked this SA. Ganglion field stimulation delivered at the L5 dorsal root ganglion blocked mechanical hyperalgesia behavior, mechanical allodynia, and ongoing spontaneous pain indicated by conditioned place preference, whereas GFS at L4 blocked evoked pain behavior but not spontaneous pain. In vivo single-unit recordings of spinal cord dorsal horn (DH) wide-dynamic-range neurons showed elevated SA after SNL, which was reduced by GFS at the L5 level but not by GFS at the L4 level. In addition, L5 GFS, but not L4 GFS, increased mechanical threshold of DH units during cutaneous mechanical stimulation, while L5 GFS exceeded L4 GFS in reducing evoked firing rates. Our results indicate that SA in injured neurons supports increased firing of DH wide-dynamic-range neurons, contributing to hyperalgesia, allodynia, and ongoing pain. Ganglion field stimulation analgesic effects after nerve injury are at least partly attributable to blocking propagation of this SA.

Objectives Electrical stimulation of the dorsal root ganglion (DRG), referred to here as ganglionic field stimulation (GFS), is effective in reducing clinical pain, probably by interrupting transmission of afferent impulse trains on sensory neurons as they pass through the DRG. We therefore tested whether efferent impulse trains conveyed by sensory neurons, which contribute to neurogenic inflammation, may also be interrupted by GFS. Materials and Methods Collagen-induced arthritis, a model of clinical rheumatoid arthritis, was initiated in rats concurrently with the insertion of an electrode for GFS at the fourth lumbar DRG. Continuous GFS (20 Hz pulse rate, current at 80% of the motor threshold) was initiated 6 days later and continued for 14 days. Plantar pain sensitivity, ankle arthritis score, and dimensions of the foot and ankle were determined one hour after termination of GFS. Results The foot/ankle contralateral to GFS developed hypersensitivity to threshold and noxious mechanical stimulation, swelling, and high arthritis score, all of which were normalized in the foot/ankle ipsilateral with GFS. Histology showed GFS limited joint destruction. Electrophysiological recording showed GFS can block efferent impulse trains. Conclusions Our findings show that GFS can reduce neurogenic inflammation and the resulting joint damage in a model of rheumatoid arthritis, probably by blocking the transit of impulse trains through the DRG. GFS may have clinical utility in limiting joint destruction in inflammatory arthritis such as rheumatoid arthritis.

Background: Hypoxic/ischemic injury to the heart is a frequently encountered clinical problem with limited therapeutic options. Since microRNAs (miRNAs) are involved in hypoxic/ischemic events, and δ-opioid receptor (DOR) activation is known to protect against hypoxic/ischemic injury, we speculated on the involvement of DOR activation in altering miRNA expression in the heart under hypoxic conditions. The present study aimed to test our hypothesis. Methods: Male Sprague Dawley rats were exposed to hypoxia (9.5-10% O2) for 1, 5, or 10 days with or without DOR activation. The target miRNAs were selected from TaqMan low-density array (TLDA) data and were further analyzed by quantitative real-time PCR. Results: We found that: 1) hypoxia alters the miRNA expression profiles depending on the hypoxic duration; 2) DOR activation shifts miRNA expression profiles in normoxic conditions and upregulates miR-128a-3p, miR-134-5p, miR-135a, miR-193a-3p, miR-196a, miR-324-3p, and miR-338; and 3) DOR activation modifies hypoxia-induced changes in miRNA expression and increases the levels of miR-128a-3p, miR-134-5p, miR-135a, miR-193a-3p, miR-196a, miR-324-3p, miR-141, miR-200b, and miR-324-3p. For example, miR-196c-5p decreased by 50% while miR-135a-5p increased 2.9 fold after 10 days under hypoxic conditions. Moreover, DOR activation further strengthened the hypoxia-induced increase of the levels of miR-7a-5p. When DOR was activated using UFP-512, the level of miR-107-3p significantly increased 1 day after the administration of UFP-512, but gradually decreased back to normal under normoxia. Conclusion: Hypoxia significantly modifies the miRNA profile in the heart, which can be mimicked or modified by DOR activation. Defining the targeted pathways that regulate the diverse cellular and molecular functions of miRNAs may provide new insights into potential therapies for hypoxic/ischemic injury of the heart.

Perinatal hypoxic-ischemic (HI) brain injury results in death or profound long-term neurologic disability in both children and adults. However, there is no effective pharmacological therapy due to a poor understanding of HI events, especially the initial triggers for hypoxic-ischemic injury such as disrupted ionic homeostasis and the lack of effective intervention strategy. In the present study, we showed that neonatal brains undergo a developmental increase in the disruption of K+ homeostasis during simulated ischemia, oxygen-glucose deprivation (OGD) and neonatal HI cortex has a triple phasic response (earlier attenuation, later enhancement, and then recovery) of disrupted K+ homeostasis to OGD. This response partially involves the activity of the δ-opioid receptor (DOR) since the earlier attenuation of ischemic disruption of K+ homeostasis could be blocked by DOR antagonism, while the later enhancement was reversed by DOR activation. Similar to DOR activation, acupuncture, a strategy to promote DOR activity, could partially reverse the later enhanced ischemic disruption of K+ homeostasis in the neonatal cortex. Since maintaining cellular K+ homeostasis and inhibiting excessive K+ fluxes in the early phase of hypoxic-ischemic insults may be of therapeutic benefit in the treatment of ischemic brain injury and related neurodegenerative conditions, and since many neurons and other cells can be rescued during the "window of opportunity" after HI insults, our first findings regarding the role of acupuncture and DOR in attenuating ischemic disruption of K+ homeostasis in the neonatal HI brain suggest a potential intervention therapy in the treatment of neonatal brain injury, especially hypoxic-ischemic encephalopathy.

Aim of review: δ-opioid receptor (DOR) is a member of opioid receptor superfamily, and is widely distributed throughout the central nervous system and plays diverse functions. Accumulated evidence has demonstrated that activation of DOR is neuroprotective against hypoxic/ischemic insults and DOR signaling may be one of the key factors determining neuronal survival during hypoxic/ischemic stress.Method: In this review, we summarized the research progress of DOR-mediated neuroprotection against hypoxic/ischemic injury, and then discussed the underlying mechanisms.Recent findings: We have made a special focus on DOR action against hypoxic/ischemic disruption of ionic homeostasis since it is an initial and key step in hypoxic/ischemic neuronal injury and death. DOR stabilization of ion homeostasis against hypoxic/ischemic stress involves multiple strategies such as ionic interplays, protein kinase mechanism, and decrease in excitability and excitatory transmission-associated ionic derangement.Summary: The findings of DOR stabilization of hypoxic/ischemic disruption of ionic homeostasis provide us a new concept of neuroprotection against neurological disorders and have potentially significant impacts on the prevention and treatment of some serious neurological conditions, such as stroke. Citation: Dongman Chao, Ying Xia. δ-opioid receptor induced neuroprotection against hypoxic/ischemic injury: regulation of ionic homeostasis. J Anesth Perioper Med 2015; 2: 325-35. doi: 10.24015/JAPM.2015.0043This is an open-access article, published by Evidence Based Communications (EBC). This work is licensed under the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium or format for any lawful purpose. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Epilepsy is one of the most common neurological disorders affecting about 1% of population. Although the precise mechanism of its pathophysiological changes in the brain is unknown, epilepsy has been recognized as a disorder of brain excitability characterized by recurrent unprovoked seizures that result from the abnormal, excessive, and synchronous activity of clusters of nerve cells in the brain. Currently available therapies, including medical, surgical, and other strategies, such as ketogenic diet and vagus nerve stimulation, are symptomatic with their own limitations and complications. Seeking new strategies to cure this serious disorder still poses a big challenge to the field of medicine. Our recent studies suggest that acupuncture may exert its antiepileptic effects by normalizing the disrupted neuronal and network excitability through several mechanisms, including lowering the overexcited neuronal activity, enhancing the inhibitory system, and attenuating the excitatory system in the brain via regulation of the interaction betweenδ-opioid receptors (DOR) and Na+channels. This paper reviews the progress in this field and summarizes new knowledge based on our work and those of others.

Hypoxia-ischemia (HI) insult induces inflammatory/oxidative injury and causes neurological disability and mortality. However, there are limited therapeutic options at present. Our recent studies have shown that the δ-opioid receptor (DOR) is neuroprotective against hypoxic-ischemic stress. In this work, we asked if DOR activation protects the brain against hypoxic-ischemic encephalopathy (HIE) by regulating inflammatory cytokines and Nrf-2, a basic leucine zipper protein that regulates the expression of antioxidant proteins. Our results showed that DOR activation with UFP-512 treatment significantly decreased TNF-α, IL-6, and ICAM-1 expression (P0.05). In the control group, no significant difference was detected after the vehicle treatment. Furthermore, we investigated the role of Nrf-2 in the DOR neuroprotection since our recent data suggest that DOR signaling promotes the expression and relocation of Nrf2 and thus induces cytoprotection. HI significantly increased nuclear Nrf-2 protein, while DOR activation by pretreatment with UFP-512 before HI further elevated the level of nuclear Nrf-2 protein by 70% (P This work was supported by NIH (AT-004422), Memorial Hermann’s Foundation and Vivian L Smith Neurologic Foundation. GD was supported by 973 Program (2012CB518502) and NSFC (81574053 & 81590953) of China.

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease resulting from the death of dopaminergic neurons in the substantia nigra pars compacta (SNc) which innervate all of the neuclei of the basal ganglia. Cell loss in the SNc causes a consequent striatal dopamine (DA) deficiency, leading to a cascade of functional changes in basal ganglia circuitry and ultimately the development of the cardinal features of PD, including resting tremor, bradykinesia, postural instability and rigidity, along with non-motor symptoms including cognitive, affective, psychiatric, and autonomic problems. DA replacement with the Levodopa (L-DOPA) is still a gold standard for symptomatic therapy of PD. However, the side effects of long-term use of L-DOPA are obvious. The emerging non-dopaminergic treatments for PD are becoming a scheduling program for the pipe-lines of drug development and clinical trials. The abundant expression of opioid receptors and their endogenous ligands, especially those for the δ-opioid system within the basal ganglia, has attracted much attention for its contribution to neurodegenerative diseases such as PD. In this article, we first discussed the relevant functional neuroanatomy and circuitry of the basal ganglia, and the evolving PD models of the basal ganglia. We then retrospected the studies on the location and expression of the δ-opioid system within the basal ganglia in health and PD, opioid-induced regulation of neurotransmitter release in basal ganglia, effects of pharmacological δ-opioid receptor (DOR) manipulation on PD and levodopa-induced dyskinesia (LID), and the effects of DOR activation on dopaminergic neuron injury/cellular model of PD. Based on these analyses, we believe that δ-opioid signaling is generally a beneficial, not detrimental factor for motor complications in PD. However, more in-depth investigations are expected to provide more solid and direct evidence for this benefit and to develop therapeutic strategies against PD by targeting δ-opioid system.

Epilepsy is one of the most common neurological disorders, affecting about 1 % of the population. Although the precise mechanism of its pathophysiological changes in the brain is unknown, epilepsy has been recognized as a disorder of brain excitability characterized by recurrent unprovoked seizures that result from the abnormal, excessive, and synchronous activity of clusters of nerve cells in the brain. Currently available therapies, including medical, surgical, and other strategies such as ketogenic diet and vagus nerve stimulation, are all used for the control of epileptic symptoms with their own limitations and complications. Seeking new strategies to cure this serious disorder still poses a big challenge in the field of medicine. Recent studies suggest that acupuncture may exert its antiepileptic effects by normalizing the disrupted neuronal and network excitability through several mechanisms, including lowering the overexcited neuronal activity, enhancing the inhibitory system, and attenuating the excitatory system in the brain via regulation of the interaction between δ-opioid receptors (DOR) and Na+ channels. This chapter reviews the progress in this field and summarizes new knowledge based on our work and the work of others.

Opioids and their analogues have been used as clinical analgesics for several centuries, with reports dating back to as early as 4000 B.C. Their anti-pain action is primarily accomplished through three major opioid receptor subtypes: μ-opioid receptor (MOR), δ-opioid receptor (DOR), and κ-opioid receptor (KOR). Although these opioid receptors have been cloned in many species, their complex functions, other than pain modulation, are still largely unknown in both physiological and pathophysiological conditions. However, recent studies have uncovered fresh insights into opioid receptor-mediated functions and their underlying mechanisms. Studies suggest that these opioid receptors participate in various physiological activities. Therefore, their dysfunction may play a role in numerous diseases, including hypoxic/ischemic injury in brain, epileptic seizures, Parkinson’s disease, Multiple Sclerosis, cardiovascular disease, respiratory depression, pulmonary artery hypertension, malignancies, diabetic cutaneous wounds, immune disease, chronic kidney disease, uremic pruritus, renal ischemia-reperfusion injury, and pre-eclampsia. There is also strong evidence showing that opioid receptors are involved in the regulation of stress, feeding and obesity, and play an essential role in hibernation in some species. One of the most exciting findings in the past decade is DOR-mediated neuroprotection and cardioprotection. The upregulation of DOR expression and activity increases the neuronal and myocardial tolerance to hypoxic and/or ischemic stress. The DOR signal triggers different mechanisms at multiple levels, depending on stress duration and severity, to preserve neuronal and myocardial survival, including the stabilization of homeostasis and increase in pro-survival signaling. DOR-mediated neuroprotection and cardioprotection may potentially influence clinical pharmacology in terms of prevention and treatment of life-threatening conditions like stroke and myocardial infarction. The main purpose of this chapter is to update recent research on opioids and their various functions, particularly in pathophysiological conditions. This chapter aims to deliver an informative reference for better understanding the opioid system from a/the pathophysiological point of view.

This study explored the association between cerebral metabolic rates of glucose (CMRGlc) and the severity of Vascular Parkinsonism (VP) and Parkinson's disease (PD). A cross-sectional study was performed to compare CMRGlc in normal subjects vs. VP and PD patients. Twelve normal subjects, 22 VP, and 11 PD patients were evaluated with the H&Y and MMSE, and underwent 18F-FDG measurements. Pearson's correlations were used to identify potential associations between the severity of VP/PD and CMRGlc. A pronounced reduction of CMRGlc in the frontal lobe and caudate putamen was detected in patients with VP and PD when compared with normal subjects. The VP patients displayed a slight CMRGlc decrease in the caudate putamen and frontal lobe in comparison with PD patients. These decreases in CMRGlc in the frontal lobe and caudate putamen were significantly correlated with the VP patients' H&Y, UPDRS II, UPDRS III, MMSE, cardiovascular, and attention/memory scores. Similarly, significant correlations were observed in patients with PD. This is the first clinical study finding strong evidence for an association between low cerebral glucose metabolism and the severity of VP and PD. Our findings suggest that these changes in glucose metabolism in the frontal lobe and caudate putamen may underlie the pathophysiological mechanisms of VP and PD. As the scramble to find imaging biomarkers or predictors of the disease intensifies, a better understanding of the roles of cerebral glucose metabolism may give us insight into the pathogenesis of VP and PD.

Cardiovascular disorders may cause hypoxic/ischemic injury to the cortex, leading to dysfunction of cortical cognition with a worse outcome in the older population. Although damage to cognitive cortex has been implicated in cognitive dysfunctions, the exact pathophysiology of a hypoxic/ischemic insult to this region is not well understood yet at the cellular and molecular levels. We used the whole-cell patch clamp in mouse slice preparations to characterize the basic electrophysiological properties of pyramidal cells of prefrontal cortex (PFC) and determine the response of these neurons to hypoxic stress in young adult (24±4 days old, n=7) and relatively older (42±12 days old, n=17) mice. In relatively older adult neurons (42±12 days old, n=17), the currents evoked by stepping from -140 mV to 20 mV (IV, holding at -60 mV) were shifted upward by hypoxic stress, indicating an increase in membrane conductance. Whole cell currents (holding at -60 mV) were found to decrease with a 3-min hypoxia, while increased with 5-min and 7-min hypoxia, suggesting that prolonged hypoxia increased open probability of ion channels. Resting membrane potential (MP) shifted upward in all three hypoxic conditions with a larger change seen with the longer duration of hypoxia. Action potentials (APs) showed the same tendency with 7-min hypoxia, showing a significant reduction in the number of hypoxia-stimulated pulses. However, all hypoxic conditions blocked the APs generation, suggesting hypoxic inhibition of neuronal excitability. In contrast, hypoxia-induced IV was apparently reversed in the younger neurons as compared to the older neurons, especially after 5 minutes of hypoxia (99.26 pA vs. -14.91 pA at -100 mV, P

Epilepsy is one of the commonest brain disorders characterized by recurrent unprovoked seizures that result from the abnormal, excessive, and synchronous activity of clusters of nerve cells in the brain. Epilepsy is very prevalent and has a high incidence. Intensive efforts have been made in the treatment for epilepsy, including medical, surgical, and other treatment strategies such as ketogenic diet and vagus nerve stimulation. However, these treatment options have their own limitations and complications. About one-third of patients show no response to pharmacological treatment. Concern regarding the adverse effects of these treatments has drawn people toward other therapies for treatment of epilepsy. Acupuncture, one of the popular therapeutic techniques in traditional Chinese medicine (TCM), has proven to be safe, efficient, and convenient with minimal side effects. Thus, it has gained popularity in treatment of various diseases, including epilepsy, in the West. However, due to the limited availability of high-quality research papers documented in English and a difference in the understanding of antiepileptic effects of acupuncture between the scientists of East and West, the application of acupuncture in the treatment of epilepsy is limited in Western community. In this chapter, we attempt to summarize the clinical observations on acupuncture in the treatment of epilepsy. Based on the underlying mechanisms of epilepsy and epileptogenesis, we have outlined the probable modes of action of acupuncture antiepilepsy in this chapter. Epileptic seizures and epileptogenesis are complex processes that result from changes in the excitability of neurons and involve synchronous discharges of a population of hyperexcitable neurons propagated through normal or pathological pathways. The increased excitability is ascribed to the changes that occur in both neurons and glial cells. In neurons, it is mainly due to (1) the innate ability of intrinsically bursting neurons in the cortex and hippocampus, (2) alterations in the membrane properties, (3) imbalance between excitatory and inhibitory transmission, and (4) alterations in existing synaptic contacts/circuits and/or establishment of new synaptic contacts/circuits. In glial cells, the most striking change is their impaired ability to maintain glutamate and K+ homeostasis. The most probable mechanism that underlies the antiepileptic effect of acupuncture is normalization of this disrupted neuronal excitability through multiple effects at different levels (from cells to molecules) with different time course (short term vs. long term) and during different stages of epilepsy (early/acute vs. later/chronic). These strategies include the modification of neuronal electrical activity and the activity of therapeutic network, the regulation of the activity of biomediators (e.g., amino acids, neuropeptides, monoamines, NO, Ca2+ and Ca2+-dependent activity, hormones, and humoral factors), the prevention from seizure-induced neuronal injury/loss and the subsequent aberrant neurogenesis and synaptic reorganization/dendritic remodeling in seizure-susceptible areas, and the regulation of ion channel activity.

The use of opioid analgesics has a long history in clinical settings, although the comprehensive action of opioid receptors is still less understood. Nonetheless, recent studies have generated fresh insights into opioid receptor-mediated functions and their underlying mechanisms. Three major opioid receptors (μ-opioid receptor, MOR; δ-opioid receptor, DOR; and κ-opioid receptor, KOR) have been cloned in many species. Each opioid receptor is functionally sub-classified into several pharmacological subtypes, although, specific gene corresponding each of these receptor subtypes is still unidentified as only a single gene has been isolated for each opioid receptor. In addition to pain modulation and addiction, opioid receptors are widely involved in various physiological and pathophysiological activities, including the regulation of membrane ionic homeostasis, cell proliferation, emotional response, epileptic seizures, immune function, feeding, obesity, respiratory and cardiovascular control as well as some neurodegenerative disorders. In some species, they play an essential role in hibernation. One of the most exciting findings of the past decade is the opioid-receptor, especially DOR, mediated neuroprotection and cardioprotection. The upregulation of DOR expression and DOR activation increase the neuronal tolerance to hypoxic/ischemic stress. The DOR signal triggers (depending on stress duration and severity) different mechanisms at multiple levels to preserve neuronal survival, including the stabilization of homeostasis and increased pro-survival signaling (e.g., PKC-ERK-Bcl 2) and antioxidative capacity. In the heart, PKC and KATP channels are involved in the opioid receptor-mediated cardioprotection. The DOR-mediated neuroprotection and cardioprotection have the potential to significantly alter the clinical pharmacology in terms of prevention and treatment of life-threatening conditions like stroke and myocardial infarction. The main purpose of this article is to review the recent work done on opioids and their receptor functions. It shall provide an informative reference for better understanding the opioid system and further elucidation of the opioid receptor function from a physiological and pharmacological point of view.