Release Of Endogenous Opioid Peptides Research Articles

Treatment of Knee Osteoarthritis with Transcutaneous Electrical Nerve Stimulation

In China, the majority of osteoarthritis patients have the disease in the knee. Clinically, knee osteoarthritis (KOA) often has joint swelling, pain, stiffness, dysfunction and other symptoms, which reduce the patients’ quality of life. There is a trend that osteoarthritis affects more and more young people in China, so it is much more important to treat KOA. Being a cheap and non-surgical option, the transcutaneous electrical nerve stimulation (TENS) has unique advantages in dealing with the pain caused by KOA. This article presents the pathogenesis and pain mechanism of KOA, describes the mechanism of TENS in KOA treatment, discusses the advantages and disadvantages, and proposes some combined treatment methods. Some studies have shown that the pathogenesis of KOA is related to the theory of unequal settlement of knee joints, and the pain comes from cartilage, subchondral bone and synovial membrane lesions. The gate control theory, endogenous opioid peptide release theory and diffuse noxious inhibitory controls theory are considered as the theoretical basis for TENS to inhibit pain. Its effectiveness, adaptability and incidence of adverse reactions are better than using drugs, but it cannot improve walking ability and the range of motion of the joints. Combination therapies of TENS are currently effective for treating KOA, including TENS combined with ultrasound, sodium hyaluronate, massage, functional training and other treatment options.

Research progress of neuroendocrine mechanism of acupuncture for dyspnea

The paper reviewed the relevant studies on dyspnea treated with acupuncture over the past 20 years, as well as the underlying neuroendocrine mechanism from the perspective of central and peripheral vagus nerves, neurotransmitter, respiratory muscle function and anti-depression-anxiety function. It revealed that the central response area was regulated by acupuncture in treatment of dyspnea, which is similar to the area affected in acupuncture analgesia. Additionally, acupuncture generates its therapeutic effects on dyspnea through promoting the release of endogenous opioid peptides and the regulation of autonomic nerve, amygdale and hypothalamic-pituitary-adrenal axis.

Aversive Stress Reduces Mu Opioid Receptor Expression in the Intercalated Nuclei of the Rat Amygdala.

The amygdala plays an important role in the integration of responses to noxious and fearful stimuli. Sensory information from many systems is integrated in the lateral and basolateral amygdala and transmitted to the central amygdala, the major output nucleus of the amygdala regulating both motor and emotional responses. The network of intercalated cells (ITC) which surrounds the lateral and basolateral amygdala and serves to modulate information flow from the lateral amygdala to the central nucleus, express a very high local concentration of mu-type opioid receptors. Loss of the ITC neurons impairs fear extinction. We demonstrate here that exposure of rats to a severe stress experience resulted in a marked downregulation of the level of expression of mu opioid receptors in the ITC nuclei over a period of at least 24h after the end of the stress exposure. The endogenous opioid dynorphin is also expressed in the central and ITC nuclei of the amygdala. Following stress exposure, we also observed an increase in the expression in the more lateral regions of the central amygdala of pro-dynorphin mRNA and a peptide product of pro-dynorphin with known affinity for mu opioid receptors. It is possible that the downregulation of mu receptors in ITC neurons after stress may result from sustained activation and internalization of mu receptors following a stress-induced increase in the release of endogenous opioid peptides.

Effects of acupuncture on plasma endogenous opioid peptides in patients with stroke-associated headache in convalescence

To observe the clinical effect of acupuncture on patients with stroke-related headache during convalescent and analyze its related factors. A total of 116 stroke-related headache patients admitted to the Acupuncture Department of Gongli Hospital of Pudong New Area, Shanghai, from October 2018 to December 2019 were divided into a treatment group and a control group according to a random number table, with 58 cases in each group. Patients in both groups were given conventional treatments for control of blood pressure, blood sugar, blood lipids and anticoagulation. At the same time, patients in the treatment group were treated with "nape seven needles" (acupuncture at Fengfu［GV16］, bilateral Fengchi［GB20］, bilateral Tianzhu［BL10］ and bilateral Wangu［GB12］)combined with penetration needling for 30 min; patients in the control group were treated with Flunarizine hydrochloride capsules (5 mg). Both interventions were conducted once daily for 4 weeks. The visual analogue scale(VAS) score and integrative sores of headache, and plasma serotonin (5-HT), dopamine (DA), substance P (SP), α-endorphin (α-EP), and β-endorphin (β-EP) levels before and after treatment were compared between the two groups. The total therapeutic effective rate of the two groups was calculated. There was no significant difference in VAS score, headache score, plasma 5-HT, DA, SP, α-EP, β-EP levels between the two groups before treatment (P>0.05). After treatment, both groups have significant decrease in the VAS score, integrative sores of headache, the plasma 5-HT, DA, SP levels (P<0.05), and significant increase in the plasma α-EP and β-EP levels (P<0.05). At the same time, the VAS score, integrative sores of headache, the plasma 5-HT, DA, SP levels of the treatment group were lower (P<0.05), and the plasma α-EP and β-EP levels were higher (P<0.05) than those in the control group. The total effective rate of the treatment group(51/58, 87.9%) was higher than that of the control group (42/58, 72.4%, P<0.05). Acupuncture therapy can increase the release of endogenous opioid peptide, reduce the secretion of 5-HT, DA, SP, and have a significant effect in treating stroke related headache.

Opioid-Mediated Modulation of Acid-Sensing Ion Channel Currents in Adult Rat Sensory Neurons.

Muscle ischemia, associated with peripheral artery disease (PAD), leads to the release of proinflammatory mediators that decrease extracellular pH and trigger the activation of proton-activated acid-sensing ion channels (ASIC). Claudication pain, linked with low blood flow, can be partially relieved by endogenous opioid peptide release. However, we previously reported that sustained ASIC currents in dorsal root ganglion (DRG) neurons were enhanced by naturally occurring endomorphin-1 and -2 opioid peptides, indicating a role of opioid involvement in hyperalgesia. The present study examined whether clinically employed synthetic (fentanyl, remifentanil) and the semisynthetic opioid (oxycodone) would also potentiate sustained ASIC currents, which arise from ASIC3 channel isoforms. Here, we show that exposure of each opioid to DRG neurons resulted in potentiation of the sustained ASIC currents. On the other hand, the potentiation was not observed in DRG neurons from ASIC3 knockout rats. Further, the enhancement of the ASIC currents was resistant to pertussis toxin treatment, suggesting that Gα i/Gα o G-proteins are not involved. Additionally, the potentiation of sustained ASIC currents was greater in DRG neurons isolated from rats with ligated femoral arteries (a model of PAD). The effect of all three opioids on the transient ASIC peak current was mixed (increase, decrease, no effect). The inhibitory action appears to be mediated by the presence of ASIC1 isoform, while the potentiating effect is primarily due to ASIC3 isoform expression. These findings reveal that, under certain conditions, these three opioids can increase ASIC channel activity, possibly giving rise to opioid-induced hyperalgesia.

Serotonin induces peripheral antinociception via the opioidergic system

PurposeStudies conducted since 1969 have shown that the release of serotonin (5-HT) in the dorsal horn of the spinal cord contributes to opioid analgesia. In the present study, the participation of the opioidergic system in antinociceptive effect serotonin at the peripheral level was examined. MethodsThe paw pressure test was used with mice (Swiss, males from 35 g) which had increased pain sensitivity by intraplantar injection of PGE2 (2 μg). Serotonin (250 ng), administered locally to the right paw of animals, produces antinociception in this model. ResultsThe selective antagonists for mu, delta and kappa opioid receptors, clocinnamox clocinnamox (40 μg), naltrindole (60 μg) and nor-binaltorfimina (200 μg), respectively, inhibited the antinociceptive effect induced by serotonin. Additionally, bestatin (400 μg), an inhibitor of enkephalinases that degrade peptides opioids, enhanced the antinociceptive effect induced by serotonin (low dose of 62.5 ng). ConclusionsThese results suggest that serotonin possibly induce peripheral antinociception through the release of endogenous opioid peptides, possible from immune cells or keratinocytes.

Propionic acid metabolism, ASD, and vitamin B12: Is there a role for environmental nitrous oxide?

Foley et al. (2014) published their findings in this journal on the role of prenatal exposure to propionic acid (PPA) and behavioral outcomes in treated rat pups. The authors show that PPA treated pups displayed subtle differences in behavior including nest seeking, novel object recognition, and locomotor activity. Others have previously proposed that PPA infusion in rat could represent a valid animal model of ASD since many of the diagnostic criteria for the disorder spectrum manifest under such conditions. A pathogenic makeover of gut microbiome to facilitate the growth of microbes capable of producing PPA, like Clostridia species, has been proposed as an infectious contributing etiology to the PPA model of ASD, however the reason for this pathogenic microbial overgrowth is not clear. This discussion highlights a previously identified novel environmental factor (i.e., nitrous oxide, N2O) in the etiopathogenesis of ASD and related neuropathology and posits that altered PPA metabolism in ASD may represent a key manifestation of this particular exposure. Trace environmental exposure to N2O may induce release of endogenous opioid peptides that have been shown to confer a virulence advantage to certain microbes, like Pseudomonas aeruginosa. Pathogenic overproduction of PPA in ASD may be a compensatory mechanism to curb this enhanced virulence potential. Therefore, future research on the PPA model of ASD should consider its role as a consequence of environmental exposure to N2O.

Imaging endogenous opioid peptide release with [11C]carfentanil and [3H]diprenorphine: influence of agonist-induced internalization.

Understanding the cellular processes underpinning the changes in binding observed during positron emission tomography neurotransmitter release studies may aid translation of these methodologies to other neurotransmitter systems. We compared the sensitivities of opioid receptor radioligands, carfentanil, and diprenorphine, to amphetamine-induced endogenous opioid peptide (EOP) release and methadone administration in the rat. We also investigated whether agonist-induced internalization was involved in reductions in observed binding using subcellular fractionation and confocal microscopy. After radioligand administration, significant reductions in [(11)C]carfentanil, but not [(3)H]diprenorphine, uptake were observed after methadone and amphetamine pretreatment. Subcellular fractionation and in vitro radioligand binding studies showed that amphetamine pretreatment only decreased total [(11)C]carfentanil binding. In vitro saturation binding studies conducted in buffers representative of the internalization pathway suggested that μ-receptors are significantly less able to bind the radioligands in endosomal compared with extracellular compartments. Finally, a significant increase in μ-receptor-early endosome co-localization in the hypothalamus was observed after amphetamine and methadone treatment using double-labeling confocal microscopy, with no changes in δ- or κ-receptor co-localization. These data indicate carfentanil may be superior to diprenorphine when imaging EOP release in vivo, and that alterations in the ability to bind internalized receptors may be a predictor of ligand sensitivity to endogenous neurotransmitter release.

Peripheral interactions between cannabinoid and opioid systems contribute to the antinociceptive effect of crotalphine.

Crotalphine is an antinociceptive peptide that, despite its opioid-like activity, does not induce some of the characteristic side effects of opioids, and its amino acid sequence has no homology to any known opioid peptide. Here, we evaluated the involvement of the peripheral cannabinoid system in the crotalphine effect and its interaction with the opioid system. Hyperalgesia was evaluated using the rat paw pressure test. Involvement of the cannabinoid system was determined using a selective cannabinoid receptor antagonist. Cannabinoid and opioid receptor activation were evaluated in paw slices by immunofluorescence assays using conformation state-sensitive antibodies. The release of endogenous opioid peptides from skin tissue was measured using a commercial enzyme immunoassay (EIA). Both p.o. (0.008-1.0 μg·kg(-1) ) and intraplantar (0.0006 μg per paw) administration of crotalphine induced antinociception in PGE2 -induced hyperalgesia. Antinociception by p.o. crotalphine (1 μg·kg(-1) ) was blocked by AM630 (50 μg per paw), a CB2 receptor antagonist, and by antiserum anti-dynorphin A (1 μg per paw). Immunoassay studies confirmed that crotalphine increased the activation of both κ-opioid (51.7%) and CB2 (28.5%) receptors in paw tissue. The local release of dynorphin A from paw skin was confirmed by in vitro EIA and blocked by AM630. Crotalphine-induced antinociception involves peripheral CB2 cannabinoid receptors and local release of dynorphin A, which is dependent on CB2 receptor activation. These results enhance our understanding of the mechanisms involved in the peripheral effect of crotalphine, as well as the interaction between the opioid and cannabinoid systems.

Sucrose-induced analgesia in mice: Role of nitric oxide and opioid receptor-mediated system

Background:The mechanism of action of sweet substance-induced analgesia is thought to involve activation of the endogenous opioid system. The nitric oxide (NO) pathway has a pivotal role in pain modulation of analgesic compounds such as opioids.Objectives:We investigated the role of NO and the opioid receptor-mediated system in the analgesic effect of sucrose ingestion in mice.Materials and Methods:We evaluated the effect of intraperitoneal administration of 10 mg/kg of NO synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME) and 20 mg/kg of opioid receptor antagonist, naltrexone on the tail flick response in sucrose ingesting mice.Results:Sucrose ingestion for 12 days induced a statistically significant increase in the latency of tail flick response which was unmodified by L-NAME, but partially inhibited by naltrexone administration.Conclusions:Sucrose-induced nociception may be explained by facilitating the release of endogenous opioid peptides. Contrary to some previously studied pain models, the NO/cyclic guanosine monophosphate (cGMP) pathway had no role in thermal hyperalgesia in our study. We recommend further studies on the involvement of NO in other animals and pain models.

OA08.02. Differential acute effects of real and sham acupuncture on mu-opioid receptor availability in treatment naive and conditioned chronic pain patients

Purpose Previous studies suggest acupuncture analgesic effects involve the release of endogenous opioid peptides. We have previously shown that while both acupuncture and sham reduced clinical pain in fibromyalgia (FM), only acupuncture increased mu-opioid receptor (MOR) baseline receptor availability in vivo (binding potential, BP). Here we investigated whether real and sham acupuncture were associated with differential changes in MOR BP in FM patients that were naive to acupuncture as compared to conditioned patients.

Is the hypothermic effect of alpha-methyldopa mediated by opioid peptides?

At an ambient temperature of 21 degrees C alpha-methyldopa (25-200 mg kg-1) induces a dose-dependent decrease in body temperature in rats. A relationship between adrenergic and opioid neuronal systems has been reported. Therefore, in this study the hypothesis that alpha-methyldopa produces hypothermia through release of endogenous opioid peptides has been investigated using the opiate antagonist naltrexone. The hypothermic effect of alpha-methyldopa is potentiated by naltrexone pointing to antagonism of an hyperthermic acting opioid system. However, at an ambient temperature of 6 degrees C, pretreatment with naltrexone did not significantly alter the hypothermic effect of alpha-methyldopa. Although the hypothesis proved not to be correct, it is concluded that depending on ambient temperature opioid peptides are involved in the determination of the ultimate effect of alpha-methyldopa on body temperature in rats.

Nitrous oxide-induced NO-dependent neuronal release of β-endorphin from the rat arcuate nucleus and periaqueductal gray

Nitrous oxide (N 2O)-induced antinociception is thought to result from nitric oxide (NO)-dependent neuronal release of endogenous opioid peptides in the central nervous system. The present study employed microdialysis to determine whether exposure to N 2O stimulates proopiomelanocortin (POMC) neurons to release β-endorphin in the arcuate nucleus (ARC) of the hypothalamus and the periaqueductal gray (PAG) of the midbrain. Male Sprague–Dawley rats were stereotaxically implanted with microdialysis probes in the ARC or PAG. Exposure to 70% N 2O significantly increased dialysate levels of oxidation products of NO as well as β-endorphin, compared to levels in fractions collected under room air. These increases in the ARC and PAG were abolished by systemic pretreatment with l-N G-nitro arginine methyl ester ( l-NAME). These findings suggest an association between increased NO activity and the stimulated release of β-endorphin during exposure of rats to N 2O.

Anesthesia Literature Review

Anesthesia Literature Review

Opioide und periphere Entzündungsmechanismen

For ages opioids were believed to act solely as central analgesic drugs. In the late 1980s studies began to show that opioids not only activate opioid receptors in the brain and spinal cord but also those on peripheral sensory neurons. Since then, a detailed model of opioid pathways outside the central nervous system has been developed. It provides insight into the effects of pathological tissue changes on the generation of pain, the local action of opioids on peripheral neurons, the production and release of endogenous opioid peptides in immune cells, as well as endogenous peripherally mediated analgesic and anti-inflammatory effects of opioids. Subsequent to this progress in basic research, peripheral opioid effects have made their way from the bench to the bedside. For example, current clinical guidelines recommend the intra-articular injection of morphine after knee joint surgery for effective postoperative pain control ( http://www.guidelines.gov ). Peripheral mechanisms of opioid analgesia provide a tempting approach to pain treatment avoiding the adverse effects of centrally acting opioids and offering anti-inflammatory action without the dreaded side effects of non-steroidal anti-inflammatory drugs (NSAIDs).

Nitrous oxide (laughing gas) inhalation as an alternative to electroconvulsive therapy

Electroconvulsive therapy (ECT) is used widely in the treatment of psychiatric conditions; however, its use is not without controversy with some recommending a moratorium on its clinical use. Complications and side effects of ECT include memory loss, injury, problems originating from sympathetic stimulation such as arrhythmias and myocardial ischemia and the risk of general anesthesia. Nitrous oxide (laughing gas) could potentially substitute for ECT as it shares some similar effects, has potential beneficial properties for these psychiatric patients and is relatively safe and easy to administer. Nitrous oxide induces laughter which has been described as nature's epileptoid catharsis which one might surmise would be beneficial for depression. It also produces a central sympathetic stimulation similar to ECT and causes release of endogenous opioid peptides, which are potential candidates for the development of antidepressant drugs. Nitrous oxide is also associated with seizure like activity itself. Administration of nitrous oxide as a substitute for ECT is eminently feasible and could be given in a series of treatments similar to ECT therapy.

Cocaine-induced mu opioid receptor occupancy within the striatum is mediated by dopamine D2 receptors

Previous studies by our laboratory have demonstrated that the mu opioid receptor antagonist, CTAP, blocks the rewarding effects of cocaine when it is injected directly into the nucleus accumbens or ventral tegmental area (VTA). This finding suggests that cocaine is causing the release of endogenous opioid peptides which activate mu opioid receptors within the nucleus accumbens and VTA. The purpose of the present study was to characterize the dose–response and time-course of mu receptor occupancy following systemic cocaine administration and to determine if release of endogenous opioids by cocaine is mediated by activation of D1 or D2 dopamine receptors. Quantitative in vitro receptor autoradiography was used to measure the regional displacement of 3H-DAMGO binding following cocaine administration. Adult male Sprague–Dawley rats were given intraperitoneal (i.p.) injections of cocaine and their brains were removed at various times and prepared for mu opioid receptor quantitation. To determine the role of dopamine D1 and D2 receptors in the effect of cocaine on mu receptor occupancy, rats were injected with the selective D1 or D2 receptor antagonists SCH23390 or eticlopride prior to cocaine. For all studies, 3H-DAMGO binding to mu opioid receptors was measured in the nucleus accumbens, caudate putamen, frontal cortex, olfactory tubercle and VTA. Results demonstrate that cocaine administration caused a time- and dose-dependent reduction in 3H-DAMGO binding within the nucleus accumbens core and shell. The reduction in mu receptor binding was attenuated by pretreatment with eticlopride. These results suggest that cocaine, acting via D2 dopamine receptors, can cause the release of an endogenous opioid peptide that binds to mu opioid receptors within the nucleus accumbens.

Human cholangiocarcinoma development is associated with dysregulation of opioidergic modulation of cholangiocyte growth

Incidence of cholangiocarcinoma is increasing worldwide, yet remaining highly aggressive and with poor prognosis. The mechanisms that drive cholangiocyte transition towards malignant phenotype are obscure. Cholangiocyte benign proliferation is subjected to a self-limiting mechanism based on the autocrine release of endogenous opioid peptides. Despite the presence of both, ligands interact with delta opioid receptor (OR), but not with microOR, with the consequent inhibition of cell growth. We aimed to verify whether cholangiocarcinoma growth is associated with failure of opioidergic regulation of growth control. We evaluated the effects of OR selective agonists on cholangiocarcinoma cell proliferation, migration and apoptosis. Intracellular signals were also characterised. Activation of microOR, but not deltaOR, increases cholangiocarcinoma cell growth. Such an effect is mediated by ERK1/2, PI3K and Ca(2+)-CamKIIalpha cascades, but not by cAMP/PKA and PKCalpha. microOR activation also enhances cholangiocarcinoma cell migration and reduces death by apoptosis. The anti-apoptotic effect of microOR was PI3K dependent. Our data indicate that cholangiocarcinoma growth is associated with altered opioidergic regulation of cholangiocyte biology, thus opening new scenarios for future surveillance or early diagnostic strategies for cholangiocarcinoma.

Effects of acute ethanol on opioid peptide release in the central amygdala: an in vivo microdialysis study

There is experimental evidence that indicates that the endogenous opioid system of the central nucleus of the amygdala (CeA) may mediate some of the reinforcing effects of ethanol. However, the precise interactions of ethanol with the endogenous opioid system at the level of the CeA have not been investigated. The aim of the current study was to investigate the hypothesis that acute systemic ethanol administration will increase the release of endogenous opioid peptides at the level of the CeA in a time- and dose-dependent manner. Rats were implanted with a unilateral guide cannula to aim microdialysis probes at the CeA. Intraperitoneal injections of saline and various doses of ethanol (0.8, 1.6, 2.0, 2.4, and 2.8 g ethanol/kg body weight) were administered to the rats. Dialysate samples were collected at 30-min intervals at distinct time points prior to and following treatment. Radioimmunoassays specific for beta-endorphin, met-enkephalin, and dynorphin A1-8 were used to determine the effect of ethanol on the content of the opioid peptides in the dialysate. We report that the 2.8-g/kg dose of ethanol induced a long-lasting increase in beta-endorphin release from 60 min onwards following administration and, later, an ongoing increase in dynorphin A1-8 release. None of the ethanol doses tested elicited significant changes in dialysate met-enkephalin content compared to the saline treatment. Acute systemic ethanol administration induced a dose- and time-dependent increase in beta-endorphin and dynorphin A1-8 release at the level of the CeA, which may be involved in ethanol consumption.

Electroacupuncture Effects in a Rat Model of Complete Freund’s Adjuvant-Induced Inflammatory Pain: Antinociceptive Effects Enhanced and Tolerance Development Accelerated

We have previously shown that electroacupuncture (EA) produced antinociception through the release of endogenous opioid peptides to activate opioid receptors during acute nociception. EA produced tolerance after its prolonged application. It has reported that 100 Hz EA could reduce mechanical hyperalgesia in complete Freund's adjuvant (CFA)-induced inflammatory nociception rats. The present study aims to investigate the antinociceptive effect of EA and the development of EA tolerance in chronic inflammatory nociception rats with CFA injection into the hind paw plantar. The results showed that the antinociceptive effect of 100 Hz EA was significantly enhanced in CFA-induced inflammatory nociception rats. Naloxone at 20 mg/kg could significantly block this antinociceptive effect. Chronic tolerance to EA was developed faster in CFA-induced inflammatory nociception rats than in normal rats. Therefore, 100 Hz EA could enhance antinociceptive effects and accelerate tolerance development in CFA-induced inflammatory nociception rats. The enhancement of EA antinociceptive effect in CFA-induced inflammatory nociception rats might involve the endogenous opioid peptides such as dynorphin.