Opioid Receptor Subtypes Research Articles

Effects of naloxone on opioid receptors in spinal cord dorsal horn of neuropathic pain rat models

Objective To investigate the effects of naloxone on the levels of opioid receptors in spinal cord dorsal horn of neuropathic pain rat models, established with chronic constriction injury(CCI). Methods Male SD rats (200-250 g) were subjected to CCI to establish neuropathic pain models. The rats were divided into 4 groups, and respectively received sham operation and saline treatment (Sham-S group, n=8), CCI and saline treatment (CCI-S group, n=8), CCI and naloxone treatment (CCI-N group, n=24), and CCI and morphine treatment (CCI-M group, n=8). Drug treatments (subcutaneous injection of normal saline, 10 mg·kg-1·d-1 naloxone, or 10 mg·kg-1·d-1 morphine in hindpaw) started from 7th day after surgery for 8 consecutive days. Paw withdrawal mechanical threshold (PWMT) and paw withdrawalthermal latency(PWTL) respectively were measured with von Frey tests and thermal plantar tests before and after CCI. Spinal cord dorsal horn at L3-L5 levels from naloxone-treated CCI rats were collected 10, 12, and 14 days after surgery, and western blot assay was employed to measure the levels of three opioid receptor subtypes. Results CCI rats exhibited ipsilateral hindpaw hyperalgesia, showing reduced PWMT and shortened PWTL (P 0.05) . Conclusions Naloxone, an opioid receptor antagonist, showed antinociceptive effects, similar to morphine, an opioid receptor agonist, on CCI neuropathic pain. This effect probably is relevant to naloxone-induced elevation of DOR in spinal cord dorsal horn. Key words: Naloxone; Neuropathic pain; Opioid receptors

Antinociceptive Activity of Methanolic Extract of Clinacanthus nutans Leaves: Possible Mechanisms of Action Involved.

Methanolic extract of Clinacanthus nutans Lindau leaves (MECN) has been proven to possess antinociceptive activity that works via the opioid and NO-dependent/cGMP-independent pathways. In the present study, we aimed to further determine the possible mechanisms of antinociception of MECN using various nociceptive assays. The antinociceptive activity of MECN was (i) tested against capsaicin-, glutamate-, phorbol 12-myristate 13-acetate-, bradykinin-induced nociception model; (ii) prechallenged against selective antagonist of opioid receptor subtypes (β-funaltrexamine, naltrindole, and nor-binaltorphimine); (iii) prechallenged against antagonist of nonopioid systems, namely, α2-noradrenergic (yohimbine), β-adrenergic (pindolol), adenosinergic (caffeine), dopaminergic (haloperidol), and cholinergic (atropine) receptors; (iv) prechallenged with inhibitors of various potassium channels (glibenclamide, apamin, charybdotoxin, and tetraethylammonium chloride). The results demonstrated that the orally administered MECN (100, 250, and 500 mg/kg) significantly (p < 0.05) reversed the nociceptive effect of all models in a dose-dependent manner. Moreover, the antinociceptive activity of 500 mg/kg MECN was significantly (p < 0.05) inhibited by (i) antagonists of μ-, δ-, and κ-opioid receptors; (ii) antagonists of α2-noradrenergic, β-adrenergic, adenosinergic, dopaminergic, and cholinergic receptors; and (iii) blockers of different K+ channels (voltage-activated-, Ca2+-activated, and ATP-sensitive-K+ channels, resp.). In conclusion, MECN-induced antinociception involves modulation of protein kinase C-, bradykinin-, TRVP1 receptors-, and glutamatergic-signaling pathways; opioidergic, α2-noradrenergic, β-adrenergic, adenosinergic, dopaminergic, and cholinergic receptors; and nonopioidergic receptors as well as the opening of various K+ channels. The antinociceptive activity could be associated with the presence of several flavonoid-based bioactive compounds and their synergistic action with nonvolatile bioactive compounds.

Role of dorsal hippocampus κ opioid receptors in contextual aversive memory consolidation in rats

The main κ opioid receptors (κORs) subtypes already described (κ1ORs and κ2ORs) are expressed in brain regions involved in aversive memory consolidation, including the dorsal hippocampus (DH). However, the role of DH κORs in consolidation of aversive memories with varied intensity and specificity is still uncertain. The present study aimed to investigate this question using pharmacological agents in rats subjected to a weak, moderate or strong contextual aversive conditioning (CAC) protocol. Antagonizing DH κORs with nor-binaltorphimine (nor-BNI), immediately after, but not 6 h later, a moderate CAC leads to intensified freezing behavior in the re-exposure to the paired context. Thus, indicating that DH κORs have an inhibitory role in the consolidation of an aversive memory. Increased DH κORs expression 1 h and 3 h after the moderate CAC was also observed. This up-regulation was absent in animals only exposed to the shock or to the context, indicating that this phenomenon requires a shock-context pairing to occur. Intra-DH nor-BNI infusion induced no changes following a weak CAC, but it was able to potentiate the expression of freezing behavior in novel and unpaired context after a strong CAC, indicating that DH κORs also modulate the consolidation of a more intense and generalized memory. Moreover, infusing the κ2ORs agonist GR 89696, but not the κ1ORs agonist U-69593, into the DH reduced the conditioned freezing expression. Nor-BNI pretreatment in a sub-effective dose prevented the κ2ORs agonist effects. Altogether, the present findings provide convergent evidence that κORs activation negatively modulates contextual aversive memory consolidation in rat dorsal hippocampus.

Noradrenaline induces peripheral antinociception by endogenous opioid release.

The aim of this study was to investigate this involvement in not inflammatory model of pain and which opioid receptor subtype mediates noradrenaline-induced peripheral antinociception. Noradrenaline is involved in the intrinsic control of pain-inducing pro-nociceptive effects in the primary afferent nociceptors. However, inflammation can induce various plastic changes in the central and peripheral noradrenergic system that, upon interaction with the immune system, may contribute, in part, to peripheral antinociception. Hyperalgesia was induced by intraplantar injection of prostaglandin E2 (PGE2, 2μg) into the plantar surface of the right hind paw and the paw pressure test to evaluated the hyperalgesia was used. Noradrenaline (NA) was administered locally into right hind paw of Wistar rat (160-200g) alone and after either agents, α2-adrenoceptor antagonist yohimbine, α1-adrenoceptor antagonist prazosin, β-adrenoceptor antagonist propranolol, μ-opioid antagonist clocinnamox, δ-opioid antagonist naltrindole and κ-opioid antagonist nor-binaltorfimina. In addition, the enkephalinase inhibitor bestatin was administered prior to NA low dose. Intraplantar injection of NA induced peripheral antinociception against hyperalgesia induced by PGE2. This effect was reversed, in dose dependent manner, by intraplantar injection of yohimbine, prazosin, propranolol, clocinnamox and naltrindole. However, injection of nor-binaltorfimina did not alter antinociception of NA after PGE2 hyperalgesia. Bestatin intensified the antinociceptive effects of low-dose of NA. Besides the α2-adrenoceptor, the present data provide evidence that, in absence of inflammation, NA activating α1 and β-adrenoceptor induce endogenous opioid release to produce peripheral antinociceptive effect by μ and δ opioid receptors.

Molecular Imaging of Opioid System in Idiopathic Parkinson's Disease.

Opioid receptors are localized throughout peripheral and central nervous system and interact with endogenous opioid peptides and drugs including heroin, synthetic opioids, and pain relievers (codeine, morphine). If several opioid PET tracers exist for preclinical studies, only a few have been used in human. Some tracers are selective for one subtype of opioid receptors (e.g., [11C]CAF (carfentanil) for μ receptor) while others are not ([11C]DPN (diprenorphine)). As shown by imaging studies, the opioid system is involved in pain processing, but also in addiction, neuropsychiatric manifestations (harm avoidance, sadness, novelty seeking behavior), feeding and food disorders and, finally, movement disorders and levodopa-induced dyskinesias. However, no imaging study has analyzed the potential dysfunction of opioid system in pain manifestations in Parkinson's disease. In addition, the involvement of opioid system in impulse control disorders and neuropsychiatric manifestations has never been studied in Parkinson's disease. Thus, there is an urgent need to understand the impact of opioid system dysfunctions in Parkinson's disease.

Probing ligand recognition of the opioid pan antagonist AT-076 at nociceptin, kappa, mu, and delta opioid receptors through structure-activity relationships

Few opioid ligands binding to the three classic opioid receptor subtypes, mu, kappa and delta, have high affinity at the fourth opioid receptor, the nociceptin/orphanin FQ receptor (NOP). We recently reported the discovery of AT-076 (1), (R)-7-hydroxy-N-((S)-1-(4-(3-hydroxyphenyl)piperidin-1-yl)-3-methylbutan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide, a pan antagonist with nanomolar affinity for all four subtypes. Since AT-076 binds with high affinity at all four subtypes, we conducted a structure-activity relationship (SAR) study to probe ligand recognition features important for pan opioid receptor activity, using chemical modifications of key pharmacophoric groups. SAR analysis of the resulting analogs suggests that for the NOP receptor, the entire AT-076 scaffold is crucial for high binding affinity, but the binding mode is likely different from that of NOP antagonists C-24 and SB-612111 bound in the NOP crystal structure. On the other hand, modifications of the 3-hydroxyphenyl pharmacophore, but not the 7-hydroxy Tic pharmacophore, are better tolerated at kappa and mu receptors and yield very high affinity multifunctional (e.g. 12) or highly selective (e.g. 16) kappa ligands. With the availability of the opioid receptor crystal structures, our SAR analysis of the common chemotype of AT-076 suggests rational approaches to modulate binding selectivity, enabling the design of multifunctional or selective opioid ligands from such scaffolds.

Activating mu-opioid receptors in the spinal cord mediates the cardioprotective effect of remote preconditioning of trauma.

Remote precoditioning of trauma (RPCT) confers cardioprotective effects against myocardial ischemia/reperfusion injury, which are mediated by spinal opioid receptors. The aim of this study was to identify the roles of opioid receptor subtypes in the cardioprotective effect of RPCT and possible mechanisms. In this study, 192 Sprague-Dawley rats were allocated to 12 groups. Except for the sham group, rats in all groups were subjected to myocardial ischemia reperfusion. Rats in the ischemia precondition (IPC) group were treated with IPC. In the RPCT groups, an abdominal incision was made 15 min before inducing ischemia. The selective delta-, kappa-, and mu-opioid receptor antagonists were administered to groups of animals receiving RPCT, respectively. Data were collected for myocardial infarct size, intercellular adhesion molecule 1 (ICAM-1), plasma cardiac troponin I (cTnI) concentrations, activation of protein kinase C epsilon (PKCe) in myocardial cell membranes, and adenosine release in the spinal cord. Compared with the control groups, infarct size, plasma concentrations of cTnI, and myocardial ICAM-1 expression were significantly lower, while adenosine release and PKCe activation were enhanced in the IPC and RPCT groups. Compared with the RPCT group, infarct size, plasma cTnI concentration, and myocardial ICAM-1 expression were greater and adenosine release and PKCe activation were reduced in the mu-opioid receptor antagonist plus RPCT group. The spinal mu-opioid receptor mediated the cardiac protective effect of RPCT. The mechanism may be enhanced by adenosine release in the spinal cord and PKCe activation in the myo-cardium, thereby inhibiting inflammation induced by ischemia/reperfusion injury.

Two delta opioid receptor subtypes are functional in single ventral tegmental area neurons, and can interact with the mu opioid receptor

The mu and delta opioid receptors (MOR and DOR) are highly homologous members of the opioid family of GPCRs. There is evidence that MOR and DOR interact, however the extent to which these interactions occur in vivo and affect synaptic function is unknown. There are two stable DOR subtypes: DPDPE sensitive (DOR1) and deltorphin II sensitive (DOR2); both agonists are blocked by DOR selective antagonists. Robust motivational effects are produced by local actions of both MOR and DOR ligands in the ventral tegmental area (VTA). Here we demonstrate that a majority of both dopaminergic and non-dopaminergic VTA neurons express combinations of functional DOR1, DOR2, and/or MOR, and that within a single VTA neuron, DOR1, DOR2, and MOR agonists can differentially couple to downstream signaling pathways. As reported for the MOR agonist DAMGO, DPDPE and deltorphin II produced either a predominant K+ dependent hyperpolarization or a Cav2.1 mediated depolarization in different neurons. In some neurons DPDPE and deltorphin II produced opposite responses. Excitation, inhibition, or no effect by DAMGO did not predict the response to DPDPE or deltorphin II, arguing against a MOR-DOR interaction generating DOR subtypes. However, in a subset of VTA neurons the DOR antagonist TIPP-Ψ augmented DAMGO responses; we also observed DPDPE or deltorphin II responses augmented by the MOR selective antagonist CTAP. These findings directly support the existence of two independent, stable forms of the DOR, and show that MOR and DOR can interact in some neurons to alter downstream signaling.

Effects of endogenous cardioprotective mechanisms on ischemia-reperfusion injury.

Ischemic heart disease have been remarked as a leading cause of morbidity and mortality in adults. Early restoration of cardiac perfusion is necessary to restore perfusion of ischemic heart muscle. Effective revascularization reduce mortality by limiting myocardial necrosis at the acute phase of the cardiac infarction. However, reperfusion may induce a cascade of pathophysiological reactions causing the increase of the infarct area of the myocardium This phenomenon known as ischemia-reperfusion injury is responsible for up to 50% of the final infarct size. Sequences of brief episodes of nonlethal ischemia and reperfusion applied before (preconditioning - IPC) or after (postconditioning - POC) the coronary occlusion are well documented to reduce the ischemiareperfusion injury. These phenomena improve cardiac function by mobilizing the molecular and cellular mechanisms limiting reperfusion injury. The mechanisms underlying IPC or POC are still not clarified, but strong experimental evidence suggests that opioids may be the part of the endogenous cardioprotective response to I/R injury. Stimulation of opioid receptors activates related to POC mechanisms affecting protection to the ischemic myocardium, while the use of non-selective opioid receptor antagonist - naloxone reduces this effect. There is no consensus that the subtype of opioid receptor is responsible for the protection of the human heart muscle. Morphine may reduce cardiac preload by peripheral vasodilatation. Numerous studies show a direct cardioprotective effect of the opioid pathway in ischemic conditions. Opioids act via membrane receptors: μ, δ, κ. The predominant subtype in the human cardiac cells are μ- and δ - opioid receptors. It has been hypothetized that opioid receptor activation exerts cardioprotection in human heart muscle pathway what may give insight into the explanation of the protective mechanisms in the acute myocardial infarction.

Effects of endogenous cardioprotective mechanisms on ischemia-reperfusion injury

Ischemic heart disease have been remarked as a leading cause of morbidity and mortality in adults. Early restoration of cardiac perfusion is necessary to restore perfusion of ischemic heart muscle. Effective revascularization reduce mortality by limiting myocardial necrosis at the acute phase of the cardiac infarction. However, reperfusion may induce a cascade of pathophysiological reactions causing the increase of the infarct area of the myocardium This phenomenon known as ischemia-reperfusion injury is responsible for up to 50% of the final infarct size. Sequences of brief episodes of nonlethal ischemia and reperfusion applied before (preconditioning — IPC) or after (postconditioning — POC) the coronary occlusion are well documented to reduce the ischemiareperfusion injury. These phenomena improve cardiac function by mobilizing the molecular and cellular mechanisms limiting reperfusion injury. The mechanisms underlying IPC or POC are still not clarified, but strong experimental evidence suggests that opioids may be the part of the endogenous cardioprotective response to I/R injury. Stimulation of opioid receptors activates related to POC mechanisms affecting protection to the ischemic myocardium, while the use of non-selective opioid receptor antagonist - naloxone reduces this effect. There is no consensus that the subtype of opioid receptor is responsible for the protection of the human heart muscle.Morphine may reduce cardiac preload by peripheral vasodilatation. Numerous studies show a direct cardioprotective effect of the opioid pathway in ischemic conditions. Opioids act via membrane receptors: μ, δ, κ. The predominant subtype in the human cardiac cells are μ- and δ – opioid receptors. It has been hypothetized that opioid receptor activation exerts cardioprotection in human heart muscle pathway what may give insight into the explanation of the protective mechanisms in the acute myocardial infarction.

Endogenous central amygdala mu-opioid receptor signaling promotes sodium appetite in mice

Due to the importance of dietary sodium and its paucity within many inland environments, terrestrial animals have evolved an instinctive sodium appetite that is commensurate with sodium deficiency. Despite a well-established role for central opioid signaling in sodium appetite, the endogenous influence of specific opioid receptor subtypes within distinct brain regions remains to be elucidated. Using selective pharmacological antagonists of opioid receptor subtypes, we reveal that endogenous mu-opioid receptor (MOR) signaling strongly drives sodium appetite in sodium-depleted mice, whereas a role for kappa (KOR) and delta (DOR) opioid receptor signaling was not detected, at least in sodium-depleted mice. Fos immunohistochemistry revealed discrete regions of the mouse brain displaying an increased number of activated neurons during sodium gratification: the rostral portion of the nucleus of the solitary tract (rNTS), the lateral parabrachial nucleus (LPB), and the central amygdala (CeA). The CeA was subsequently targeted with bilateral infusions of the MOR antagonist naloxonazine, which significantly reduced sodium appetite in mice. The CeA is therefore identified as a key node in the circuit that contributes to sodium appetite. Moreover, endogenous opioids, acting via MOR, within the CeA promote this form of appetitive behavior.

Abstract PR317

Background & Objectives: Our previous study showed that results showed that MBD1 knockout mice showed dramatically higher pain thresholds in Mechanical, Thermal, and Cold test in acute pain and SNL-pain models compared to wild-type mice. However, it remains unknown how MBD1 to regulate genesis of acute pain and chronic pain. This observation led us to hypothesize that MBD1 might regulate some related factors of pain. So, we first investigated both the mRNA and protein level of pain-related opioid receptors and potassium channels in the dorsal root ganglia, spinal cord and cortex, and determined whether MBD1 targeted tissue-specific subtypes of opioid receptors and/or potassium channels. Second, we used MBD1-AAV5 overexpression viral to treat those specific tissue sites and observed pain behavior and related expression of pain related mRNA and proteins. Finally, we determined whether MBD1 co-localization with opioid receptors or potassium channels gene in a single DRG cell or not. Materials & Methods: All experiments were carried out with the approval of the Animal Care Committee at Rutgers New Jersey Medical School. For detected opioid receptors or potassium channels mRNA, we used RT-qPCR to detect Oprm1, Oprk1, Oprd1, Kcna1 and Kcna2 mRNA gene expression and used western blot to detected mu, kappa, delta, Kv1.1 and Kv1.2 protein expression on the level of dorsal root ganglia, the spinal cord and cortex. For in vivo experiments, wild-type mice were microinjected with GFP-AAV5 viral (1 µl) or MBD1-AAV5 viral (1 µl) in DRG. CPP test was carried out to test the spontaneous pain behavior. Overexpression of MBD1 in wild-type mice induced spontaneous pain behavior after 6 weeks. On week 8, DRG was collected. For in vitro experiments, cultured DRG neurons were exposed to GFP or MBD1-AAV5 viral and proteins were assessed by Western blot. Single cell RT-PCR was carried out to test whether MBD1 co-localization with opioid receptors or potassium channels gene in a single DRG cell or not. Results: Oprm1, Oprk1, and Kcna2 mRNA gene expressed at high levels in DRG, spinal cord and cortex, but not midbrain. Interestingly, only mu opioid receptor and Kv1.2 receptor protein significantly increased in DRG, other proteins and sites were not altered. These increases were blocked by MBD1 over-expression in DRG, and MBD1 over-expression can cause spontaneous pain behavior. Furthermore, MBD1 overexpression in cultured DRG neurons down-regulate mu opioid receptor and Kv1.2 receptor protein expression. Single cell RT-PCR assay revealed that MBD1 co-localization with mu opioid receptor and Kv1.2 receptor gene in a single DRG cell. Conclusion: Our findings indicate that Expression of mu opioid receptor and Kv1.2 controlled by MBD1 in the dorsal root ganglion. Disclosure of Interest: None declared

Opioid system mediated anti-nociceptive effect of agomelatine in mice

AimsThis study was planned to examine the antinociceptive efficacy of agomelatine against acute mechanical, thermal, and chemical nociceptive stimuli, as well as to determine the opioid receptor subtypes mediating these effects. Main methodsTail-clip, hot-plate, and acetic acid-induced writhing tests were performed to evaluate anti-nociceptive effect. Besides, possible effect of agomelatine on the motor coordination of animals was assessed with a Rota-rod test. Key findingsAgomelatine (40mg/kg and 60mg/kg) significantly prolonged the reaction time of mice in both the tail-clip and hot-plate tests, suggesting the antinociceptive activity is related to both spinal and supraspinal mechanisms. This drug also reduced the number of writhing behaviors indicating the presence of a peripherally mediated antinociceptive effect. Rota-rod testing displayed no notable effect on the motor activity of the animal supporting the conclusion that the observed antinociceptive effect is specific. The agomelatine-induced antinociceptive activity abrogated following pretreatment with naloxone (a non-selective opioid receptor antagonist, 5.48mg/kg, i.p.), which suggested the participation of opioid mechanisms to the antinociception. The possible contribution of μ, δ and ҡ subtypes of opioid receptors to the anti-nociceptive effect were evaluated using naloxonazine (7mg/kg, s.c.), naltrindole (0.99mg/kg, i.p.), and nor-binaltorphimine (1.03mg/kg, i.p.), respectively. Pretreatments using these antagonists abolished the antinociceptive activity of agomelatine in all of the nociceptive test paradigms used, which pointed out that μ, δ, and ҡ opioid receptors participated to the action of agomelatine on pain. SignificanceThese results demonstrated the therapeutic potential of agomelatine in the treatment of pain disorders.

SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL PROPERTIES OF NEW CODEINE FE(III) COMPLEX

ABSTRACT The reaction of FeCl 3 hexahydrate with C 18 H 20 NO 3 .PO 4 in acetonitrile produced new complex with general formula [Fe(L)]Cl 2 , (L= codeine). Characterization of the ligand and its complex were made by elemental analysis, FT-IR, 1 H-NMR, Raman and UV–visible spectroscopy. This new complex showed antitumor activity against two kinds of cancer cell lines: AGS (Stomach) and MCF-7 (Breast). Cell cytotoxic effects of the ligand and its complex were assayed by MTT and Natural-red tests. The antibacterial activity of ligand and complex against Pseudomonas aeruginosa , Staphylococcus aureus , Streptococcus pyogenes and Escherichia coli were also examined. Keywords: Codeine; Fe(III) complex; Synthesis; Anti-tumor; AGS and MCF-7; Antibacterial. e-mail: mojdeh.golzani@gmail.com INTRODUCTION Natural products play an important role in diseases control and treatment. The plants extracts are used in the treatment of human diseases all the time. From the last century, a scientific interest for phototherapy increased in several medical fields such as immunology, hematology and oncology [1-5].Currently there are three major ways of treating cancer: radiation therapy, surgery and cytotoxic drugs. Application of plants in medicine has affected the identification of natural compounds such as cocaine, morphine, vinblastine, tax land codeine [5-8].Many different coordination compounds and the mechanism of cytotoxic action have been discussed with regard to the development of new antitumor agents [8-15]. Numerous medicinal plants have been screened extensively for their antimicrobial potential worldwide [1, 11]. Morphine and its derivatives have received considerable attention as narcotic and used in lenitive drudge products. Morphine plays an important role in the therapy of acute and chronic pain. Exogenously delivered morphine acts in the body by activating different subtypes of opioid receptors [14].Over the last decades, proposals have accumulated that morphine present in mammalian tissues and fluids comes not only from an exogenous or dietary origin, but may also be biosynthesized de novo. Latest studies have unequivocally proven the existence of a mammalian morphine biosynthetic pathway [15], which consists of at least 19 steps and is different in its primary steps from that occurring in plants [16]. Meanwhile the endogenous morphine biosynthesis takes place in mammals, their cells and tissues are constantly exposed to certain amounts of morphine and its precursors [17].Investigation of lithium effect in opioid receptors on inhibitory avoidance response in mice has been reported. The results suggest that the opioid receptors in the central nervous system may be involved in the retrieval of lithium state dependent learning [18]. The lithium efficacy in controlling behaviors related with dopamine stimulants and manic states has been proposed [19]. Thus, it may be suggested that lithium‘s action may be mediated through dopamine receptors [20].Furthermore interactions between lithium and opioids have been reported. There is evidence that lithium is able to affect some actions of morphine. In particular, it has been shown that lithium inhibits morphine withdrawal signs in morphine-dependent mice [21], reduces the self-stimulation facilitated by morphine and the expression of tolerance to morphine [22] and alters the morphine induced analgesia in mice [23]. Both drugs produce a conditioned taste avoidance response and suppress schedule-induced polydipsia [24]. Another morphine precursor codeine, which stands in the biosynthetic pathway after salutaridinol, had a higher partial agonist efficacy. Their metal chelates are of interest due to their fascinating chemistry as well as antimicrobial and anti-cancer activities. The other natural ligand from plants such as phenolic compound of mono and sesquiterpenoid, flavonoids also can be used in synthesis of metal complex [25].Codeine is generally named codeine phosphate (Cod.P), morphine-3-methyl ether phosphate, methyl-morphine phosphate, or morphine monomethyl ether phosphate. It takes the general formulae of C

The Role of the Opioid System of the Myocardium in Mediating the Cardioprotective Effect of Postconditioning

The involvement of endogenous myocardial opioid receptor agonists in mediating the cardioprotective effect of postconditioning was studied in a model of isolated Langendorff-perfused rat hearts. This phenomenon was found to occur using three sessions of reperfusion (30 sec) and ischemia (30 sec) at the end of a 45-min period of total ischemia. Studies using selective blockers of different opioid receptor subtypes, added to the perfusion solution at the beginning of the reperfusion period, showed that the resistance of the heart to the actions of ischemia-reperfusion in ischemic postconditioning are mediated by activation of δ1 opioid receptors. It is suggested that the mechanism of the cardioprotective phenomenon of postconditioning involves a significant role for endogenous opioids synthesized in the myocardium.

Opioid κ Receptors as a Molecular Target for the Creation of a New Generation of Analgesic Drugs

This review provides a brief description of the main structural and functional features of the κ opioid receptor, along with the properties of its agonists and the potential for using these in medicine. Of all the opioid receptor subtypes, κ receptors are the most attractive in terms of creating new drugs with a minimum of side effects. The opioid κ receptor is a member of the superfamily of metabotropic G-protein-coupled receptors. Opioid κ receptors are widely distributed in the CNS and at the periphery. They are involved in numerous physiological processes, including analgesia, regulation of neuroendocrine secretion, water balance, drinking and feeding behavior, autonomic functions, and the mechanisms of learning and memory. Data have been reported on the existence of three subtypes of κopioid receptor, though the molecular properties of only subtype 1 (e1) have been studied.

Опиоидные κ-Рецепторы как молекулярная мишень для создания нового поколения обезболивающих лекарственных средств

В обзоре кратко описаны основные особенности строения и функций каппа-опиоидного рецептора, приведена характеристика его агонистов и перспектива их использования в медицине. Из всех подтипов опиоидных рецепторов именно κ-рецепторы являются наиболее привлекательными для создания новых препаратов с минимальным количеством нежелательных эффектов. Опиоидный κ-рецептор — представитель суперсемейства метаботропных G-белок сопряженных рецепторов. Опиоидные κ-рецепторы широко представлены как в ЦНС, так и на периферии. Они вовлечены в многочисленные физиологические процессы, включая анальгезию, регуляцию нейроэндокринной секреции, водного баланса, питьевого и пищевого поведения, вегетативных функций, механизмов обучения, памяти. На сегодняшний день имеется информация о существовании 3 подтипов κ-опиоидных рецепторов, но изученной является лишь молекулярная характеристика первого подтипа (κ1).

Kappa Opioids, Salvinorin A and Major Depressive Disorder.

Opioids are traditionally associated with pain, analgesia and drug abuse. It is now clear, however, that the opioids are central players in mood. The implications for mood disorders, particularly clinical depression, suggest a paradigm shift from the monoamine neurotransmitters to the opioids either alone or in interaction with monoamine neurons. We have a special interest in dynorphin, the last of the major endogenous opioids to be isolated and identified. Dynorphin is derived from the Greek word for power, dynamis, which hints at the expectation that the neuropeptide held for its discoverers. Yet, dynorphin and its opioid receptor subtype, kappa, has always taken a backseat to the endogenous b-endorphin and the exogenous morphine that both bind the mu opioid receptor subtype. That may be changing as the dynorphin/ kappa system has been shown to have different, often opposite, neurophysiological and behavioral influences. This includes major depressive disorder (MDD). Here, we have undertaken a review of dynorphin/ kappa neurobiology as related to behaviors, especially MDD. Highlights include the unique features of dynorphin and kappa receptors and the special relation of a plant-based agonist of the kappa receptor salvinorin A. In addition to acting as a kappa opioid agonist, we conclude that salvinorin A has a complex pharmacologic profile, with potential additional mechanisms of action. Its unique neurophysiological effects make Salvinorina A an ideal candidate for MDD treatment research.

Identification of Antagonists Selective for Sigma Receptor Subtypes that are Active In vivo.

σRs have been mischaracterized [2-4] and were initially thought to be opioid receptor subtypes [5]. They have been classified into two subtypes based on specific radioligand binding assays using [3H](+)pentazocine for σ1Rs and [3H]1,3-di-o-tolylguanidine ([3H]DTG), in the presence of (+)-pentazocine to mask the σ1R, for σ2Rs [6-11] (Table 1). The σ1R has already been cloned and is a 25-29 kDa intracellular chaperone protein composed of 223 amino acids [12-14]. In contrast, the [3H](+)-pentazocine-inaccessible σR, the σ2R, is an 18–21 kDa protein that has not yet been cloned. Until recently, there have been no reports of antagonists that are selective for either receptor subtype or that are active in vivo, probably because of the lack of reliable in vivo assays for σR subtypes. The paper by Katz et al. [1] finally identifies antagonists selective for σR subtypes [1] that are active in vivo.

Identification of the Sigma-2 Receptor: Distinct from the Progesterone Receptor Membrane Component 1 (PGRMC1).

σRs are unique intracellular chaperone proteins [8] initially thought to be opioid receptor subtypes [9]. They have been classified into two subtypes based on specific radioligand binding assays using [3H](+)pentazocine for σ1Rs and [3H]1,3-di-o-tolylguanidine ([3H]DTG, in the presence of dextrallorphan to mask the σ1R) for σ2Rs in rat liver and kidney membranes [10]. Currently, the more selective σ1R ligand (+)-pentazocine has replaced dextrallorphan to mask the σ1R [7,11-14]. The σ1R has already been cloned as a 25-29 kDa chaperone protein composed of 223 amino acids [4,8,15]. It is widely distributed throughout the body [16-20]. Upon binding with agonists or under cellular stress, σ1Rs translocate from their primary endoplasmic reticulum (ER) location to different subcellular compartments where they can regulate ion channels and G-protein-coupled-receptor (GPCR) signaling [8,21-24]. In vivo functional studies on σ1Rs suggest that they play a substantial role in various cellular functions. Drugs acting at this receptor have been studied for their potential therapeutic effects in cancer, human immunodeficiency virus (HIV) infection, various psychiatric disorders, and substance abuse [1,25].