Search

Apelin, a regulatory peptide, is an endogenous ligand of the apelin receptor (APJ), which belongs to the G protein-coupled receptor family. The peptide and its receptor are distributed in animal and human tissues, including the cardiovascular and central nervous systems, and studies indicate that apelin signaling could play a role in cytoprotection of cells where it is found. Apelin activity may be modulated by interactions of the APJ receptor with other receptors that result in heteromerization. The interaction of the APJ with other receptor systems increases the signaling repertoire of apelin, thereby allowing it to exert a widened degree of control over cellular physiological functions. This article reviews studies which provide evidence for the physiological importance of APJ /Kappa opioid receptor (KOR) heterodimers in several critical cellular processes, including cell proliferation, and results are discussed that support a role of this peptide and the APJ receptor in functioning of the cardiovascular, gastrointestinal and central nervous systems under normal conditions and pathology, as well as novel signal transduction characteristics resulting following the interaction of APJ and KOR. A better understanding of the cellular protective actions of apelin, and the physiological outcomes from interaction of its receptor with other receptor types could lead to new pharmaceutical targets for various diseases affecting among other organs, the heart, the gastrointestinal system and the brain. [ABSTRACT FROM AUTHOR]

The kappa opioid receptor (k receptor) and its endogenous ligand dynorphin have received significant attention due to their involvement in pathophysiology of mood disorders, drug addiction, psychotic disorders and pain. Multiple lines of evidences suggest that the k receptor modulates overlapping neurocircuits connecting brainstem monoaminergic nuclei with forebrain limbic structures and thereby regulates neurobiological effects of stress and psychostimulants. The emerging concept of “biased agonism” (also known as functional selectivity) for G Protein Coupled Receptor (GPCR) ligands have provided new insights into overall response generated by a ligand, which could be exploited for drug discovery. According to this concept, every ligand possesses the unique ability (coded in its structure) that dictates distinct signalling pattern, and consequently beneficial or adverse response. Although still a long way to comprehend the clinical potential of biased GPCR ligands, such ligand could be vital pharmacological probes. This article highlights various lines of evidence, which indicates different ligands of k receptor as “biased”, and their potential implications in mood and pain disorders. [ABSTRACT FROM AUTHOR]

Several investigators recently identified biased κ opioid receptor (KOP receptor) agonists. However, no comprehensive study of the functional selectivity of available KOP receptor agonists at the human and mouse KOP receptors (hKOP receptor and mKOP receptor, respectively) has been published. Here we examined the ability of over 20 KOP receptor agonists to activate G proteins and to internalize the receptor. Clonal neuro-2a mouse neuroblastoma (N2a) cells stably transfected with the hKOP receptor or mKOP receptor were used. We employed agonist-induced [ 35 S]GTPγS binding and KOP receptor internalization as measures of activation of G protein and β-arrestin pathways, respectively. The method of Ehlert and colleagues was used to quantify intrinsic relative activities at G protein activation ( RA i-G ) and receptor internalization ( RA i-I ) and the degree of functional selectivity between the two [Log RA i-G – log RA i-I , RA i-G / RA i-I and bias factor]. The parameter, RA i , represents a relative estimate of agonist affinity for the active receptor state that elicits a given response. The endogenous ligand dynorphin A (1–17) was designated as the balanced ligand with a bias factor of 1. Interestingly, we found that there were species differences in functional selectivity. The most striking differences were for 12-epi-salvinorin A, U69,593, and ICI-199,441. 12-Epi-salvinorin A was highly internalization-biased at the mKOP receptor, but apparently G protein-biased at hKOP receptor. U69,593 was much more internalization-biased at mKOP receptor than hKOP receptor. ICI199,441 showed internalization-biased at the mKOP receptor and G protein-biased at the hKOP receptor. Possible mechanisms for the observed species differences are discussed. [ABSTRACT FROM AUTHOR]

β-funaltrexamine (β-FNA) is an irreversible μ opioid (MOP) receptor antagonist and a reversible agonist of κ opioid (KOP) receptor. β-FNA binds covalently to the MOP receptor at Lys233 5.39 , which is conserved among opioid receptors. Molecular docking of β-FNA showed that K303 6.58 in the MOP receptor and E297 6.58 in the KOP receptor played distinct roles in positioning β-FNA. K303 6.58 E MOP receptor and E297 6.58 K KOP receptor mutants were generated. The mutations did not affect β-FNA affinity or efficacy. K303 6.58 E mutation in the MOP receptor greatly reduced covalent binding of [ 3 H]β-FNA; however, E297 6.58 K did not enable the KOP receptor to bind irreversibly to β-FNA. Molecular modeling demonstrated that the ε-amino group of K303 6.58 in the MOP receptor interacted with C O of the acetate group of β-FNA to facilitate covalent bond formation with Lys233 5.39 . Replacement of K303 6.58 with Glu in the MOP receptor resulted in repulsion between the COOH of Glu and the C O of β-FNA and increased the distance between K233 5.39 and the fumarate group, making it impossible for covalent bond formation. These findings will be helpful for design of selective non-peptide MOP receptor antagonists. [ABSTRACT FROM AUTHOR]

Opioid receptor agonists are effective analgesic agents. Central activation of the mu and/or kappa opioid receptors (KOR) is associated with CNS side effects, which limits their effectiveness. Recent studies indicated that peripherally restricted, selective KOR agonists were potent analgesics and devoid of CNS-related side effects. To confirm this hypothesis, we designed a novel, potent, and peripherally restricted KOR-selective agonist, ZYKR1. The analgesic efficacy, brain penetration and safety of ZYKR1 were assessed in pre-clinical models. ZYKR1 showed KOR agonistic activity in the cAMP assay, with an EC 50 of 0.061 nM and more than 105-fold selectivity over the mu and delta opioid receptors (EC 50 > 10 μM). ZYKR1 was not found to bind mu, delta opioid, and NOP receptors in radioligand binding assays. ZYKR1 produced concentration-dependent inhibition of electrically evoked contractions in isolated mouse vas deferens with an IC 50 of 1.6 nM ZYKR1 showed peripheral restriction and potent analgesic efficacy in various in-vivo animal models (acetic acid induced visceral pain mouse model, ED 50 : 0.025 mg/kg, IV; ovariohysterectomy induced postoperative pain rat model, ED 50 : 0.023 mg/kg, IV; and C48/80 induced pruritus mouse model, ED 50 : 0.063 mg/kg, IV). In addition, ZYKR1 was devoid of motor coordination, physical dependence, dysphoria, and respiratory depression at 30, 400, 10 and 10-fold of efficacy dose, respectively. In conclusion, ZYKR1 has potent antinociceptive action in visceral pain and pruritus with limited CNS side effects in preclinical models owing to its peripheral restriction. [ABSTRACT FROM AUTHOR]

Abstract: This study examined the involvement of neural cell adhesion molecule (NCAM), a member of the immunoglobulin superfamily, in the development of tolerance to morphine. Furthermore, we focused on fibroblast growth factor (FGF) receptor and protein kinase C (PKC)-α as part of the intracellular signal transduction pathways underlying NCAM stimulation. The development of analgesic tolerance to morphine was gradually observed during daily treatment of morphine (10mg/kg, s.c.) for 5days. Morphine treatment gradually and significantly decreased the NCAM expression levels. However it returned to normal levels immediately after re-treatment of morphine. Treatment of AS-ODN against NCAM completely inhibited analgesic tolerance to morphine. Protein expression levels of PKC-α were significantly increased by repeated morphine treatment in a NCAM-AS-ODN-reversible manner. Interestingly, alterations of protein interactions between NCAM and FGF receptor were observed under repeated morphine treatment. In addition, SU5402 (2μg/mouse, i.c.v.), an inhibitor of FGF receptor, completely abolished the development of analgesic tolerance to morphine. Furthermore, κ-opioid receptor stimulation using U-50,488H, a κ-opioid receptor agonist, or establishment of formalin-induced chronic pain can completely suppress these changes in protein expression levels of NCAM and PKC-α and inhibit development of analgesic tolerance to morphine. These findings suggest that NCAM and its interaction with FGF receptor in the mechanism of up-regulation of PKC-α may contribute to the development of analgesic tolerance to morphine. Chronic pain or κ-opioid receptor stimulation could modulate these phenomena and suppress the development of analgesic tolerance to morphine. [Copyright &y& Elsevier]

Abstract: The long-lasting post-surgical changes in nociceptive thresholds in mice, indicative of latent pain sensitization, were studied. The contribution of kappa opioid and N-methyl-d-aspartate (NMDA) receptors was assessed by the administration of nor-binaltorphimine or MK-801; dynorphin levels in the spinal cord were also determined. Animals underwent a plantar incision and/or a subcutaneous infusion of remifentanil (80μg/kg), and mechanical thresholds (von Frey) were evaluated at different times. On day 21, after complete recovery of mechanical thresholds and healing of the wound, one of the following drugs was administered subcutaneously: (−)-naloxone (1mg/kg), (+)-naloxone (1mg/kg), naloxone-methiodide (3mg/kg), or nor-binaltorphimine (5mg/kg). Another group received subcutaneous MK-801 (0.15mg/kg) before nor-binaltorphimine administration. Dynorphin on day 21 was determined in the spinal cord by immunoassay. In mice receiving remifentanil during surgery, the administration of (−)-naloxone or nor-binaltorphimine induced significant hyperalgesia even 5months after manipulation. Nociceptive thresholds remained unaltered after (+)-naloxone or naloxone-methiodide. On day 21 after manipulation, the administration of MK-801 prevented nor-binaltorphimine-induced hyperalgesia. No changes in dynorphin levels were observed before or after opioid antagonist administration. In conclusion, surgery produced latent pain sensitization evidenced by opioid antagonist-precipitated hyperalgesia. The effect was stereospecific, centrally originated, and mediated by kappa opioid receptors. The blockade of nor-binaltorphimine-induced hyperalgesia by MK-801, suggests that NMDA receptors are also involved. Our results show for the first time that surgery induces latent, long-lasting changes in the processing of nociceptive information that can be induced by non-nociceptive stimuli such as the administration of opioid antagonists. [Copyright &y& Elsevier]

Abstract: Long-term therapy with L-3,4-dihydroxyphenylalanine (L-DOPA) in parkinsonian patients is known to lead to dyskinesia within a few years, and repeated administration of L-DOPA is also likely to alter the expression of kappa opioid receptors in the basal ganglia, especially the striatum and substantia nigra pars reticulata, suggesting that kappa opioid receptors might be deeply involved in motor functions. Therefore, effects of TRK-820 ((E)-N-[17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl]-3-(furan-3-yl)-N-methylprop-2-enamide monohydrochloride), a selective kappa opioid receptor agonist, were investigated on rotational behavior in unilateral 6-hydroxydopamine (6-OHDA)-treated rats (hemi-parkinsonian rats) and on L-DOPA-induced dyskinesia produced by administering L-DOPA to hemi-parkinsonian rats for 3weeks (dyskinesia rats). A single administration of subcutaneous TRK-820 significantly increased spontaneous ipsilateral rotational behavior of hemi-parkinsonian rats at 30µg/kg though the efficacy was moderate and also significantly inhibited L-DOPA-induced dyskinesia at 10 and 30µg/kg; this inhibition was reversed in the presence of nor-binaltorphimine, a kappa opioid receptor antagonist. In vivo microdialysis study, TRK-820 (30µg/kg, s.c.) significantly inhibited L-DOPA-derived extracellular dopamine content in the 6-OHDA-treated striatum in dyskinesia rats, but not in hemi-parkinsonian rats. Moreover, the development of L-DOPA-induced dyskinesia was suppressed by the 3-week co-administration of TRK-820 (3 and 10µg/kg, s.c.) with L-DOPA. These results have suggested that TRK-820 ameliorates L-DOPA-induced dyskinesia with a moderate anti-parkinsonian effect by inhibiting L-DOPA-induced excessive dopamine release through kappa opioid receptors only in dyskinesia rats; therefore, TRK-820 is expected to become a useful agent for the treatment of L-DOPA-induced dyskinesia. [Copyright &y& Elsevier]

Abstract: We have previously demonstrated that activation of κ-opioid receptor located in the temporomandibular joint (TMJ) of rats induces a significantly greater TMJ antinociception in diestrus females than in proestrus females (higher estradiol serum levels than diestrus) and males. These findings indicate that gonadal hormones decrease TMJ kappa-mediated antinociception. The aim of this study was to investigate some of the mechanisms by which gonadal hormones decrease TMJ kappa-mediated antinociception. Western blot analysis demonstrated a significantly lower κ-opioid receptor expression in the trigeminal ganglia of intact males than in intact and ovariechtomized (OVX) females and orchidectomized (ORX) males. In females, κ-opioid receptor expression in the trigeminal ganglia was significantly lower in proestrus than in diestrus and OVX females. Taken together these findings suggest that gonadal hormones, especially male gonadal hormones, down-regulate κ-opioid receptor expression. Co-application of the NOS inhibitor l-NMMA or the NO-sensitive guanylyl cyclase inhibitor ODQ with the κ-opioid receptor agonist U50,488 blocked TMJ kappa-mediated antinociception in males and females. These findings suggest that antinociception induced by activation of kappa opioid receptors in the TMJ region is mediated by the l-arginine/NO/cGMP pathway in both sexes. Despite the involvement of the l-arginine/NO/cGMP pathway in TMJ kappa-mediated antinociception in both sexes, gonadal hormones do not diminish the activity of this pathway to decrease TMJ kappa-mediated antinociception. Alternatively, they significantly reduce κ-opioid receptor expression in the trigeminal ganglia. [Copyright &y& Elsevier]

Abstract: Abnormalities in dopaminergic and serotonergic neurotransmission in the forebrain are believed to be involved in the underlying mechanism of schizophrenia; therefore, the direct blockade of the receptors associated with these systems is a central strategy for schizophrenia treatment, even though this strategy concurrently produces adverse effects like extrapyramidal effects. Kappa opioid receptors exist extensively in the brain and recent reports have suggested that these receptors are involved in modulating the release of several neurotransmitters including dopamine and serotonin. In the present study, we investigated the effect of TRK-820, (E)-N-[17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl]-3-(furan-3-yl)-N-methylprop-2-enamide monohydrochloride, a selective kappa opioid receptor agonist, on phencyclidine-induced rat behavioral changes and on biochemical changes in the prefrontal cortex. First, TRK-820 dose-dependently inhibited phencyclidine-induced rat hyperlocomotion, which is one of the abnormal behaviors recognized as a rodent schizophrenia model. The inhibitory effect was completely antagonized with nor-BNI (nor-binaltorphimine hydrochloride), a selective kappa opioid receptor antagonist. Second, TRK-820 dose-dependently inhibited phencyclidine-induced stereotyped behaviors including head-weaving, which is considered a behavioral syndrome based on the impairment of the serotonergic system. Third, in an in vivo microdialysis study, TRK-820 dose-dependently attenuated the biochemical changes of both dopamine and serotonin in the prefrontal cortex of rats treated with phencyclidine without affecting their basal levels in normal rats. The initial findings that TRK-820 potentially modulates such monoamine changes and ameliorates abnormal behaviors related to their changes may suggest its therapeutic potential against the symptoms of schizophrenia. [Copyright &y& Elsevier]

Abstract: Salvia divinorum is a hallucinogenic plant used by the Mazatec Indians of Mexico for traditional spiritual ceremonies. The active constituent, salvinorin A, induces profound hallucinations, however the biological mechanism for this action is not known. Affinity-binding studies suggest that the biologic activity of salvinorin A involves the κ-opioid receptor. The purpose of this study was to evaluate the antinociceptive effect of salvinorin A in mice. Salvinorin A and opioid receptor antagonists were administered intrathecally and the tail-flick latencies were used as a measure of antinociception. Salvinorin A increased tail-flick latencies in a dose-dependent manner (13.9–23.1 nmol) compared to control trials. Pretreatment with the κ-opioid receptor antagonist nor-binaltorphimine attenuated the salvinorin A induced increase in tail-flick latency. In contrast, neither the μ-opioid receptor antagonist β-funaltrexamine nor δ-opioid receptor antagonist naltrindole significantly affected the antinociceptive response of salvinorin A administration. These data support previous reports that salvinorin A represents a unique non-alkaloidal agonist for the κ-opioid receptor. [Copyright &y& Elsevier]

Differences in the anorectic activity of morphinan (e.g., naltrexone) and 3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (4PP) opioid receptor antagonists have been described. In an attempt to explain these differences, the influence of Na+ on opioid binding affinity and functional activity of 4PP antagonists was compared to other opioid antagonists. The binding affinities of neutral antagonists were unaffected by the addition of Na+, whereas that for the peptide, inverse agonist N,N-diallyl-Tyr–Aib–Aib–Phe–Leu–OH (ICI174864) was increased. Similarly, the binding affinities of the 4PP antagonist (3R,4R)-1-((S)-3-hydroxy-3-cyclohexylpropyl)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidine (LY255582) and other 4PP antagonists were increased in the presence of Na+ with the greatest effects at the delta opioid receptor followed by the mu and kappa opioid receptors, respectively. Similar to ICI174864, 4PP antagonists were found to inhibit basal GTPγ[35S] binding at the delta opioid receptor indicating inverse agonist activity. A correlation was observed between the binding affinities in the presence of Na+, the inverse agonist potency, and the anorectic potency of 4PP antagonists. These data suggest that 4PP antagonists differ from morphinan antagonists in their inverse agonist activity and suggest a relationship between inverse agonism and anorectic activity. [Copyright &y& Elsevier]