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All 10 posts | Subject: Novel Targets - 1. Kinases | Please login to post | Down | |
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scarmani (Hive Bee) 08-24-04 21:38 No 527136 
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Novel Targets - 1. Kinases | ||||||
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Protein Kinases are involved in the addictive -- and possibly the rewarding -- effects of reinforcing drugs. If Protein Kinases are involved only in acquisition of conditioned responses, then PK modulating substances might, when co-adminstered, block addiction to compounds of abuse while preserving such compounds' hedonic (euphoric) effects. If on the other hand Protein Kinases mediate the pleasurable and rewarding effects themselves, then PKs may represent promising targets for modulation by novel recreational drugs. Most evidence suggests the former rather than the latter. Of course, Kinases have broad important roles in brain function, so global inhibition (or activation) of a particular Kinase might have all sorts of non-specific effects, (for example, produce amnesia). ______ _____ ____ ___ __ _ Role of the calcium/calmodulin-dependent protein kinase ii (CaMKII) in the morphine-induced pharmacological effects in the mouse. Narita M, Matsumura Y, Ozaki S, Ise Y, Yajima Y, Suzuki T., Neuroscience. 126(2), 415-421 (2004) DOI:doi:10.1016/j.neuroscience.2004.03.006; Abstract: Calcium/calmodulin-dependent protein kinase II (CaMKII) is a family of multifunctional protein kinases that activates signaling pathways. The present study was designed to ascertain whether CaMKII could play a substantial role in the expression of morphine-induced antinociception, hyperlocomotion and rewarding effect in the mouse. An i.c.v. pretreatment with a CaMKII inhibitor KN-93 failed to affect the antinociception and hyperlocomotion induced by s.c. administration of a prototype µ-opioid receptor agonist morphine. In contrast, the morphine-induced place preference was significantly attenuated by i.c.v. pretreatment with KN-93. The levels of phosphorylated-CaMKII (p-CaMKII) in the limbic forebrain, but not in the frontal cortex and the lower midbrain, were significantly increased in morphine-conditioned mice, whereas the levels of CaMKII in three brain regions obtained from morphine-conditioned mice were not changed. This up-regulation of p-CaMKII in the limbic forebrain obtained from morphine-conditioned mice was significantly inhibited by i.c.v. pretreatment with KN-93. These results provide evidence that the increase in CaMKII activity in the mouse limbic forebrain may contribute to the rewarding effect, but not the antinociception and the hyperlocomotion, induced by morphine. However, place-preference and rewarding effect are two different things. Place preference is induced by nicotine in rats but this does not mean that nicotine causes a pleasurable state, only that it causes elevated dopamine release in specific brain areas, activates certain cascades (through protein kinases) which lead to "long-lasting neuronal adaptive responses" and therefore is habit-forming. http://cogprints.ecs.soton.ac.uk/archive/00001390/00/vta-rev-87.pdf http://www.thebrain.mcgill.ca/flash/i/i_03/i_03_cr/i_03_cr_que/i_03_cr_que.html So CPP may be more indicative of addiction / attraction to drug-associated cues. If this is so, then CaMKII inhibition might block addiction but not euphoria. (Notice the painkilling and movement-increasing effects of morphine were not affected) ______ _____ ____ ___ __ _ Regulations of methamphetamine reward by extracellular signal-regulated kinase 1/2/ets-like gene-1 signaling pathway via the activation of dopamine receptors. Mizoguchi H, Yamada K, Mizuno M, Mizuno T, Nitta A, Noda Y, Nabeshima T., Mol Pharmacol. 65(5), 1293-1301 (2004) DOI:10.1111/j.1460-9568.2004.03278.x Abstract: Little is known about molecular mechanisms for long-lasting neuroadaptation related to the rewarding effects of methamphetamine (MAP). In the present study, we examined the intracellular signaling that is associated with the expression of conditioned place preference (CPP) induced by MAP in rats. Rats were given MAP or saline (control group) for conditioning to the CPP test. MAP-treated and control animals were killed immediately after the CPP test [CPP(+)]. Some of the MAP-treated rats were killed without the CPP test [CPP(-)]. Hyperphosphorylation of mitogen-activated protein kinase (MAPK) ERK1/2, but not p38 and c-Jun N-terminal kinase/stress-activated protein kinase, was found in the nucleus accumbens (NAc) and striatum but not in other brain areas of MAP-treated CPP(+) animals. No such phosphorylation was seen in control and MAP-treated CPP(-) animals. Moreover, the transcription factor ets-like gene-1 (Elk-1), but not cAMP response element-binding protein, also showed a similar hyperphosphorylation in the same regions of MAP-treated CPP(+). Tyrosine kinase receptors, including tyrosine kinase B, were not activated in any brain regions examined in all groups. Both the dopamine D1 receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390) and the D2 receptor antagonist raclopride inhibited the expression of CPP as well as the activation of ERK1/2 in MAP-treated CPP(+) animals, when they were injected before the CPP test. The microinjection of 2'-amino-3'-methoxyflavone (PD98059), a selective MAPK kinase inhibitor, into the NAc before the test, abolished the MAP-induced ERK1/2 activation and decreased the expression of MAP-induced CPP. These results suggest the importance of the ERK1/2 signaling pathway through activation of dopamine D1 and D2 receptors in the expression of CPP induced by MAP. ______ _____ ____ ___ __ _ Cyclin-dependent kinase 5 regulates dopaminergic and glutamatergic transmission in the striatum Karima Chergui, Per Svenningsson and Paul Greengard, Proc. Natl. Acad. Sci. 101(7), 2191-2196 (2004) Medline (PMID=14769920) DOI:10.1073/pnas.0308652100 Abstract: Dopaminergic and glutamatergic neurotransmissions in the striatum play an essential role in motor- and reward-related behaviors. Dysfunction of these neurotransmitter systems has been found in Parkinson's disease, schizophrenia, and drug addiction. Cyclin-dependent kinase 5 (CDK5) negatively regulates postsynaptic signaling of dopamine in the striatum. This kinase also reduces the behavioral effects of cocaine. Here we demonstrate that, in addition to a postsynaptic role, CDK5 negatively regulates dopamine release in the striatum. Inhibitors of CDK5 increase evoked dopamine release in a way that is additive to that of cocaine. This presynaptic action of CDK5 also regulates glutamatergic transmission. Indeed, inhibition of CDK5 increases the activity and phosphorylation of N-methyl-D-aspartate receptors, and these effects are reduced by a dopamine D1 receptor antagonist. Using mice with a point mutation of the CDK5 site of the postsynaptic protein DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, molecular mass of 32 kDa), in the absence or in the presence of a dopamine D1 receptor antagonist, we provide evidence that CDK5 inhibitors potentiate dopaminergic transmission at both presynaptic and postsynaptic locations. These findings, together with the known ability of CDK5 inhibitors to prevent degeneration of dopaminergic neurons, suggest that this class of compounds could potentially be used as a novel treatment for disorders associated with dopamine deficiency, such as Parkinson's disease. ______ _____ ____ ___ __ _ Intra-accumbens protein kinase C inhibitor NPC 15437 blocks amphetamine-produced conditioned place preference in rats. Harinder Aujla, Richard J. Beninger, Behav Brain Res. 147(1-2), 41-48 (2003) DOI:10.1016/S0166-4328(03)00136-0 Abstract: In a previous study, intracerebroventricular calcium-dependent protein kinase (PKC) inhibition attenuated cocaine place conditioning. This suggested the hypothesis that intra-nucleus accumbens (NAc) injections of the PKC inhibitor NPC 15437 may block place conditioning produced by NAc injections of amphetamine. An unbiased conditioned place preference paradigm was employed to evaluate the present hypothesis. Thus, during pre-conditioning rats had access to an apparatus consisting of two chambers connected by a tunnel for three 15-min sessions. During 8 conditioning days with the tunnel blocked, one chamber was paired with NAc injections of drug for four 30-min sessions alternating with pairing of the other chamber with NAc injections of saline. Time spent on the drug-paired side was assessed in a final drug-free test session and compared to the amount of time spent there in pre-conditioning; a significant increase was defined as a place preference. Intra-NAc amphetamine (20.0 microg/0.5 microl/side) produced a place preference. This effect was blocked dose dependently by NPC 15437 (0.1, 0.5 and 1.0 microg/0.5 microl/side). NPC 15437 (1.0 microg) alone did not produce a place preference or aversion. None of the doses of NPC 15437 affected the locomotor stimulant effect of intra-NAc amphetamine during conditioning revealing a dissociation between the locomotor stimulating and rewarding effects of intra-NAc amphetamine. Results implicate PKC in the NAc in reward-related learning. ______ _____ ____ ___ __ _ cAMP-dependent protein kinase and reward-related learning: intra-accumbens Rp-cAMPS blocks amphetamine-produced place conditioning in rats. Richard J. Beninger, Patricia L. Nakonechny, Ioulia Savina, Psychopharmacology. 170(1), 23-32 (2003) DOI:10.1007/s00213-003-1510-2 Abstract: RATIONALE: Dopamine may produce reward-related learning by activating D(1)-like receptors in the nucleus accumbens (NAc) and stimulating the formation of cyclic adenosine monophosphate (cAMP) and the activation of cAMP-dependent protein kinase (PKA). OBJECTIVES: This hypothesis was tested using the conditioned place preference (CPP) based on NAc injections of amphetamine (amph) and evaluating the effects of PKA inhibition with Rp-cAMPS. METHODS: The CPP procedure consisted of three phases: pre-exposure (three 15-min sessions in a chamber consisting of two distinct compartments connected by a tunnel), conditioning (four 30-min placements into one compartment with the tunnel blocked following drug injection into the NAc alternating with four similar placements into the other side following NAc injection of saline), and test (one 15-min session with the tunnel open). A CPP was defined as an increase in time spent on the drug-paired side from mean pre-exposure to test. RESULTS: Dose-response experiments showed that 15.0 or 20.0 but not 5.0 or 10.0 micro g/0.5 micro l per side of amph produced a CPP. The amph (20.0 micro g) CPP was blocked by Rp-cAMPS co-injections of 25.0 and 250 but not 2.5 ng/0.5 micro l per side. Rp-cAMPS or the PKA activator Sp-cAMPS (50.0, 250, 500, 600 ng/0.5 micro l per side) alone had no effect on side preference. Co-injection of 10.0 micro g amph+Sp-cAMPS (25.0, 50.0, 250, 500 ng) did not result in a CPP but co-injection of 20.0 micro g amph+Sp-cAMPS (250 ng) led to a loss of the CPP normally seen with that dose of amph. Doses of Rp-cAMPS that blocked CPP did not block the locomotor stimulatory effect of amph during conditioning sessions. CONCLUSIONS: Results supported the hypothesis that PKA activation in NAc is necessary for reward-related learning. ______ _____ ____ ___ __ _ Phosphatidylinositol 3-kinase, protein kinase C, and MEK1/2 kinase regulation of dopamine transporters (DAT) require N-terminal DAT phosphoacceptor sites. Zhicheng Lin, Ping-Wu Zhang , Xuguang Zhu , Jean-Marc Melgari , Robin Huff, Rachel L. Spieldoch and George R. Uhl, J Biol Chem. 278(22), 20162-20170 (2003) Medline (PMID=12660249) DOI:10.1074/jbc.M209584200 Abstract: The dopamine transporter (DAT) modulates dopamine neurotransmission and is a primary target for psychostimulant influences on locomotion and reward. Selective DAT expression by dopaminergic neurons has led to use of cocaine analog DAT radioligands to assess rates of progression of dopamine neuronal degeneration in Parkinson's disease. We have documented that DAT is a phosphoprotein that is regulated by phosphorylation through pathways that include protein kinase C cascades. We now extend this work using drugs selective for phosphatidylinositol 3-kinase (PI3K), protein kinase C, MEK1/2, p38 kinase, and Ca2+/calmodulin kinase II. We compare the drug effects on wild type DAT to the effects on 20 DAT mutants and a DAT deletion. PI3K and MEK1/2 modulators exert strong effects on DAT expression patterns and dopamine uptake Vmax. PKC principally modulates Vmax. Neither p38 nor Ca2+/calmodulin kinase II agents exert significant influences on wild type DAT. Several mutants and a DAT with an N-terminal deletion display alterations that interact with the effects of kinase modulators, especially S7A for PKC effects; T62A, S581A, and T612A for PI3K effects; and S12A and T595A mutants for MEK1/2 effects. 32P-Labeling studies confirm several of these effects of kinase pathway modulators on DAT phosphorylation. DAT expression and activities can be regulated by kinase cascades that require phosphoacceptor sites most concentrated in its N terminus. These results have a number of implications for DAT regulation and mandate caution in using DAT radioligand binding to infer changes in dopaminergic neuronal integrity after treatments that alter activities of these kinase pathways. ______ _____ ____ ___ __ _ Suppression of the morphine-induced rewarding effect and G-protein activation in the lower midbrain following nerve injury in the mouse; involvement of G-protein-coupled receptor kinase 2.Ozaki S, Narita M, Narita M, Iino M, Miyoshi K, Suzuki T., Neuroscience. 116(1), 89-97 (2003) DOI:10.1016/S0306-4522(02)00699-1 Abstract: The present study was designed to investigate whether a state of neuropathic pain induced by sciatic nerve ligation could alter the rewarding effect, antinociception, and G-protein activation induced by a prototype of mu-opioid receptor agonist morphine in the mouse. The sciatic nerve ligation caused a long-lasting and profound thermal hyperalgesia. Under this neuropathic pain-like state, an i.c.v. morphine-induced place preference was observed in sham-operated mice but not in sciatic nerve-ligated mice. However, no differences in the antinociceptive effect of i.c.v.-administered morphine were noted between the groups. The increases in the binding of guanosine-5'-o-(3-[(35)S]thio)triphosphate induced by morphine in lower midbrain membranes including the ventral tegmental area, which contributes to the expression of the rewarding effect of opioid, were significantly attenuated in sciatic nerve-ligated mice. On the other hand, there were no differences in the stimulation of guanosine-5'-o-(3-[(35)S]thio)triphosphate binding to pons/medulla membranes, which plays an important role in the antinociception of mu-opioid receptor agonists, between the groups. In addition, no changes in levels of guanosine-5'-o-(3-[(35)S]thio)triphosphate binding by either the selective delta- or kappa-opioid receptor agonists were noted in membrane of the lower midbrain and limbic forebrain membranes obtained from sciatic nerve-ligated mice. Reverse transcription-polymerase chain reaction analysis showed that sciatic nerve ligation did not alter the mRNA product of mu-opioid receptors in the lower midbrain, indicating that a decrease in some mu-opioid receptor functions may result from the uncoupling of mu-opioid receptors from G-proteins. We found a significant increase in protein levels of G-protein-coupled receptor kinase 2, which causes receptor phosphorylation in membranes of the lower midbrain but not in the pons/medulla, obtained from mice with nerve injury, whereas there were no changes in the protein level of phosphorylated-protein kinase C in the lower midbrain. These results suggest that the uncoupling of mu-opioid receptors from G-proteins by G-protein-coupled receptor kinase 2 in the lower midbrain may, at least in part, contribute to the suppression of the rewarding effect of morphine under neuropathic pain. boot from the shadow of a broken mirror |
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scarmani (Hive Bee) 08-25-04 00:39 No 527166
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Kinases Cntd' | ||||||
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Additional evidence that CPP is distinct from rewarding effects comes from the remarkable finding that CPP can be temporarily reversed AFTER the fact. This would suggest that the long-term neuronal changes caused by release of dopamine can be modified independently of a dug's rewarding effects. Effect of gabapentin-like compounds on development and maintenance of morphine-induced conditioned place preference. Nick Andrews, Sally Loomis, Robert Blake, Leanne Ferrigan, Lakhbir Singh, Alexander T. McKnight, Psychopharmacology. 157(4), 381-387 (2001) DOI:10.1007/s002130100839; Abstract: RATIONALE: Psychological dependence to the opioid analgesic morphine is attributable to the rewarding properties of the drug, and its evolution can be divided into two distinct phases: development and maintenance. Both phases can be studied using conditioned place preference (CPP). OBJECTIVES: To determine whether the two phases can be influenced by pre-treatment with gabapentin-like compounds. METHODS: CPP to morphine was used to demonstrate the rewarding properties of morphine in the presence or absence of gabapentin-like compounds. In-vivo microdialysis in the nucleus accumbens was used to determine the effects of gabapentin or pregabalin on morphine-induced dopamine release. RESULTS: Pretreatment with either gabapentin (10-100 mg/kg p.o.) or pregabalin (3-30 mg/kg p.o.) attenuated CPP induced by a submaximal dose of morphine (0.75 mg/kg). Neither gabapentin nor pregabalin had any effect alone in the CPP test. Both gabapentin-like compounds blocked the effect of morphine (0.75 mg/kg s.c.) to increase the release of dopamine in the nucleus accumbens. Studies of the maintenance of CPP to morphine showed CPP was maintained for at least 4 days after the initial test. In a second experiment, it was found that pregabalin (injected once, 24 h after CPP had been demonstrated) was able to reverse morphine-induced CPP. CONCLUSIONS: Neither gabapentin nor pregabalin induced CPP, but both compounds blocked the development of CPP to morphine and also blocked morphine's effects on dopamine release. Furthermore, pregabalin blocked the maintenance of morphine-induced CPP. It is concluded that gabapentin-like compounds, which have no intrinsic rewarding properties, may have some therapeutic use in the treatment of opioid dependence. This accords with other studies showing that GABAergic compounds such as baclofen have anti-addictive effects. It seems difficult to imagine that Gabapentin (with an unclear, but "GABA-increasing" mode of action) or GABA-B agonists like baclofen, would block the euphoric effects of opiates. Rather, it seems they interfere with the expression of long-term changes associated with addiction and tolerance, and they can do it even after the fact. ______ _____ ____ ___ __ _ GABA(A) receptors in the ventral tegmental area control bidirectional reward signalling between dopaminergic and non-dopaminergic neural motivational systems. Steven R. Laviolette and Derek van der Kooy, Eur J Neurosci. 13(5), 1009-1015 (2001) DOI:10.1046/j.1460-9568.2001.01458.x Abstract: In the midbrain ventral tegmental area (VTA), both dopaminergic and nondopaminergic neural substrates mediate various behavioural reward phenomena. VTA GABAergic neurons are anatomically positioned to influence the activity of both the mesolimbic dopamine system and nondopamine efferents from the VTA. In order to examine the possible functional role of VTA GABA(A) receptors in neural reward processes, we performed discrete, bilateral microinjections of the GABA(A) receptor agonist, muscimol, or the GABA(A) receptor antagonist, bicuculline, into the VTA. Using a fully counterbalanced, unbiased conditioned place-preference paradigm, we demonstrate that activation of VTA GABA(A) receptors, with the GABA(A) receptor agonist muscimol (5--50 ng/microL), or inhibition of VTA GABA(A) receptors, with the GABA(A) receptor antagonist bicuculline (5--50 ng/microL), both produce robust rewarding effects. Furthermore, these rewarding effects can be pharmacologically dissociated: blockade of dopamine receptors with a dopamine receptor antagonist, alpha-flupenthixol (0.8 mg/kg; i.p.), or concurrent activation of VTA GABA(B) receptors with a GABA(B) receptor agonist, baclofen (70 ng/microL), blocked the rewarding properties of the GABA(A) receptor agonist, but had no effect on the rewarding properties of the GABA(A) receptor antagonist. These results suggest that, within the VTA, a single GABA(A) receptor substrate controls bidirectional reward signalling between dopaminergic and nondopaminergic brain reward systems. So this paper might explain how modulating GABA is able to produce such effects. ______ _____ ____ ___ __ _ Conditioned place preference; what does it add to our preclinical understanding of drug reward? Bardo MT, Bevins RA., Psychopharmacology. 153(1), 31-43 (2000) DOI:10.1007/s002130000569 Abstract: RATIONALE: Among the various experimental protocols that have been used to measure drug reward in laboratory animals, conditioned place preference (CPP) has been one of the most popular. However, a number of controversial issues have surrounded the use of this experimental protocol. OBJECTIVE: The present review provides a theoretical overview of some critical issues relevant to CPP. The advantages and limitations of CPP are also covered. RESULTS: Based on modern and traditional theoretical formulations of Pavlovian conditioning, CPP appears to reflect a preference for a context due to the contiguous association between the context and a drug stimulus. Within this theoretical framework, it seems clear that CPP measures a learning process that is fundamentally distinct from drug self-administration. The main advantages of CPP are that it: (1) tests animals in a drug-free state; (2) is sensitive to both reward and aversion; (3) allows for simultaneous determination of CPP and locomotor activity; (4) is adaptable to a variety of species; (5) typically yields dose-effect curves that are monophasic rather than biphasic; and (6) has utility in probing the neural circuits involved in drug reward. The main limitations of CPP are that it: (1) is subject to interpretation based on the notion of novelty seeking; (2) is cumbersome for providing the graded dose-effect curves needed for answering some pharmacological questions; (3) is difficult to interpret when animals prefer one context prior to drug conditioning; and (4) lacks face validity as an experimental protocol of drug reward in humans. CONCLUSION: Despite some limitations, CPP provides unique information about the rewarding effect of contextual cues associated with a drug stimulus. So, to sum up, if you can prevent the brain from "learning" (e.g. making the association between the rewarding effects of a drug and drug-related cues such as the context in which the drug was administered, or e.g. downregulating receptors), this may dissociate addiction and tolerance from euphoria. This is why agents that can block CPP, or drug-induced lcomotor sensitization, are worth a closer look. ______ _____ ____ ___ __ _ Stimulation of protein kinase a activity in the rat amygdala enhances reward-related learning J. David Jentsch, Peter Olausson, Eric J. Nestler, and Jane R. Taylor, Biol Psychiatry. 52(2), 111-118 (2002) DOI:10.1016/S0006-3223(02)01358-6 Delta 9-tetrahydrocannabinol-induced MAPK/ERK and Elk-1 activation in vivo depends on dopaminergic transmission. Emmanuel Valjent, Christiane Pages, Monique Rogard, Marie-Jo Besson, Rafael Maldonado and Jocelyne Caboche, Eur J Neurosci. 14(2), 342-52 (2001) DOI:10.1046/j.0953-816x.2001.01652.x Limbic-cortical-ventral striatal activation during retrieval of a discrete cocaine-associated stimulus: a cellular imaging study with gamma protein kinase C expression. Thomas KL, Everitt BJ., J Neurosci. 21(7), 2526-2535 (2001) Medline (PMID=11264326) Conditioned locomotion in rats following amphetamine infusion into the nucleus accumbens: blockade by coincident inhibition of protein kinase A. Sutton MA, McGibney K, Beninger RJ., Behav Pharmacol. 11(5), 365-376 (2000) boot from the shadow of a broken mirror |
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scarmani (Hive Bee) 08-25-04 02:49 No 527197
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More Kinases | ||||||
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Involvement of the extracellular signal-regulated kinase cascade for cocaine-rewarding properties. Emmanuel Valjent, Jean-Christophe Corvol, Christiane Pagès, Marie-Jo Besson, Rafael Maldonado, and Jocelyne Caboche, J Neurosci. 20(23), 8701-8709 (2000) Medline (PMID=11102476) Dopamine D1-like receptors and reward-related incentive learning. Beninger RJ, Miller R., Neurosci Biobehav Rev. 22(2), 335-345 (1998) DOI:10.1016/S0149-7634(97)00019-5 Protein kinases A and C are involved in the mechanisms underlying consolidation of cocaine place conditioning Luigi Cervo, Samipa Mukherjee, Andrea Bertaglia and Rosario Samanin, Brain Res. 775(1-2), 30-36 (1997) DOI:10.1016/S0006-8993(97)00866-4 boot from the shadow of a broken mirror |
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scarmani (Hive Bee) 08-25-04 06:04 No 527218
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Novel Targets - 2. NOP (Nociceptin / OrphaninFQ) | ||||||
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Nociceptin is the endogenous peptide agonist for the NOP receptor ("orphan opioid-receptor-like-1", ORL1). Despite the high sequence homology between ORL1 and the opioid receptors, most opioids lack affinity for the nociceptin receptor. However NOP is now sometimes considered the fourth member of the opioid receptor family, after mu, delta and kappa. Nociceptin itself is not at all pleasant. By agonizing NOP, Nociceptin can "amplify pain or enhance harmless stimuli into a painful sensation". (This depends on the site of action however... in the spine or peripherally, agonism of NOP can prioduce antinociceptive, not pronociceptive, effects.) Additionally, nociceptin suppresses firing of dopaminergic neurons, inhibits release of dopamine in the reward centers, and blocks the rewarding effects of pleasurable drugs but not the aversive effects of unpleasant ones. It is involved in neuropathic pain which does not respond to traditional opioids. In contrast, nociceptin receptor antagonists show anti-depressant effects, reduce tolerance to opioids, yet enhance opioid antinociceptive effects. NOP receptors represent extremely interesting and exciting targets for novel classes of drugs, both therapeutic and recreational. ______ _____ ____ ___ __ _ The NOP (ORL1) receptor antagonist Compound B stimulates mesolimbic dopamine release and is rewarding in mice by a non-NOP-receptor-mediated mechanism. Koizumi M, Sakoori K, Midorikawa N, Murphy NP., Br J Pharmacol. 2004 Aug 2 [Epub ahead of print] Medline (PMID=15289286) DOI:10.1038/sj.bjp.0705906 Abstract: Compound B (1-[(3R, 4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one, CompB) is a nociceptin/orphanin FQ (N/OFQ) antagonist showing high selectivity for the NOP (ORL1) receptor over classical opioid receptors. We studied the effect of subcutaneous CompB administration on the release of mesolimbic dopamine (DA) and the expression of hedonia in mice. CompB (0.3-30 mg kg(-1)) dose dependently stimulated mesolimbic DA release as measured by in vivo freely moving microdialysis, without any change in locomotor activity. However, intracerebroventricular administered N/OFQ (endogenous agonist of the NOP receptor, 6 nmol) did not influence CompB- (10 mg kg(-1)) induced DA release, despite clearly suppressing release when administered alone. Studies using NOP receptor knockout mice and no-net-flux microdialysis revealed mildly, but not statistically significantly higher endogenous DA levels in mice lacking the NOP receptor compared to wild-type mice. Administration of CompB (10 mg kg(-1)) induced identical increases in mesolimbic DA release in wild-type and NOP receptor knockout mice. CompB was rewarding in approximately the same dose range in which CompB induced major increases in mesolimbic DA release when assayed using a conditioned place preference paradigm. The rewarding effect of CompB (30 mg kg(-1)) was maintained in NOP receptor knockout mice. These results show that CompB stimulates mesolimbic DA release and is rewarding by an action independent of the NOP receptor, the precise site of which is unclear. Consequently, caution should be exercised when interpreting the results of studies using this drug, particularly when administered by a peripheral route. ______ _____ ____ ___ __ _ Short-term effects of the nociceptin receptor antagonist Compound B on the development of methamphetamine sensitization in mice: a behavioral and c-fos expression mapping study. Chinami Okabe, Niall P. Murphy, Brain Res. 1017(1-2), 1-12 (2004) DOI:10.1016/j.brainres.2004.04.076 Abstract: The nociceptin antagonist Compound B (CompB) stimulates mesolimbic dopamine release and induces a conditioned place preference but has little effect on locomotion. As behavioral sensitization often occurs as an epiphenomenon to mesolimbic activation and reward, we studied the effect of CompB on behavioral sensitization to methamphetamine. Locomotor responses of C57BL6 mice to repeated methamphetamine (2 mg/kg s.c.) administration alone or immediately following CompB (10 mg/kg s.c.) were recorded for 3 alternating days. Six days later, methamphetamine (1 mg/kg s.c.) was administered and locomotor activity monitored again before determining neural activity by analysis of c-fos expression. Methamphetamine treatment induced a progressive locomotor (behavioral) sensitization, with CompB pretreatment enhancing the locomotor response to methamphetamine during the early stages only. Previous CompB administration little affected methamphetamine-sensitized or acute methamphetamine-induced locomotion on the challenge day. Analysis of c-fos expression supported these results as of the 36 neuroanatomical regions quantified; very few showed CompB-dependent responses. However, numerous regions differentially responsive to either acute (e.g. ventromedial, ventrolateral and central caudate putamen), chronic (e.g. central amygdala, lateral habenula, dorsomedial caudate putamen) or sensitized (e.g. medial nucleus accumbens core, central amygdala, lateral habenula) methamphetamine treatment were identified, thereby providing a comprehensive map of the short and long-term effects of methamphetamine on mouse brain activity per se. Thus, despite its mesolimbic activating and rewarding properties, CompB has little long-term influence on neural activity, suggesting CompB is able to induce short-term increases in hedonic state in the absence of locomotion or major long-term effects. ______ _____ ____ ___ __ _ Orphanin FQ/nociceptin blocks cocaine-induced behavioral sensitization in rats Lutfy K, Khaliq I, Carroll FI, Maidment NT., Psychopharmacology. 164(2), 168-176 (2002) DOI:10.1007/s00213-002-1192-1 Abstract: RATIONALE: Orphanin FQ/nociceptin (OFQ/N), the endogenous ligand of the opioid receptor-like (ORL-1) receptor, shows similarities to dynorphin A (1-17) in structure and functions. Dynorphin and other kappa opioid receptor agonists have been shown to block cocaine sensitization. OBJECTIVE: The present study was designed to examine the ability of OFQ/N to block cocaine-induced behavioral sensitization. METHODS: Rats were habituated to testing chambers for 1 h, injected with artificial cerebrospinal fluid (aCSF) or OFQ/N (15 nmol) followed by saline or cocaine (20 mg/kg) and locomotor activity was measured for a further 1 h. Rats were treated similarly for the next 2 days except the dose of OFQ/N was doubled on each subsequent day. Rats were then challenged with cocaine (7.5 mg/kg) in the absence of OFQ/N on day 8. The specificity of OFQ/N's action was examined in the presence of J-113397 (30 nmol), an ORL-1 receptor antagonist. The ability of OFQ/N to block the context-independent component of cocaine sensitization was also tested wherein rats were treated in their home cages on days 1-3. Finally, the effect of intra-VTA OFQ/N administration on cocaine sensitization was examined. RESULTS: Sensitization did not develop in rats repeatedly treated with OFQ/N, via either route of administration, prior to cocaine administration on days 1-3. The inhibitory effect of OFQ/N was not dependent on context and was blocked by pretreatment with J-113397. CONCLUSION: Our results indicate that OFQ/N blocks cocaine-induced behavioral sensitization through activation of the ORL-1 receptor and that the VTA may be one of the substrates for this action of OFQ/N. ______ _____ ____ ___ __ _ Nociceptin receptor antagonists display antidepressant-like properties in the mouse forced swimming test. John P. Redrobe, Girolamo Calo, Domenico Regoli, Rémi Quirion, Naunyn Schmiedebergs Arch Pharmacol. 365(2), 164-167 (2002) DOI:10.1007/s00210-001-0511-0 Abstract: The present study investigated the effects of nociceptin, the peptide nociceptin receptor antagonist, [Nphe(1)]-nociceptin (1-13)-NH(2), and the non-peptide antagonist, J-113397, in the mouse forced swimming test, an animal model used for the screening of potential antidepressant drugs. Additional studies were performed with naloxone to exclude effects on traditional opioid receptors. Intracerebroventricular (ICV) administration of nociceptin (0.01-1 nmole) was devoid of any activity in the mouse forced swimming test, as was intraperitoneal (i.p.) administration of naloxone (1-10 mg/kg). ICV treatment with [Nphe(1)]-nociceptin (1-13)-NH(2) (25 nmole and 50 nmole) induced significant antidepressant-like activity ( P<0.01), as did administration of J-113397 (20 mg/kg, i.p; P<0.05). Open field analysis revealed that acute treatment with these molecules did not induce significant changes in locomotor activity at the doses tested. These results suggest that nociceptin, and its receptor, may play a role in depressive disorders and that the nociceptin system could represent a novel target for the development of new antidepressant drugs. ______ _____ ____ ___ __ _ Why does Buprenorphine have lower abuse potential than other opioids? NOP agonism may play a role. Buprenorphine-induced antinociception is mediated by mu-opioid receptors and compromised by concomitant activation of opioid receptor-like receptors. Lutfy K, Eitan S, Bryant CD, Yang YC, Saliminejad N, Walwyn W, Kieffer BL, Takeshima H, Carroll FI, Maidment NT, Evans CJ., J Neurosci. 23(32), 10331-10337 (2003) Medline (PMID=14614092) Involvement of the neuropeptide nociceptin/orphanin FQ in kainate seizures. Bregola G, Zucchini S, Rodi D, Binaschi A, D'Addario C, Landuzzi D, Reinscheid R, Candeletti S, Romualdi P, Simonato M., J Neurosci. 22(22), 10030-10038 (2002) Medline (PMID=12427860) boot from the shadow of a broken mirror |
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Lilienthal (Moderator) 08-25-04 07:49 No 527229 
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Stop please... | ||||||
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Please be a bit more selective with what files you are uploading to the board. I don't think these are interesting for others. Maybe you should learn more about receptor signaling pathways from books, review articles, or lectures. Such specialized publications don't really give an idea about the whole system. 
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scarmani (Hive Bee) 08-25-04 08:14 No 527235
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More NOP | ||||||
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A new synthetic approach to 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-benzimidazol-2-one(J-113397), the first non-peptide ORL-1 receptor antagonist De Risi C, Piero Pollini G, Trapella C, Peretto I, Ronzoni S, Giardina GA., Bioorg Med Chem. 9(7), 1871-1877 (2001) DOI:10.1016/S0968-0896(01)00085-2 Abstract: An efficient approach to 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-benzimidazol-2-one (J-113397) 1, the first non-peptide ORL-1 receptor antagonist described in literature, is outlined. After construction of the piperidine framework through Dieckmann cyclization of the Michael adduct 8 of cyclooctylmethylamine to methyl acrylate, condensation with o-phenylendiamine produced the beta-enamino ester 2, which has been conveniently used to construct the benzimidazolone substituent at C-4. Catalytic hydrogenation of intermediate 11 followed by base-promoted cis--trans isomerization of the key compound 12 led to the formation of ester 13, which was converted to the racemic title compound by LiAlH(4) reduction. The pure enantiomers were obtained by chiral preparative HPLC separation using a derivatized cellulose-based stationary phase. ______ _____ ____ ___ __ _ Bi-directional modulation of 5-hydroxytryptamine-induced plasma extravasation in the rat knee joint by nociceptin S. Grond, A. Gabriel, C. Pietruck, L.-C. Yu, G.-X. Xie and P. Pierce Palmer, Neuroscience. 103(4), 1085-1092 (2001) DOI:10.1016/S0306-4522(01)00040-9 Abstract: The role of nociceptin, the endogenous ligand for the opioid receptor-like (ORL1) receptor, in nociceptive processing is controversial. Most studies demonstrate hyperalgesia following supraspinal administration, analgesia following intrathecal and peripheral administration at higher doses, and hyperalgesia following intrathecal and peripheral application at lower doses. The present study investigates the effect of nociceptin on synovial plasma extravasation and its ability to modulate 5-hydroxytryptamine-induced synovial plasma extravasation using the rat knee joint model of inflammation. Nociceptin alone does not alter synovial plasma extravasation from baseline. Nociceptin at concentrations up to 1 nM enhances 5-hydroxytryptamine-induced synovial plasma extravasation (up to 50%) and nociceptin at concentrations above 100 nM inhibits 5-hydroxytryptamine-induced synovial plasma extravasation (down to 45%). The novel, selective ORL1 receptor antagonist J-113397 potently inhibits the pro-inflammatory effect of nociceptin, but only partly inhibits, at higher concentrations, the anti-inflammatory effects of nociceptin.These findings demonstrate a dose-dependent bi-directional effect of nociceptin on inflammatory processes and may indicate a target for novel therapeutics. ______ _____ ____ ___ __ _ Enhanced spinal nociceptin receptor expression develops morphine tolerance and dependence. Ueda H, Inoue M, Takeshima H, Iwasawa Y., J Neurosci. 20(20), 7640-7647 (2000) Medline (PMID=11027224) Abstract: The tolerance and dependence after chronic medication with morphine are thought to be representative models for studying the plasticity, including the remodeling of neuronal networks. To test the hypothesis that changes in neuronal plasticity observed in opioid tolerance or dependence are derived from increased activity of the anti-opioid nociceptin system, the effects of chronic treatments with morphine were examined using nociceptin receptor knock-out (NOR(-/-)) mice and a novel nonpeptidic NOR antagonist, J-113397, which shows a specific and potent NOR antagonist activity in in vitro [(35)S]GTPgammaS binding assay and in vivo peripheral nociception test. The NOR(-/-) mice showed marked resistance to morphine analgesic tolerance without affecting morphine analgesic potency in tail-pinch and tail-flick tests. The NOR(-/-) mice also showed marked attenuation of morphine-induced physical dependence, manifested as naloxone-precipitated withdrawal symptoms after repeated morphine treatments. Similar marked attenuation of morphine tolerance was also observed by single subcutaneous (10 mg/kg) or intrathecal (1 nmol) injection of J-113397, which had been given 60 min before the test in morphine-treated ddY mice. However, the intracerebroventricular injection (up to 3 nmol) did not affect the tolerance. On the other hand, morphine dependence was markedly attenuated by J-113397 that had been subcutaneously given 60 min before naloxone challenge. There was also observed a parallel enhancement of NOR gene expression only in the spinal cord during chronic morphine treatments. Together, these findings suggest that the spinal NOR system develops anti-opioid plasticity observed on morphine tolerance and dependence. ______ _____ ____ ___ __ _ In vitro and in vivo pharmacological characterization of J-113397, a potent and selective non-peptidyl ORL1 receptor antagonist Satoshi Ozaki, Hiroshi Kawamoto, Yoshiki Itoh, Mitsuru Miyaji, Tomoko Azuma, Daisuke Ichikawa, Hirohide Nambu, Tomoko Iguchi, Yoshikazu Iwasawa and Hisashi Ohta, Eur J Pharmacol. 402(1-2), 45-53 (2000) DOI:10.1016/S0014-2999(00)00520-3 Abstract: 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl -1, 3-dihydro-2H-benzimidazol-2-one (J-113397) was found to be the first potent nonpeptidyl ORL1 receptor antagonist (K(i): cloned human ORL1=1.8 nM) with high selectivity over other opioid receptors (K(i): 1000 nM for human mu-opioid receptor, >10,000 nM for human delta-opioid receptor, and 640 nM for human kappa-opioid receptor). In vitro, J-113397 inhibited nociceptin/orphanin FQ-stimulated [35S]guanosine 5'-O-(gamma-thio)triphosphate (GTP gamma S) binding to Chinese Hamster Ovary (CHO) cells expressing ORL1 (CHO-ORL1) with an IC(50) value of 5.3 nM but had no effect on [35S]GTP gamma S binding by itself. Schild plot analysis of the [35S]GTP gamma S binding assay and cAMP assay using CHO-ORL1 indicated competitive antagonism of J-113397 on the ORL1 receptor. In CHO cells expressing mu-, delta- or kappa-opioid receptors, J-113397 had no effects on [35S]GTP gamma S binding up to a concentration of 100 nM, indicating selective antagonism of the compound on the ORL1 receptor. In vivo, J-113397, when administered subcutaneously (s.c.), dose-dependently inhibited hyperalgesia elicited by intracerebroventricular (i.c.v.) administration of nociceptin/orphanin FQ in a tail-flick test with mice. An in vitro binding study using mouse brains indicated that J-113397 possesses high affinity for the mouse ORL1 receptor (K(i): 1.1 nM) as well as the human receptor. In summary, J-113397 is the first potent, selective ORL1 receptor antagonist that may be useful in elucidating the physiological roles of nociceptin/orphanin FQ. ______ _____ ____ ___ __ _ Discovery of the first potent and selective small molecule opioid receptor-like (ORL1) antagonist: 1-[(3R,4R)-1-cyclooctylmethyl-3- hydroxymethyl-4-piperidyl]-3-ethyl-1, 3-dihydro-2H-benzimidazol-2-one (J-113397). Kawamoto H, Ozaki S, Itoh Y, Miyaji M, Arai S, Nakashima H, Kato T, Ohta H, Iwasawa Y., J Med Chem. 42(25), 5061-5063 (1999) DOI:10.1021/jm990517p ______ _____ ____ ___ __ _ [edit] Ok, sorry about that... I'll stop here (although personally I think these are interesting). If you are concerned about storage, bandwidth or copyright issues you can delete the posts. [/edit] boot from the shadow of a broken mirror |
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Nicodem (Hive Bee) 08-25-04 08:42 No 527238 
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Intracelular targets are a hard job | ||||||
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OK, I agree there might be a future in developing various kinase inhibitors, but do you have any idea of how huge the doses of even the best inhihibitors have to be to block such intracellular targets in vivo? Even if a ligand has a ~1nM affinity you still need doses of a few 100mg! And I'm talking about compounds with good lipophylicity! Just imagine an low lipophylic amine going trough the BBB and the cell membrane. The concentration in blood and the nerve cytosol might reach a few 1000 times difference. “The real drug-problem is that we need more and better drugs.” – J. Ott |
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Lilienthal (Moderator) 08-25-04 10:35 No 527249
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All those protein kinases are part of the... | ||||||
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All those protein kinases are part of the general signaling cascade. They can be activated by many different receptors, depending on which receptors a cell expresses. Therefore targeting those signaling enzymes would probably result in a very broad and unspecific action. Targeting receptors definitely would me more specific in which cells are affected. Kind of like writing computer viruses compared to blowing up a power plant
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scarmani (Hive Bee) 08-25-04 23:51 No 527355
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Speculative and Theoretical | ||||||
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Admittedly this is a lot of speculative pharmacology that doesn't exist yet and may not be of much general interest at the moment, (especially to the practical clandestine chemist.) But given the development of delivery systems for pharmaceutical drugs (transdermal patches, slow-release implants, metered intrathecal delivery, microcapsules / nanotechnology) ten or twenty years from now it may be possible to envision targeted delivery of microgram quantities of chemicals directly into the brain, even specific regions of the brain. One thing that would drive the development of this technology develop is the desire to treat illnesses such as inoperable brain cancer, or localized brain trauma / stroke. If this technology ever becomes possible, then the whole area of targeted modulation of peptides and cellular messengers may open up as a way to engineer the brain much more precisely than the orally administered drugs of today. And I believe that eventually, wherever there is an existing technological way, there will be a clandestine chemist with the will... Not practical, but definitely fun to read about (at least for me, heh  )
boot from the shadow of a broken mirror |
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jsorex (Hive Addict) 08-25-04 23:56 No 527357 
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perhaps a digest with only the doi's would've... | ||||||
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perhaps a digest with only the doi's would've been better. 
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