Neurobiological mechanisms involved in nicotine dependence and reward: Participation of the endogenous opioid system

Nicotine is the primary component of tobacco that maintains the smoking habit and develops addiction. The adaptive changes of nicotinic acetylcholine receptors produced by repeated exposure to nicotine play a crucial role in the establishment of dependence. However, other neurochemical systems also participate in the addictive effects of nicotine including glutamate, cannabinoids, GABA and opioids. This review will cover the involvement of these neurotransmitters in nicotine addictive properties, with a special emphasis on the endogenous opioid system. Thus, endogenous enkephalins and beta-endorphins acting on mu-opioid receptors are involved in nicotine-rewarding effects, whereas opioid peptides derived from prodynorphin participate in nicotine aversive responses. An up-regulation of mu-opioid receptors has been reported after chronic nicotine treatment that could counteract the development of nicotine tolerance, whereas the down-regulation induced on kappa-opioid receptors seems to facilitate nicotine tolerance. Endogenous enkephalins acting on mu-opioid receptors also play a role in the development of physical dependence to nicotine. In agreement with these actions of the endogenous opioid system, the opioid antagonist naltrexone has shown to be effective for smoking cessation in certain sub-populations of smokers.     

大鼠三叉神经中脑核内PPD、PPE样阳性终末与PAG和PV共存神经元的联系

目的：观察大鼠三叉神经中脑核（Vme)神经元内磷酸激活的谷氨酰胺酶（PAG）和小白蛋白（PV）的共存关系，以及前强啡肽原（PPD）样和前脑啡肽原（PPE）样阳性科末与PAG和PV共存神经元之间的联系。方法和PV样免疫反应神经元，吻尾方向上几乎在其全长出现，多为大的假单极神经元，许多PAG样阳性神经元同时呈PV燕免疫反应，双标细胞占全部标记细胞的95％以上，在激光共聚焦显微镜下观察到，少量PPD或PPE样阳性终末围绕在PAG样和PV样双重标记的Vme神经元胞体周围，并与之形成密切接触，结论：在面口部本体感觉住处由Vme向更高一级神经元的过程中，PV可能和谷氨酸一起发挥着重要的作用，与此同时Vme神经元还可能接受中枢内强啡肽样和脑啡肽样神经终末对它的调控。     

内皮素、一氧化氮、强啡肽A与肝硬化的关系

目的：探讨内皮素－１（ＥＴ－１）、一氧化氮（ＮＯ）、强啡肽Ａ在肝硬化腹水形成中的作用。方法：应用放射免疫分析法及荧光法测定５６例肝硬化伴腹水，４８例经无腹水及４０例正常对照的血浆ＥＴ－１、ＮＯ、ＤｙｎＡ的含量，结果：肝硬化伴腹水、肝化无腹水及正常组中ＥＴ－１的含量分别为９３．７３±４５．３８．７６．５２±１５．７４ｎｇ／ｌ，ＮＯ的含量分别为２６．６１±１１．２，２２．８２±８．９、１９．２１±６．     

Comparative distribution of GABAergic and peptide-containing neurons in the lateral lemniscal nuclei of the rat

By immunostaining, neurons expressing peptides (dynorphin and corticotropin-releasing factor, CRF) and glutamate decarboxylase (GAD), a GABA-synthesizing enzyme, were precisely mapped in the rat lateral lemniscal nuclei. While GAD neurons were numerous and preferably localized in the dorsal (DLL) and ventral (VLL) nuclei, neurons expressing these peptides were less numerous and localized primarily in the intermediate (ILL) nucleus of the lateral lemniscus. The ILL nucleus was shown to project to the inferior colliculus and to express Fos rapidly in response to peripheral acoustic stimulation, suggesting that the ILL nucleus may take part in non-GABAergic relay of acoustic information in the lateral lemniscus.     

Effects of κ-opioid receptor ligands on intracranial self-stimulation in rats

Rationale Elevations in cAMP response element binding protein (CREB) function within the mesolimbic system of rats reduce cocaine reward in place conditioning studies and increase immobility in the forced swim test. Each of these behavioral adaptations can be interpreted as a depressive-like effect (i.e., anhedonia, despair) that may reflect reduced activity of brain reward systems. Furthermore, each effect appears due to increases in CREB-mediated expression of dynorphin, since each is attenuated by intracranial injections of the -opioid receptor antagonist norBNI.Objectives Intracranial self-stimulation (ICSS) studies were conducted in rats to determine whether administration of a -agonist would have depressive-like effects on brain stimulation reward, and whether pretreatment with a -antagonist would attenuate any such effects. Conditions that have depressive effects in people (e.g., drug withdrawal) increase the threshold amounts of stimulation required to sustain ICSS in rats.Methods Sprague-Dawley rats with lateral hypothalamic stimulating electrodes were tested in a curve-shift variant of the ICSS procedure after systemic administration of the -agonist U-69593 alone, the novel -antagonist 5-acetamidinoethylnaltrindole (ANTI) alone, or co-administration of both drugs.Results U-69593 dose dependently increased ICSS thresholds, suggesting that activation of -receptors reduced the rewarding impact of the brain stimulation. ANTI had no effects on its own, but it attenuated increases in ICSS thresholds caused by the agonist.Conclusions These data provide further evidence that stimulation of brain -receptors may trigger certain depressive-like signs, and that antagonists may have efficacy as antidepressants without having reward-related actions of their own.     

Alterations in mRNA levels of D2 receptors and neuropeptides in striatonigral and striatopallidal neurons of rats with neuroleptic-induced dyskinesias

Chronic neuroleptic treatment in rat produces vacuous chewing movements (VCMs), analogous to TD in humans. We hypothesized that these hyperkinetic movements were due to alterations in striatonigral and striatopallidal GABAergic spiny II neurons. Rats were treated for 36 weeks with haloperidol decanoate and withdrawn for 28 weeks. Striatonigral and striatopallidal neurons were assessed using in situ hybridization histochemistry for mRNA levels of D1 and D2 dopamine receptors, preproenkephalin (ENK), prodynorphin (DYN), protachykinin (substance P), and glutamate decarboxylase (GAD67) in the dorsolateral and ventromedial striatum as well as the nucleus accumbens. Rats that did not develop VCMs (- VCM) had increased D2 receptor and DYN mRNA, and reduced substance P mRNA in the dorsolateral striatum. Rats with persistent VCMs (+VCM,) had increased D2 receptor, ENK, and DYN mRNA in both striatal regions, and increased ENK and DYN mRNA in the nucleus accumbens, compared with controls. Relative to -VCM rats, however, +VCM rats only had increased ENK mRNA in the nucleus accumbens. Considering the overall pattern of mRNA changes, the data suggest that alterations in both the D1-mediated striatonigral and the D2-mediated striatopallidal pathways play a role in the expression of the VCM syndrome. To the extent that gene expression parallels changes in neuronal activity, this implies that the VCM syndrome is associated with increased activity in both pathways. © 1994 Wiley-Liss, Inc

1 This article is a US Government work and as such, is in the public domain in the United States of America.

     

Development of highly potent and ective dynorphin A analogues as new medicines

Abstract: Dynorphin A (Dyn A), a 17 amino acid peptide H‐Tyr‐Gly‐Gly‐Phe‐Leu‐Arg‐Arg‐Ile‐Arg‐Pro‐Lys‐Leu‐Lys‐Trp‐Asp‐Asn‐Gln‐OH, is a potent opioid peptide which interacts preferentially with κ‐opioid receptors. Research in the development of selective and potent opioid peptide ligands for the κ‐receptor is important in mediating analgesia. Several cyclic disulphide bridge‐containing peptide analogues of Dyn A, which were conformationally constrained in the putative message or address segment of the opioid ligand, were designed, synthesized and assayed. To further investigate the conformational and topographical requirements for the residues in positions 5 and 11 of these analogues, a systematic series of Dyn A_1?11‐NH₂ cyclic analogues incorporating the sulphydryl‐containing amino acids l ‐ and d ‐Cys and l ‐ and d ‐Pen in positions 5 and 11 were synthesized and assayed. Cyclic lactam peptide analogues were also synthesized and assayed. Several of these cyclic analogues, retained the same affinity and selectivity (vs. the μ‐ and δ‐receptors) as the parent Dyn A_1?11‐NH₂ peptide in the guinea‐pig brain (GPB), but exhibited a much lower activity in the guinea‐pig ileum (GPI), thus leading to centrally vs. peripherally selective peptides. Studies of the structure–activity relationship of Dyn A peptide provide new insights into the importance of each amino acid residue (and their configurations) in Dyn A analogues for high potency and good selectivity at κ‐opioid receptors. We report herein the progress towards the development of Dyn A peptide ligands, which can act as agonists or antagonists at cell surface receptors that modulate cell function and animal behaviour using various approaches to rational peptide ligand‐based drug design.     

Constitutive and inducible nitric oxide synthases after dynorphin-induced spinal cord injury

It has recently been demonstrated that selective inhibition of both neuronal constitutive and inducible nitric oxide synthases (ncNOS and iNOS) is neuroprotective in a model of dynorphin (Dyn) A(1-17)-induced spinal cord injury. In the present study, various methods including the conversion of 3H-L-arginine to 3H-citrulline, immunohistochemistry and in situ hybridization are employed to determine the temporal profiles of the enzymatic activities, immunoreactivities, and mRNA expression for both ncNOS and iNOS after intrathecal injection of a neurotoxic dose (20 nmol) of Dyn A(1-17). The expression of ncNOS immunoreactivity and mRNA increased as early as 30 min after injection and persisted for 1-4 h. At 24-48 h, the number of ncNOS positive cells remained elevated while most neurons died. The cNOS enzymatic activity in the ventral spinal cord also significantly increased at 30 min 48 h, but no significant changes in the dorsal spinal cord were observed. However, iNOS mRNA expression increased later at 2 h, iNOS immunoreactivity and enzymatic activity increased later at 4 h and persisted for 24-48 h after injection of 20 nmol Dyn A(1-17). These results indicate that both ncNOS and iNOS are associated with Dyn-induced spinal cord injury, with ncNOS predominantly involved at an early stage and iNOS at a later stage.     

慢性充血性心力衰竭患者血浆精氨酸加压素及内源性阿片肽含量的变化

应用放射免疫法测定了45例慢性风湿性心脏病患者和43例正常人血浆精氨酸加压素(AVP)、β-内啡肽(β-EP)、亮氨酸脑啡肽(LEK)和强啡肽Al-13(DynAl-13)的含量。结果显示,与正常对照组相比,风湿性心脏病患者血浆AVP和LEK含量明显增高(p<0.05),DynA1-13却明显降低(p<0.05);β-EP在两组间无明显差异。二尖瓣狭窄组血浆AVP含量显著高于二尖瓣关闭不全组(p<0.05);β-EP、LEK和DynAl-13含量在两组间无显著差异。提示AVP和内源性阿片肽系统参与了慢性心功能不全的病理生理过程。     

强啡肽对大鼠脊髓损伤的作用及其受体机制

目的 探明强啡肽（Dyn）在继发性脊髓损伤中的作用及其受体机制。方法观察鞘内注射DynA（1-13）或联合注射Kappa阿片受体拮抗剂卡匹帕明（nor-BNI）或兴奋性氨基酸（EAA）的NMDA受体拮抗剂MK-801后运动功能和脊髓前角神经元酶组织化学的变化。结果注射30nmol DynA（1-13）3d时,Rivlin斜板临界角变化增大,前角神经元酸性磷酸酶（ACP）活性增强;14d时,Rivlin斜板临界角变化未恢复,ACP活性轻度增强。鞘内联合注射100n mol nor-BNI、100n mol MK-801后3d,Rivlin斜板临界角增大和ACP活性增强,但在14d时Rivlin斜板临界角变化明显恢复、ACP活性接近正常,与Dyn组的差异有显著性;nor-BNI组与MK-801组的差异无显著性。结论Dyn鞘内注射可损害大鼠运动功能和脊髓组织,而nor-BNI或MK-801能对抗其损害作用。Dyn的病理作用是通过Kappa阿片受体和NMDA受体两种途径介导的。