Modulatory role of neuropeptide FF system in nociception and opiate analgesia

The tetra-peptide FMRF-NH(2) is a cardioexcitatory peptide in the clam. Using the antibody against this peptide, FMRF-NH(2)-like immunoreactive material was detected in mammalian CNS. Subsequently, mammalian FMRF-NH(2) immunoreactive peptides were isolated from bovine brain and characterized to be FLFQPQRF-NH(2) (NPFF) and AGEGLSSPFWSLAAPQRF-NH(2) (NPAF). The genes encoding NPFF precursor proteins and NPFF receptors 1 and 2 are expressed in all vertebrate species examined to date and are highly conserved. Among many biological roles suggested for the NPFF system, the possible modulatory role of NPFF in nocicetion and opiate analgesia has been most widely investigated. Pharmacologically, NPFF-related peptides were found to exhibit analgesia and also potentiate the analgesic activity of opiates when administered intrathecally but attenuate the opiate induced analgesia when administered intracerebroventricularly. RF-NH(2) peptides including NPFF-related peptides were found to delay the rate of acid sensing ion channels (ASIC) desensitization resulting in enhancing acid gated currents, raising the possibility that NPFF also may have a pain modulatory role through ASIC. The genes for NPFF as well as NPFF-R2, preferred receptor for NPFF, are highly unevenly expressed in the rat CNS with the highest levels localized to the superficial layers of the dorsal spinal cord. These two genes are also present in the dorsal root ganglia (DRG), though at low levels in normal rats. NPFF and NPFF-R2 mRNAs were found to be coordinately up-regulated in spinal cord and DRG of rats with peripheral inflammation. In addition, NPFF-R2 immunoreactivity in the primary afferents was increased by peripheral inflammation. The findings from the early studies on the analgesic and morphine modulating activities suggested a role for NPFF in pain modulation and this possibility is further supported by the distribution of NPFF and its receptor and the regulation of the NPFF system in vivo.     

Modulatory role of presynaptic nicotinic receptors in synaptic and non-synaptic chemical communication in the central nervous system

Neuronal nicotinic acetylcholine receptors (nAChRs) belong to a family of ligand-gated channels closely related to but distinct from the muscle nAChRs. Recent progress in neurochemical and pharmacological methods supports the hypothesis of presynaptically located nAChRs on axon terminals and indicates that the major effect of nAChR is the modulation rather than processing of fast synaptic transmission. Strong neurochemical evidence indicate that the most important function of presynaptic nAChRs in either synaptic or non-synaptic localization is to increase transmitter release initiated by axonal firing, or directly induce Na⁺ and Ca²⁺ influx followed by a depolarization sufficient to activate local voltage-sensitive Ca²⁺ channels, as a result transmitter of vesicular origin will be released. Therefore, it is somewhat expected that nicotine-induced transmitter release of different monoamines including norepinephrine (NE), dopamine (DA), serotonin (5-HT) can be tetrodotoxin (TTX)- and [Ca²⁺]_o-sensitive. However, some of the nAChR agonists at higher concentrations (1,1-dimethyl-4-phenylpiperazinium (DMPP) and lobeline), besides their effects on presynaptic nAChRs, are able to inhibit the uptake of NE and 5-HT into nerve terminals, thereby their transmitter releasing effects are extended in time and space. The effect on the uptake process is different from classical nicotinic actions, not being sensitive to nAChR antagonism, but can be prevented by selective uptake blockers or reduced temperature. Considering neurochemical, pharmacological and electrophysiological evidence it seems likely that presynaptic nAChRs on monoaminergic fibers are composed of 3 or 4 subunits in combination with the β2 subunit. This is supported by the observation that nicotinic agonists have no presynaptic effect on transmitter release in knockout mice lacking the β2 nAChR subunit gene. The essential brain function lies not only in impulse transmission within a hard-wired neuronal circuitry but also within synaptic and non-synaptic communication subjected to presynaptic modulation. Since the varicose noradrenergic, dopaminergic, serotonergic, glutamatergic and cholinergic axon terminals mainly do not make synaptic contact, but their varicosities are equipped with nAChRs and these non-synaptically localized receptors are of high affinity, it is suggested that nicotine inhaled during smoking might exert its behavioral, psychological, neurological and neuroendocrinological effects via these receptors.     

Modulatory role for CCK-B antagonists in Parkinson's disease

We examined the ability of selective CCK-A and CCK-B receptor antagonists to induce or modulate the locomotor stimulant effects of dopamine agonists in MPTP-treated squirrel monkeys. Administration of 1-100 micrograms/kg i.p. of either the selective CCK-A receptor antagonist devazepide (MK-329) or the CCK-B receptor antagonist L-365,260 alone failed to stimulate a locomotor response in parkinsonian monkeys. In contrast, treatment with L-365,260 caused a 50-60% potentiation of the locomotor stimulatory effects of L-DOPA or (+)-PHNO. No such modulatory effects were observed following pretreatment with devazepide. We suggest that CCK-B receptor antagonists may be useful adjuncts to existing dopamine replacement therapy for improved management of Parkinson's disease.     

Modulatory role of grape seed extract on age-related oxidative DNA damage in central nervous system of rats

Aging is the accumulation of diverse deleterious changes in the cells and tissues leading to increased risk of diseases. Oxidative stress is considered as a major risk factor and contributes to age related increase in DNA oxidation and DNA protein cross-links in central nervous system during aging. In the present study, we have evaluated the salubrious role of grape seed extract on accumulation of oxidative DNA damage products such as 8-OHdG and DNA protein cross-links in aged rats. Male albino rats of Wistar strain were divided into four groups: Group I, young control rats; Group II, young rats treated with grape seed extract (100 mg/kg b.wt.) for 30 days; Group III, aged control rats; Group IV, aged rats supplemented with grape seed extract (100 mg/kg b.wt.) for 30 days. Our results, thus, revealed that grape seed extract has inhibiting effect on the accumulation of age-related oxidative DNA damages in spinal cord and in various brain regions such as cerebral cortex, striatum and hippocampus.     

Modulatory role for biogenic amines in the cerebral cortex. Microiontophoretic studies

In order to investigate the mode of action of biogenic amines in rat cerebral cortex, the unitary activity of spontaneously firing neurons and their excitatory response to acetylcholine (ACh) were examined using microiontophoretic administration of dopamine (DA), noradrenaline (NA) and serotonin (5-HT). The predominant effect of these biogenic amines on the spontaneous activity was a profound and prolonged inhibition of firing (2–4 min), which attained its maximum within 15–120 sec. This response was generally more abrupt in onset and of greater magnitude with NA and 5-HT than with DA. Most units inhibited by DA, NA and 5-HT also showed marked depression of their excitatory response to ACh when pretreated with these biogenic amines. With repetitive administration of ACh, it could be shown that the total duration of inhibition of ACh responses by DA and NA was not as prolonged as the inhibition of the spontaneous firing of the same cells. With 5-HT, the initial ACh responses of many neurons could be completely blocked, and this inhibitory effect lasted as long as the inhibition of spontaneous firing.In view of the anatomical data demonstrating a relative sparsity of monoamine nerve terminals in cerebral cortex, the strong inhibition induced by DA, NA or 5-HT may have reflected slow inactivation of the biogenic amines. However, it could also be indicative of underlying mechanisms of action dependent on metabolic changes. Indeed, the interaction between biogenic amines and ACh might imply a balance between the intracellular pools of cAMP and cGMP is directly or indirectly influenced by the biogenic amines and ACh, respectively. This hypothesis would not exclude other modes of local interaction between DA, NA, 5-HT and ACh, and appears compatible with the modulatory role of biogenic amines in cerebral cortex.     

Modulatory role of lysophosphatidic acid on opioid receptor binding

Arachidonic acid (AA) and lysophosphatidic acid (LPA) are two important signaling molecules generated by the hydrolysis of membrane phospholipids by the action of phospholipase A2 (PLA2) enzymes. We have previously shown that arachidonic acid affects opioid receptor binding in a negative manner. In the present study, we have investigated the modulatory role of LPA on equilibrium binding of [3H]naloxone to rat brain opioid receptors. The preliminary data demonstrates that LPA at physiological concentrations (100-400 nM) was capable of modulating opioid receptor binding. 100 nM free lysophosphatidic acid concentration stimulates while 200 and 400 nM concentrations inhibit binding. This observation brings the possibility of a cross talking mechanism between opioid and LPA signaling pathways.     

Modulatory action and distribution of the neuropeptide proctolin in the crustacean stomatogastric nervous system

Immunocytochemical methods were used to map the distribution of proctolinlike immunoreactivity in the stomatogastric nervous systems (stomatogastric ganglion (STG), paired commissural ganglia (CG), oesophageal ganglion (OG), and connecting nerves) of three crustacean species: Panulirus interruptus, Cancer borealis, and Homarus americanus. Although the patterns of proctolinlike staining were similar among the three species, some differences were also observed. Over 70% of the proctolinlike material in STGs, as measured by radioimmunoassay, was indistinguishable from authentic proctolin in reverse-phase high-performance liquid chromatography. Bath application of proctolin to STGs from Cancer and Panulirus induced characteristic and robust (though somewhat different) changes in their motor patterns. The threshold concentration was approximately 10(-9)M proctolin, and the effects were dose-dependent. These data suggest that the neuropeptide proctolin serves as a neuromodulator of the stomatogastric ganglion.     

Modulatory action of noradrenergic system on spinal motoneurons in humans.

Previous findings in animals demonstrated that the noradrenergic coeruleospinal system exerts a tonic facilitation on spinal reflexes and that activation of alpha2-autoinhibitory receptors can be responsible for a disfacilitation of the spinal activity. To investigate this issue further, we examined whether this system is also involved in descending facilitatory control of spinal motoneurons in healthy humans. The H-reflex technique was utilized to assay the motoneuronal excitability. The ratio between the maximal reflex response (H) and maximal direct response (M) was determined in each subject and was calculated at 10 min intervals before and after i.v. administration of the alpha2-agonist clonidine (0.5 microg/kg). In all subjects a marked decrease of the H/M ratio, due to depression of the H response, occurred 10 min following the clonidine injection and reached its maximum within 30 min. No significant changes of blood pressure values were provoked by drug injections. These results suggest that an autoinhibitory action may be induced by alpha2-receptor activation of locus coeruleus neurons in humans, and that this device may serve as a mechanism for a myotonolytic action on spinal motoneurons.     

GABAb受体在海马 PP-DG习得性LTP中的调制作用

应用慢性埋植电极技术以电生理结合行为学的方法,在大鼠明暗分辨学习中,于每实验日训练前给DG微量注射GABAb受体拮抗剂saclofen 1μl,观察此处理对海马DG突触效应及行为习得的影响,结果表明:较高浓度(50 μmol/L)的saclofen对DG突触效应的习得性长时程增强(Long-term potentiation,LTP)的形成有明显的抑制性影响,相应地阻抑明暗分辨学习的习得;加快习得性LTP的消退,使行为消退加速.较低浓度(25μmol/L)的saclofen却易化习得性LTP的形成,加快条件反射的建立;延缓习得性LTP及行为的消退.提示GABAb受体在海马DG习得性LTP的形成与保持中有重要的调制作用,本文并就此予以讨论.     

GABA_b受体在海马PP-DG习得性LTP中的调制作用

应用慢性埋植电极技术以电生理结合行为学的方法 ,在大鼠明暗分辨学习中 ,于每实验日训练前给DG微量注射 GABAb 受体拮抗剂 saclofen1 μl,观察此处理对海马 DG突触效应及行为习得的影响 ,结果表明 :较高浓度 (50 μmol/L)的 saclofen对 DG突触效应的习得性长时程增强 (Long- term potentiation,LTP)的形成有明显的抑制性影响 ,相应地阻抑明暗分辨学习的习得 ;加快习得性 LTP的消退 ,使行为消退加速。较低浓度 (2 5μmol/L)的 saclofen却易化习得性 LTP的形成 ,加快条件反射的建立 ;延缓习得性 LTP及行为的消退。提示 GABAb 受体在海马 DG习得性 LTP的形成与保持中有重要的调制作用 ,本文并就此予以讨论     

Plasticity of neuroendocrine-immune interactions during aging.

Intact neuroendocrine-immune interactions are essential for the development and functional maintenance of both systems. Normal physiological aging appears to be, in part, dependent on age-related modifications of neuroendocrine-immune interactions. The thymus plays a major role in this context. Experimental manipulation at the thymic or neuroendocrine level may reciprocally correct the age-associated dysfunctions, suggesting the reversible nature of such phenomena.     

Behavioral alterations in reward system function: the role of childhood maltreatment and psychopathology

OBJECTIVE: To examine in children the influence of maltreatment and associated psychiatric sequelae on behavioral responses to reward stimuli. METHOD: A computerized two-choice decision-making task involving probabilistic monetary gains was used to probe elemental processes of goal-directed actions. Using different risk contingencies, the authors examined decision-making, expectations of outcomes, and affective responses to rewards in 38 maltreated children and 21 demographically matched controls (8-14 years old). RESULTS: Maltreated children selected risk options faster than controls; however, whereas controls responded more quickly as the chance of winning increased, maltreated children did not vary in response speed as a function of the likelihood of winning. When choosing between high- and low-risk options, maltreated children with depressive disorders more frequently selected safe over risky choices than did controls. No group differences emerged in self-report ratings of positive or negative reactions to winning or not winning, respectively. CONCLUSIONS: This initial experimental study of responses to reward lays the groundwork for subsequent research on neurodevelopmental aspects of reward processes in relationship to maltreatment and psychopathology. Clinical applications of these data may be relevant for developing treatment plans for maltreated children, particularly those with depression.     

Modulatory role of cyclooxygenase inhibitors in aging- and scopolamine or lipopolysaccharide-induced cognitive dysfunction in mice

Inflammation processes may play a critical role in the pathogenesis of the degenerative changes and cognitive impairments associated with Alzheimer's disease (AD). Non-steroidal anti-inflammatory drugs are reported to be effective in reducing the risk of developing AD or cognitive impairments. Present experiments were performed to study the possible effect of various NSAIDs on cognitive performance of young, aged and scopolamine or lipopolysaccharide (LPS) treated mice (an animal model of AD) using one trial step through type of passive avoidance and in elevated plus maze task. Chronic administration of NSAIDs at the ED(50) doses (nimesulide, rofecoxib and naproxen for 15 days) significantly reversed the age or scopolamine-induced retention deficits in both test paradigms. However, in both the memory paradigms chronic administration of NSAIDs failed to modulate the retention performance of young mice. Acute administration of LPS (50 mcg/mouse, i.p.) significantly exhibited retention deficits after 24 h and seventh day of its administration in both test paradigms. Chronic administration (7 days) of rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor (1.92 mg/kg, p.o.) significantly reversed the LPS-induced retention deficits in both tests. The results of this study showed chronic treatment of NSAIDs reverses the cognitive deficits in age and scopolamine or LPS treated mice. These findings establish a link between the central nervous system expression of various pro-inflammatory cytokines and learning impairment in mice.     

Stress-related peripheral neuroendocrine-immune interactions in women with ulcerative colitis

OBJECTIVES: The mechanisms underlying the interaction of psychological stress with the disease course in inflammatory bowel diseases remain unclear. We analyzed the neuroendocrine and cellular immune responses to public speaking stress, and the in vitro adrenergic and glucocorticoid modulation of cytokine production by peripheral blood cells (PBCs) in women with ulcerative colitis (UC) compared to healthy female controls. METHODS: In 22 female UC patients with inactive disease or mild disease activity and 24 healthy females we analyzed the neuroendocrine and cellular immune responses to public speaking stress and the vitro beta-adrenergic and glucocorticoid regulation of IL-10 and TNF-alpha production by PBCs. RESULTS: Public speaking stress-induced neuroendocrine and sympatho-adrenal activation, as well as the redistribution of circulating leukocytes were comparable in UC and controls. Significant but comparable public speaking stress-induced increases in LPS-stimulated TNF-alpha and IL-10, as well as in CD2/CD28-stimulated IFN-gamma were observed in both groups. UC demonstrated significantly reduced baseline IFN-gamma production, as well as significantly lower basal cortisol and prolactin levels. The in vitro beta-adrenergic stimulation of PBCs revealed reduced IL-10 response in UC. CONCLUSIONS: Psychosocial stress-induced activation of the neuroendocrine and sympatho-adrenal systems remain unaltered in UC, suggesting that the mechanism(s) mediating effects of psychological stress on disease activity are likely operative downstream at the level of the intestine. However, UC patients show disturbances in basal endocrine and cytokine measures. Together with our in vitro evidence of disturbed adrenergic regulation of IL-10 production by stimulated PBCs in UC, these may indicate the existence of subtle disturbance of peripheral cellular neuroendocrine-immune interactions in UC.     

Modulatory role of 5-HT3 receptors in mediation of apomorphine-induced aggressive behaviour in male rats

We have studied the effects of serotonin (5-HT) 5-HT3 receptor agonists 1-phenylbiguanide (1-PBG) and 1-(m-chlorophenyl)biguanide (mCPBG), and antagonists 3-tropanyl-3,5-dichlorobenzoate (MDL-72222) and tropisetron (3-tropanyl-indole-3-carboxylate HCl; ICS-205930) on apomorphine-induced aggressive behaviour in normal or DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride] pre-treated male Wistar rats. DSP-4 (50 mg/kg) pre-treatment significantly accelerated the development of apomorphine-induced aggressive behaviour. mCPBG (1.0 and 10 mg/kg) did not modify the aggressiveness, but 1-PBG (3.0 and 30 mg/kg) attenuated the aggressiveness in normal but not DSP-4 pre-treated rats. MDL-72222 (0.4 and 4.0 mg/kg) attenuated the aggressive behaviour in normal rats, tropisetron (0.3 mg/kg) had an antiaggressive effect only by citalopram (10 mg/kg) challenge. MDL-72222 and tropisetron were ineffective in DSP-4 pre-treated rats. In conclusion, our results indicate that the 5-HT3 receptors modulate the apomorphine-induced aggressive behaviour and the 5-HT3 receptor antagonists have moderate antiaggressive effect in this test.