Home About us Contact
|
Home About us Contact | ||
|
|
||
Receptor Mechanism (receptor + mechanism)
Selected AbstractsAre CB1 receptor antagonists nootropic or cognitive impairing agents?DRUG DEVELOPMENT RESEARCH, Issue 8 2009Stephen A. Varvel Abstract For more than a decade, a considerable amount of research has examined the effects of rimonabant (SR 141716) and other CB1 receptor antagonists in both in vivo and in vitro models of learning and memory. In addition to its utility in determining whether the effects of drugs are mediated though a CB1 receptor mechanism of action, these antagonists are useful in providing insight into the physiological function of the endogenous cannabinoid system. Several groups have reported that CB1 receptor antagonists enhance memory duration in a variety of spatial and operant paradigms, but not in all paradigms. Conversely, disruption of CB1 receptor signaling also impairs extinction learning in which the animal actively suppresses a learned response when reinforcement has been withheld. These extinction deficits occur in aversively motivated tasks, such as in fear conditioning or escape behavior in the Morris water maze task, but not in appetitively motivated tasks. Similarly, in electrophysiological models, CB1 receptor antagonists elicit a variety of effects, including enhancement of long-term potentiation (LTP), while disrupting long-term depression (LTD) and interfering with transient forms of plasticity, including depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE). The collective results of the in vivo and in vitro studies employing CB1 receptor antagonists, demonstrate that these receptors play integral roles in different components of cognitive processing. Functionally, pharmacological blockade of CB1 receptors may strengthen memory duration, but interferes with extinction of learned behaviors that are associated with traumatic or aversive memories. Drug Dev Res 70:555,565, 2009. © 2009 Wiley-Liss, Inc. [source] Adenosine A2a receptor-mediated inhibition of rod opsin mRNA expression in tiger salamanderJOURNAL OF NEUROCHEMISTRY, Issue 3 2002Peter D. Alfinito Abstract The neuromodulator adenosine mediates dark-adaptive changes in retinal photoreceptors through A2a receptors. In cold-blooded vertebrates, opsin mRNA expression is lower at night than during the day. In the present study, we tested whether adenosine could inhibit opsin mRNA expression in cultured rod cells and if endogenous adenosine acts to suppress opsin mRNA in the intact retina at night. Semi-quantitative in situ hybridization showed that treatment with 100 nm of the A2a/A2b agonist N,6 -[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)-ethyl]adenosine (DPMA) reduced opsin mRNA 41% in cultured rod cells. The effect of DPMA was blocked by 10 µm of the A2a antagonist 8-(3-chlorostyryl)caffeine (CSC) but not by 10 µm of the A2b antagonist alloxazine. One micromolar adenosine alone had no effect on opsin mRNA. However, in the presence of the adenosine deaminase inhibitor erythro -9-(2-hydroxy-3-nonyl)adenine hydrochloride (EHNA), 1 µm adenosine reduced opsin mRNA 61%. EHNA alone reduced opsin mRNA by 26%. Consistent with an A2a receptor mechanism, 100 nm forskolin (adenylate cyclase agonist) decreased opsin mRNA 34%. Finally, northern blots showed that intravitreal injection of 10 µm CSC at night increased opsin I mRNA 38%. Thus, endogenous adenosine suppresses rod opsin I mRNA expression at night; in vitro results indicate this reduction occurs through A2a -like receptor binding and stimulation of adenylate cyclase activity. [source] Activated platelets contribute to stimulation of cardiac afferents during ischaemia in cats: role of 5-HT3 receptorsTHE JOURNAL OF PHYSIOLOGY, Issue 3 2002Liang-Wu Fu Myocardial ischaemia activates blood platelets and cardiac sympathetic afferents, which mediate chest pain and cardiovascular reflex responses. We have demonstrated that activated platelets stimulate ischaemically sensitive cardiac sympathetic afferents. Platelets absorb and release 5-hydroxytryptamine (5-HT) when they are activated. In the present study we hypothesized that, by releasing 5-HT, activated platelets stimulate cardiac afferents during ischaemia through a 5-HT3 receptor mechanism. Platelet-rich plasma (PRP) and platelet-poor plasma (PPP) were obtained from cats. Activation of platelets in PRP was induced by thrombin (5 units ml,1) or collagen (2 mg kg,1). Using high-performance liquid chromatography, we observed that the concentration of 5-HT was increased significantly in suspensions of platelets activated with thrombin (PRP+thrombin, 28 ± 1.7 ,m) or collagen (PRP+collagen, 27 ± 2.5 ,m) compared with suspensions of unactivated platelets (PRP+saline, 2.3 ± 0.8 ,m) and PPP. During myocardial ischaemia and reperfusion, tirofiban, a specific inhibitor of platelet glycoprotein (GP) IIb-IIIa receptors (100 ,g kg,1, I.V., followed by 5 ,g kg,1 min,1), significantly reduced the increase in the concentration of 5-HT in cardiac venous plasma from ischaemic region. Nerve activity of single-unit cardiac afferents was recorded from the left sympathetic chain (T2-T5) in anaesthetized cats. Eighty ischaemically sensitive and seven ischaemically insensitive cardiac afferents were identified. Tirofiban reduced the ischaemia-related increase in activity of seven cardiac sympathetic afferents by 50 %. Injection of 1.5 ml of PRP+collagen or PRP+thrombin into the left atrium (LA) increased activity of 16 cardiac afferents. Tropisetron (300 ,g kg,1, I.V.), a selective 5-HT3 receptor antagonist, eliminated the afferent's responses to platelets activated with collagen or thrombin. Moreover, LA injection of 5-HT (20-40 ,g kg,1) and PBG (100 ,g kg,1), a 5-HT3 receptor agonist, stimulated nine ischaemically sensitive cardiac sympathetic afferents, significantly increasing the activity of these afferents. However, injection of ,-M-5-HT (100 ,g kg,1, LA), a 5-HT2 receptor agonist, stimulated only two of the nine ischaemically sensitive cardiac afferents, and thus did not significantly alter impulse activity of this group of afferents. Both the 5-HT1 (5-CT, 100 ,g kg,1, LA) and 5-HT4 receptor agonists (SC53116, 100 ,g kg,1, LA) did not stimulate any of the nine afferents tested. Tropisetron (300 ,g kg,1, I.V.) also eliminated the response of seven ischaemically sensitive cardiac afferents to exogenous 5-HT and attenuated the ischaemia-related increase in activity of nine cardiac sympathetic afferents by 41 %. Conversely, LA injection of 5-HT (40 ,g kg,1) did not stimulate any of seven ischaemically insensitive cardiac afferents, although this group of afferents consistently responded to bradykinin (3 ,g, LA). These data indicate that during myocardial ischaemia the activated platelets stimulate cardiac sympathetic afferents, at least in part, through a 5-HT3 receptor mechanism. [source] Endoluminal Norepinephrine Inhibits Smooth Muscle Activity of the Pig Pyeloureter by Stimulation of ,-Adrenoceptors without Side EffectsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 5 2008Jens Mortensen The purposes were to describe concentration,response relationship and receptor mechanism of the effect of norepinephrine on muscle function of pyeloureter and to reveal possible side effects on cardiovascular and renal functions. Renal pelvis was perfused, while pelvic pressure, cardiovascular and renal functional parameters were recorded. In group A, a pelvic pressure increase was examined during pressure flow studies with norepinephrine solutions (0, 1, 5, 50 and 100 µg/ml). In group B, pelvis was perfused with 6 ml/min. norepinephrine solutions (0, 0.001, 0.01, 0.1 and 1 µg/ml). In group C, pelvis was perfused with 6 ml/min. norepinephrine, norepinephrine + sotalol 10,6 mol/l and norepinephrine + phentolamine 10,6 mol/l. Norepinephrine solutions of 0, 10,8, 10,7, 10,6, 10,5 and 10,4 mol/l were used. In group A, all norepinephrine solutions lowered the pelvic pressure increase significantly. Large increases in plasma and urine norepinephrine occurred with 50 and 100 µg/ml, but cardiovascular and renal functions remained unchanged. In group B, a significant diminishing pelvic pressure increase with all solutions was seen with a significant difference between all solutions. In group C, norepinephrine demonstrated a concentration,response curve with EC50 between 10,8 and 10,7 mol/l (10,7.27±0.40). Sotalol had a smooth muscle inhibitory effect on the pyeloureter and inhibited the effect of norepinephrine increasing EC50 by about a factor 10 (10,6.40±1.17). No convincing effect of phentolamine was observed. Endoluminal norepinephrine probably stimulates ,-adrenoceptors and inhibits a renal pelvis pressure increase to perfusion in a dose-related way without side effects. Endoluminal norepinephrine is safe in pigs and may be useful under endoscopy of the pyeloureter. [source] In vivo effects of CB2 receptor-selective cannabinoids on the vasculature of normal and arthritic rat knee jointsBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2008J J McDougall Background and purpose: Cannabinoids (CBs) are known to be vasoactive and to regulate tissue inflammation. The present study examined the in vivo vasomotor effects of the CB2 receptor agonists JWH015 and JWH133 in rat knee joints. The effect of acute and chronic joint inflammation on CB2 receptor-mediated responses was also tested. Experimental approach: Blood flow was assessed in rat knee joints by laser Doppler imaging both before and following topical administration of CB2 receptor agonists. Vasoactivity was measured in normal, acute kaolin/carrageenan inflamed and Freund's complete adjuvant chronically inflamed knees. Key results: In normal animals, JWH015 and JWH133 caused a concentration-dependent increase in synovial blood flow which in the case of JWH133 was blocked by the selective CB2 receptor antagonist AM630 as well as the transient receptor potential vanilloid-1 (TRPV1) antagonist SB366791. The vasodilator effect of JWH133 was significantly attenuated in both acute and chronically inflamed knees. Given alone, AM630 had no effect on joint blood flow. Conclusion and implications: In normal joints, the cannabinomimetic JWH133 causes hyperaemia via a CB2 and TRPV1 receptor mechanism. During acute and chronic inflammation, however, this vasodilatatory response is significantly attenuated. British Journal of Pharmacology (2008) 153, 358,366; doi:10.1038/sj.bjp.0707565; published online 5 November 2007 [source] Dissociable effects of cocaine-seeking behavior following D1 receptor activation and blockade within the caudal and rostral basolateral amygdala in ratsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 8 2009Yasmin Mashhoon Abstract Research with dopamine D1 receptor antagonists or neuronal inactivating agents suggests that there is dissociable regulation of cocaine-seeking behavior by the rostral and caudal basolateral amygdala. In the present study, discrete infusions of the D1 receptor agonist SKF 81297 (0.0,0.8 ,g per side) were compared with those of the D1 receptor antagonist SCH 23390 (0.0,2.0 ,g per side) to demonstrate directly the importance of D1 receptor mechanisms within the rostral and caudal basolateral amygdala for their functional heterogeneity in regulating cocaine-seeking behavior. Under a second-order schedule, cocaine-seeking behavior was studied during maintenance (cocaine and cocaine cues present) and reinstatement (only cocaine cues present). Food-maintained responding was used to examine the specificity of maximal behaviorally effective doses of SKF 81297 and SCH 23390. The results demonstrated that the D1 agonist (0.4 or 0.8 ,g) increased and the D1 antagonist (1.0 ,g) decreased cocaine-seeking behavior during maintenance when infused into the caudal but not the rostral basolateral amygdala. Cocaine intake was not affected by the agonist, and was decreased by the antagonist. During reinstatement, the D1 agonist (0.4 ,g) increased and the D1 antagonist (1.0 ,g) decreased cocaine-seeking behavior when infused into the rostral but not the caudal basolateral amygdala. In tests for behavioral specificity, the above effective doses of SKF 81297 and SCH 23390 used in self-administration experiments did not alter food-maintained responding. However, the 2.0-,g dose of SCH 23390 suppressed drug-maintained and food-maintained responding after infusion into both subregions. Collectively, these findings indicate dissociable sensitivity to D1 receptor ligands within the caudal and rostral basolateral amygdala for altering cocaine-seeking behavior under different conditions that model phases of addiction. [source] The Influence of Gender and Sex Steroids on Craniofacial NociceptionHEADACHE, Issue 2 2007Brian E. Cairns PhD Several pain conditions localized to the craniofacial region show a remarkable sex-related difference in their prevalence. These conditions include temporomandibular disorders and burning mouth syndrome as well as tension-type, migraine, and cluster headaches. The mechanisms that underlie sex-related differences in the prevalence of these craniofacial pain conditions remain obscure and likely involve both physiological and psychosocial factors. In terms of physiological factors relevant to the development of headache, direct evidence of sex-related differences in the properties of dural afferent fibers or durally activated second-order trigeminal sensory neurons has yet to be provided. There is, however, evidence for sex-related differences in the response properties of afferent fibers and second-order trigeminal sensory neurons that convey nociceptive input from other craniofacial tissues associated with sex-related differences in chronic pain conditions, such as those that innervate the masseter muscle and temporomandibular joint. Further, modulation of craniofacial nociceptive input by opioidergic receptor mechanisms appears to be dependent on biological sex. Research into mechanisms that may contribute to sex-related differences in trigeminal nociceptive processing has primarily focused on effect of the female sex hormone estrogen, which appears to alter the excitability of trigeminal afferent fibers and sensory neurons to noxious stimulation of craniofacial tissues. This article discusses current knowledge of potential physiological mechanisms that could contribute to sex-related differences in certain craniofacial pain conditions. [source] Olfactory responses to steroids in an African mouth-brooding cichlid, Haplochromis burtoni(Günther)JOURNAL OF FISH BIOLOGY, Issue 3 2006T. B. Cole Underwater electro-olfactogram (EOG) recordings involving 150 steroids and eight prostaglandins were used to determine which of these potential odorants are detected by the olfactory organ of an African cichlid, Haplochromis burtoni. In initial EOG tests at 10,9 M, H. burtoni did not respond to unconjugated steroids or prostaglandins, but did respond to 17 conjugated steroids, 11 of which (17,-oestradiol-17,-glucuronide; 17,-oestradiol-3-sulphate; 17,-oestradiol-3,17,-disulphate; epiandrosteron-3,-sulphate; etiocholanolone-3,-glucuronide; testosterone-17,-sulphate; dehydroepiandrosterone-3,-sulphate; 5,-pregnan-3,-ol-20-one-3,-sulphate; 5,-pregnan-3,,17-diol-20-one-3,-glucuronide; 5,-pregnan-3,,17,21-triol-11,20-dione-3,-glucuronide; pregnenolone-3,-sulphate) were selected for EOG concentration-response, cross-adaptation and binary mixture tests. The EOG detection thresholds ranged from 10,11 to 10,9 M in all but one instance (female threshold to pregnenolone-3,-sulphate; 10,8 M), and males and females exhibited only minor differences in EOG threshold or response magnitude. Results of EOG cross-adaptation tests, which were supported by results of binary mixture tests, indicated that the response to the 11 steroid conjugates is mediated by five putative olfactory receptor mechanisms characterized by specificity for conjugate position and type: 3-sulphate, 17-sulphate, 3,17-disulphate, 3-glucuronide, 17-glucuronide. Although there is no evidence that H. burtoni releases, or exhibits biological response to, the steroids shown to be detected in this study, the present results are suggestive of a complex pheromone system utilizing steroid conjugates. [source] The Effects of the ,2 -Adrenergic Receptor Agonists Clonidine and Rilmenidine, and Antagonists Yohimbine and Efaroxan, on the Spinal Cholinergic Receptor System in the RatBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2004Klas S. P. Abelson The cholinergic receptor system interacts with several other receptor types, such as ,2 -adrenergic receptors. To fully understand these interactions, the effects of various receptor ligands on the cholinergic system must be investigated in detail. This study was initiated to investigate the effects of the ,2 -adrenergic receptor agonists clonidine and rilmenidine and the ,2 -adrenergic receptor antagonists yohimbine and efaroxan on spinal cholinergic receptors in the rat. Spinal microdialysis was used to measure in vivo changes of acetylcholine after administration of the ligands, with or without nicotinic receptor blockade. In addition, in vitro binding properties of the ligands on muscarinic and nicotinic receptors were investigated. It was found that clonidine and rilmenidine increased, while yohimbine decreased spinal acetylcholine release. Efaroxan affected acetylcholine release differently depending on concentration. Nicotinic receptor blockade attenuated the effect of all ligands. All ligands showed poor binding affinity for muscarinic receptors. On the other hand, all ligands possessed affinity for nicotinic receptors. Clonidine and yohimbine binding was best fit to a one site binding curve and rilmenidine and efaroxan to a two site binding curve. The present study demonstrates that the tested ,2 -adrenergic receptor ligands affect intraspinal acetylcholine release in the rat evoked by nicotinic receptor mechanisms in vivo, and that they possess binding affinity to nicotinic receptors in vitro. The binding of ,2 -adrenergic receptor ligands to nicotinic receptors might affect the intraspinal release of acetylcholine. [source] FK506-binding protein localizations in human penile innervationBJU INTERNATIONAL, Issue 5 2008Gwen Lagoda OBJECTIVE To determine if FK506-binding proteins (FKBPs) are localized to the autonomic nerve supply of the human penis because FK506 (an immunosuppressant drug) has been linked to enhanced nerve regeneration after nerve injury and neurodegenerative diseases by binding to FKBPs, a select group of immunophilins. MATERIALS AND METHODS Human lower genitourinary tract specimens were obtained and embedded in paraffin wax. The tissue was sectioned (10 µm) and processed for immunohistochemistry using antibodies for FKBPs 12, 38, 52, 65, 135 and neuronal nitric oxide synthase (nNOS). To confirm specificity of the antibody, we processed some tissue in the absence of primary antibody, with mouse or rabbit IgG, and with a blocking peptide for FKBP12. RESULTS In the pelvis, immunoreactivity for all the FKBPs and nNOS was localized to the periprostatic ganglia although FKBP12 was the only FKBP localized to nerve bundles in this location. In penile tissue, immunoreactivity for all five FKBPs and nNOS was localized to nerves, although immunoreactivity for FKBP38 was minimal. The FKBPs were also evident in epithelial, endothelial and smooth muscle cells of the prostate and penis. Negative controls did not produce staining. CONCLUSIONS Identification and localization of immunophilins to nerves coursing in prostate and penile tissue suggest a likely molecular basis to apply immunophilin ligand therapy to protect or regenerate cavernosal nerves. Our findings support the hypothesis that immunosuppressant drugs such as FK506, working via specific receptor mechanisms, are potentially useful to sustain erectile function in men after radical prostatectomy. [source] | |||||||||||||