Role of gaseous neurotransmitters in the effects and expression of opioid and cannabinoid receptors during neuropathic pain (original) (raw)
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British journal of …, 2007
Background and purpose:Relaxation of corpus cavernosum, which is mediated by nitric oxide (NO) released from non-adrenergic non-cholinergic (NANC) neurotransmission, is critical for inducing penile erection and can be affected by many pathophysiological conditions. However, the peripheral effect of liver cirrhosis on erectile function is as yet unknown. The aim of the present study was to investigate the effect of biliary cirrhosis on NANC-mediated relaxation of rat corpus cavernosum and the possible roles of endocannabinoid and nitric oxide systems in this model.Experimental approach:Cirrhosis was induced by bile duct ligation. Controls underwent sham operation. Four weeks later, strips of corpus cavernosum were mounted in a standard organ bath and NANC-mediated relaxations were obtained by applying electrical field stimulation.Key results:The NANC-mediated relaxation was enhanced in corporal strips from cirrhotic animals. Anandamide potentiated the relaxations in both groups. Either AM251 (CB1 antagonist) or capsazepine (vanilloid VR1 antagonist), but not AM630 (CB2 antagonist), prevented the enhanced relaxations of cirrhotic strips. Either the non-selective NOS inhibitor L-NAME or the selective neuronal NOS inhibitor L-NPA inhibited relaxations in both groups, but cirrhotic groups were more resistant to the inhibitory effects of these agents. Relaxations to sodium nitroprusside (NO donor) were similar in tissues from the two groups.Conclusions and implications:Cirrhosis potentiates the neurogenic relaxation of rat corpus cavernosum probably via the NO pathway and involving cannabinoid CB1 and vanilloid VR1 receptors.
Dor neuropática: aspectos neuroquímicos
Revista Brasileira de Anestesiologia, 2008
A dor neuropática é causada por lesão ou inflamação do sistema nervoso. É síndrome complexa, com mecanismos biológicos pouco esclarecidos, envolvendo teorias inflamatórias e imunes. O objetivo desta revisão foi descrever os principais fatores biológicos relacionados com a dor neuropática, associando de forma lógica as hipóteses sugeridas pela literatura. CONTEÚDO: Foram descritos os principais neuromediadores, canais iônicos e células, incluindo as do sistema imune envolvidos na excitabilidade neuronal, assim como enfatizada possível seqüência de ativação ou interação desses agentes na alteração neuroplástica decorrente da agressão ao nervo. CONCLUSÕES: Do estudo, foi possível concluir que os avanços no conhecimento da fisiopatologia da dor neuropática podem determinar novos alvos para abordagem farmacológica dessa síndrome.
European Urology, 2010
Background: Anandamide, a proposed endogenous cannabinoid (CB) agonist, has been shown to enhance neurogenic responses in vitro of the rat corpus cavernosal tissue (CC). However, no information is available on the distribution of CB-receptors or effects by anandamide in CC from primates or humans. Objective: To characterize the distribution of CB-receptor isoforms in the human and primate CC and to investigate the effects of anandamide on isolated CC preparations. Design, setting, and participants: CC tissue was excised from the crura penis of six rhesus monkeys and five patients. Expression and distribution of CB1 and CB2 receptors were characterized with Western blot analyses and immunohistochemical investigations. The effects of anandamide on isolated CC preparations were analyzed during pharmacologic and nerve-mediated activation of primate tissue in aerated organ baths. Measurements: The expression and localization of CB1 and CB2 receptors in the primate CC and effects of anandamide on nerve-mediated relaxations and pharmacologically evoked contractions. Results and limitations: Western blot experiments revealed CB1 and CB2 receptors at expected band weights. Within and between strands of CC smooth muscle, CB1 and CB2 immunoreactivity (IR) was found in nerve fibers that also expressed IR for nitric oxide synthase (NOS) or transient receptor potential V1 (TRPV1). Neither CB1-IR nor CB2-IR nerves were colocalized with calcitoningene-related peptide (CGRP)-containing or tyrosine hydroxylase-containing nerves. No differences were observed between primate and human CC sections. Anandamide (10 À9 to 10 À4 M) had no contractile effects on CC smooth muscle, no relaxant effects on precontracted preparations, and no effect on phenylephrine-induced contractions. However, anandamide (10 mM) inhibited electrically evoked smooth-muscle relaxations (34-48%; p 0.05). Conclusions: CB1 and CB2 receptors are located on NOS-containing nerves in primate and human CC tissue. In contrast to findings in rats, anandamide antagonized nerve-mediated relaxations of the primate CC, suggesting important species differences for CB-mediated functions. The results also suggest a peripheral mechanism for cannabis-related sexual dysfunction.
European Urology, 2010
Background: Anandamide, a proposed endogenous cannabinoid (CB) agonist, has been shown to enhance neurogenic responses in vitro of the rat corpus cavernosal tissue (CC). However, no information is available on the distribution of CB-receptors or effects by anandamide in CC from primates or humans. Objective: To characterize the distribution of CB-receptor isoforms in the human and primate CC and to investigate the effects of anandamide on isolated CC preparations. Design, setting, and participants: CC tissue was excised from the crura penis of six rhesus monkeys and five patients. Expression and distribution of CB1 and CB2 receptors were characterized with Western blot analyses and immunohistochemical investigations. The effects of anandamide on isolated CC preparations were analyzed during pharmacologic and nerve-mediated activation of primate tissue in aerated organ baths. Measurements: The expression and localization of CB1 and CB2 receptors in the primate CC and effects of anandamide on nerve-mediated relaxations and pharmacologically evoked contractions. Results and limitations: Western blot experiments revealed CB1 and CB2 receptors at expected band weights. Within and between strands of CC smooth muscle, CB1 and CB2 immunoreactivity (IR) was found in nerve fibers that also expressed IR for nitric oxide synthase (NOS) or transient receptor potential V1 (TRPV1). Neither CB1-IR nor CB2-IR nerves were colocalized with calcitoningene-related peptide (CGRP)-containing or tyrosine hydroxylase-containing nerves. No differences were observed between primate and human CC sections. Anandamide (10 À9 to 10 À4 M) had no contractile effects on CC smooth muscle, no relaxant effects on precontracted preparations, and no effect on phenylephrine-induced contractions. However, anandamide (10 mM) inhibited electrically evoked smooth-muscle relaxations (34-48%; p 0.05). Conclusions: CB1 and CB2 receptors are located on NOS-containing nerves in primate and human CC tissue. In contrast to findings in rats, anandamide antagonized nerve-mediated relaxations of the primate CC, suggesting important species differences for CB-mediated functions. The results also suggest a peripheral mechanism for cannabis-related sexual dysfunction.
Fischer et al J Physiology 2004.pdf
We have compared the functional properties of nicotinic acetylcholine receptors (nAChRs) within both somatic and presynaptic domains of superior cervical ganglion (SCG) neurones from wild-type (WT) mice with those expressed by SCG neurones from mice with a targeted deletion of the gene for the α5-subunit. The functional profile of somatic nAChRs was assayed by direct macroscopic current recording and from measurements of nicotinic agonist-induced calcium transients with fura-2 imaging. The profile of nAChRs at presynaptic sites was assayed by measurement of nicotinic agonist-induced transmitter release (as preloaded [ 3 H]noradrenaline) under conditions of action potential blockade. We have examined the responses to the nicotinic agonists acetylcholine, nicotine, cytisine, dimethylphenylpiperazinium iodide (DMPP) and epibatidine. Macroscopic current and calcium imaging assays revealed several differences in the functional profile of somatic nAChRs in WT SCG neurones compared with those from mice with the α5 subunit deleted. Somatic nAChRs in control animals were more potently activated by cytisine as compared to DMPP. In contrast, DMPP was consistently more potent than cytisine in mice lacking the α5 nAChR subunit. Differences in the somatic nAChR rank order of potency were most prominent after a least 1 day in vitro. The magnitude of somatic nAChR responses to nicotinic agonists was not substantially different in control mice compared with those of α5 subunit-deleted animals. Comparison of presynaptic nAChR-mediated responses in WT versus α5 subunit-deleted animals revealed a very different set of changes in the functional profile of prejunctional nAChRs compared with somatic nAChRs. In contrast to somatic nAChRs, the responses of prejunctional receptors were markedly enhanced in α5 knockout animals compared with control. Furthermore, all prejunctional receptor responses were most potently activated by DMPP in both control and in α5 subunit-deleted mice. Hence, the presence or absence of the α5 subunit did not affect the rank order of potency of agonists at preterminal sites but greatly affected the magnitude of presynaptic nAChR-mediated responses. The enhanced efficacy of nicotine at presynaptic receptors was corroborated in an acute atrium preparation from postnatal α5 subunit-deleted mice. These results confirm and significantly extend our previous observation that in the sympathetic nervous system, somatic and prejunctional receptors are different and rely on the presence of the α5 subunit in a distinct manner.
CNS & Neurological Disorders - Drug Targets, 2012
This study analyzed the effect of intra-ventrolateral periaqueductal grey (VL PAG) cannabinoid receptor (CB) stimulation on pain responses and rostral ventromedial medulla (RVM) neural activity in the chronic constriction injury (CCI) model of neuropathic pain in rats. Interaction between CB 1 and metabotropic glutamate 1 and 5 (mGlu 1 /mGlu 5) receptors was also investigated together with the expression of the CB 1 receptor associated G i3 and cannabinoid receptor interacting 1a (CRIP 1a) proteins and the endocannabinoid synthesising and hydrolysing enzymes. In rats not subjected to CCI-induced pain, intra-VL PAG (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN 55,212-2) (2-4-8 nmol), a CB receptor agonist, increased the tail flick latency and changed the ongoing activity of RVM OFF and the tail flick-related activity of the ON and OFF cells, accordingly. These effects were prevented by SR141716A and MPEP, selective CB 1 and mGlu 5 receptor antagonists, respectively, though not by CPCCOEt, a selective mGlu 1 receptor antagonist. A higher dose up to 16 nmol of WIN 55,212-2 was necessary to increase tail flick latency and change ON and OFF cell activity in CCI rats. Consistently, CCI rats showed a decrease in the expression of CB 1 receptors, NAPE-PLD, G i3 and CRIP 1a proteins;the expression of diacylglycerol lipase A (DAGLA) was increased while fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL) did not change. As in control rats, MPEP and SR141716A also blocked WIN 55,212-2induced effects in CCI rats. These data demonstrate a down regulation of the endocannabinoid system and a functional interaction between mGlu 5 and CB 1 receptors for cannabinoid-mediated effect in the PAG-RVM pain circuitry in neuropathic pain inflicted rats.
Cardiovascular Drug Reviews, 1998
The Vascular Neuroeffector Mechanisms Symposia are held as satellite symposia of the International Congresses of Pharmacology. The present symposium consisted of poster presentations and the following five sessions of oral communications: Adrenoceptors (chaired by R. Ruff010 and 0. E. Brodde), Endothelium and Vascular Wall Physiology (R. F. Furchgott and S. Guimariies), New Trends in Cardiovascular Research (J. Bevan), Cotransmission (K. Starke and T. C. Cunnane), and Modulation of Neurotransmitter Release in the Cardiovascular System (M. Gothert). The meeting was attended by about 150 participants who listened to 32 lectures and discussed 72 posters. This article summarizes the scientific highlights.