Opioidy a progresja nowotworowa

Od dawna powszechnie wiadomo, że opioidy pomagają organizmowi w zmaganiach z niekorzystnymi czynnikami środowiska, uszkodzeniem tkanek, zakażeniem patogenami, zapaleniem i rozrostem nowotworowym. Opioidy wywierają działanie immunosupresyjne, które może być dobrodziejstwem w kontekście przewlekłego procesu zapalnego, jednak w odniesieniu do naprawy tkanek może być niekorzystne. Bezpośredni wpływ immunosupresyjny opioidów prawdopodobnie może ułatwiać wzrost nowotworu, jednak jeśli chodzi o ból i cierpienie, które jak wiadomo, mogą się przyczyniać do szybszego wzrostu guza poprzez zmniejszenie cytotoksyczności komórek NK, opioidy są bardzo skuteczne w zapobieganiu lokalnemu wzrostowi nowotworu, a także rozwojowi przerzutów nowotworowych. W ostatnim czasie wzrasta liczba dowodów na to, że komórki nowotworowe mają zarówno receptory opioidowe, jak i ich ligandy, czyli peptydy opioidowe, dzięki czemu opioidy prawdopodobnie mogą bezpośrednio wpływać na progresję nowotworu. Met-enkefalina zdaje się odgrywać istotną rolę, działając poprzez receptory inne niż klasyczny receptor opioidowy. Jednak konieczne są dalsze badania potwierdzające tę tezę

Identification of Mineralocorticoid Receptors, Aldosterone, and Its Processing Enzyme CYP11B2 on Parasympathetic and Sympathetic Neurons in Rat Intracardiac Ganglia

Recent interest has focused on the mineralocorticoid receptor (MR) and its impact on the myocardium and the performance of the heart. However, there is a lack of evidence about MR expression and its endogenous ligand aldosterone synthesis with specific regard to the intrinsic cardiac nervous system. Therefore, we looked for evidence of MR and aldosterone in sympathetic and parasympathetic neurons of intracardiac ganglia. Tissue samples from rat heart atria were subjected to conventional reverse-transcriptase polymerase chain reaction (PCR), Western blot, and double immunofluorescence confocal analysis of MR, corticosterone-inactivating enzyme 11β-hydroxysteroid-dehydrogenase-2 (11β-HSD2), aldosterone, and its processing enzyme CYP11B2 together with the neuronal markers vesicular acetylcholine transporter (VAChT) and tyrosine hydroxylase (TH). Our results demonstrated MR, 11β-HSD2, and CYP11B2 specific mRNA and protein bands in rat heart atria. Double immunofluorescence labeling revealed coexpression of MR immunoreactivity with VAChT in large diameter parasympathetic principal neurons. In addition, MR immunoreactivity was identified in TH-immunoreactive small intensely fluorescent (SIF) cells and in nearby VAChT- and TH-immunoreactive nerve terminals. Interestingly, the aldosterone and its synthesizing enzyme CYP11B2 and 11β-HSD2 colocalized in MR– immunoreactive neurons of intracardiac ganglia. Overall, this study provides first evidence for the existence of not only local expression of MR, but also of 11β-HSD2 and aldosterone with its processing enzyme CYP11B2 in the neurons of the cardiac autonomic nervous system, suggesting a possible modulatory role of the mineralocorticoid system on the endogenous neuronal activity on heart performance

Superior control of inflammatory pain by corticotropin-releasing factor receptor 1 via opioid peptides in distinct pain-relevant brain areas

Background: Under inflammatory conditions, the activation of corticotropin-releasing factor (CRF) receptor has been shown to inhibit pain through opioid peptide release from immune cells or neurons. CRF's effects on human and animal pain modulation depend, however, on the distribution of its receptor subtypes 1 and 2 (CRF-R1 and CRF-R2) along the neuraxis of pain transmission. The objective of this study is to investigate the respective role of each CRF receptor subtype on centrally administered CRF-induced antinociception during inflammatory pain. Methods: The present study investigated the role of intracerebroventricular (i.c.v.) CRF receptor agonists on nociception and the contribution of cerebral CRF-R1 and/or CRF-R2 subtypes in an animal model of Freund's complete adjuvant (FCA)-induced hind paw inflammation. Methods used included behavioral experiments, immunofluorescence confocal analysis, and reverse transcriptase-polymerase chain reaction. Results: Intracerebroventricular, but systemically inactive, doses of CRF elicited potent, dose-dependent antinociceptive effects in inflammatory pain which were significantly antagonized by i.c.v. CRF-R1-selective antagonist NBI 27914 (by approximately 60%) but less by CRF-R2-selective antagonist K41498 (by only 20%). In line with these findings, i.c.v. administration of CRF-R1 agonist stressin I produced superior control of inflammatory pain over CRF-R2 agonist urocortin-2. Intriguingly, i.c.v. opioid antagonist naloxone significantly reversed the CRF as well as CRF-R1 agonist-elicited pain inhibition. Consistent with existing evidence of high CRF concentrations in brain areas such as the thalamus, hypothalamus, locus coeruleus, and periaqueductal gray following its i.c.v. administration, double-immunofluorescence confocal microscopy demonstrated primarily CRF-R1-positive neurons that expressed opioid peptides in these pain-relevant brain areas. Finally, PCR analysis confirmed the predominant expression of the CRF-R1 over CRF-R2 in representative brain areas such as the hypothalamus. Conclusion: Taken together, these findings suggest that CRF-R1 in opioid-peptide-containing brain areas plays an important role in the modulation of inflammatory pain and may be a useful therapeutic target for inflammatory pain control

Histopathological Changes in the Kidney following Congestive Heart Failure by Volume Overload in Rats

Background. This study investigated histopathological changes and apoptotic factors that may be involved in the renal damage caused by congestive heart failure in a rat model of infrarenal aortocaval fistula (ACF). Methods. Heart failure was induced using a modified approach of ACF in male Wistar rats. Sham-operated controls and ACF rats were characterized by their morphometric and hemodynamic parameters and investigated for their histopathological, ultrastructural, and apoptotic factor changes in the kidney. Results. ACF- induced heart failure is associated with histopathological signs of congestion and glomerular and tubular atrophy, as well as nuclear and cellular degeneration in the kidney. In parallel, overexpression of proapoptotic Bax protein, release of cytochrome C from the outer mitochondrial membrane into cell cytoplasm, and nuclear transfer of activated caspase 3 indicate apoptotic events. This was confirmed by electron microscopic findings of apoptotic signs in the kidney such as swollen mitochondria and degenerated nuclei in renal tubular cells. Conclusions. This study provides morphological evidence of renal injury during heart failure which may be due to caspase-mediated apoptosis via overexpression of proapoptotic Bax protein, subsequent mitochondrial cytochrome C release, and final nuclear transfer of activated caspase 3, supporting the notion of a cardiorenal syndrome

A Modified Approach to Induce Predictable Congestive Heart Failure by Volume Overload in Rats

The model of infrarenal aortocaval fistula (ACF) has recently gained new interest in its use to investigate cardiac pathophysiology. Since in previous investigations the development of congestive heart failure (CHF) was inconsistent and started to develop earliest 8-10 weeks after fistula induction using a 18G needle, this project aimed to induce a predictable degree of CHF within a definite time period using a modified approach. An aortocaval fistula was induced in male Wistar rats using a 16G needle as a modification of the former 18G needle-technique described by Garcia and Diebold. Results revealed within 28 +/- 2 days of ACF significantly increased heart and lung weight indices in the ACF group accompanied by elevated filling pressure. All hemodynamic parameters derived from a pressure-volume conductance-catheter in vivo were significantly altered in the ACF consistent with severe systolic and diastolic left ventricular dysfunction. This was accompanied by systemic neurohumoral activation as demonstrated by elevated rBNP-45 plasma concentrations in every rat of the ACF group. Furthermore, the restriction in overall cardiac function was associated with a beta 1- and beta 2-adrenoreceptor mRNA downregulation in the left ventricle. In contrast, beta 3-adrenoreceptor mRNA was upregulated. Finally, electron microscopy of the left ventricle of rats in the ACF group showed signs of progressive subcellular myocardial fragmentation. In conclusion, the morphometric, hemodynamic and neurohumoral characterization of the modified approach revealed predictable and consistent signs of congestive heart failure within 28 +/- 2 days. Therefore, this modified approach might facilitate the examination of various questions specific to CHF and allow for pharmacological interventions to determine pathophysiological pathways

Chronic Naltrexone Therapy Is Associated with Improved Cardiac Function in Volume Overloaded Rats

Purpose: Myocardial opioid receptors were demonstrated in animals and humans and seem to colocalize with membranous and sarcolemmal calcium channels of the excitation-contraction coupling in the left ventricle (LV). Therefore, this study investigated whether blockade of the cardiac opioid system by naltrexone would affect cardiac function and neurohumoral parameters in Wistar rats with volume overload-induced heart failure. Methods: Volume overload in Wistar rats was induced by an aortocaval fistula (ACF). Left ventricular cardiac opioid receptors were identified by immunohistochemistry and their messenger ribonucleic acid (mRNA) as well as their endogenous ligand mRNA quantified by real-time polymerase chain reaction (RT-PCR). Following continuous delivery of either the opioid receptor antagonist naltrexone or vehicle via minipumps (n = 5 rats each), hemodynamic and humoral parameters were assessed 28 days after ACF induction. Sham-operated animals served as controls. Results: In ACF rats mu-, delta-, and kappa-opioid receptors colocalized with voltage-gated L-type Ca2+ channels in left ventricular cardiomyocytes. Chronic naltrexone treatment of ACF rats reduced central venous pressure (CVP) and left ventricular end-diastolic pressure (LVEDP), and improved systolic and diastolic left ventricular functions. Concomitantly, rat brain natriuretic peptide (rBNP-45) and angiotensin-2 plasma concentrations which were elevated during ACF were significantly diminished following naltrexone treatment. In parallel, chronic naltrexone significantly reduced mu-, delta-, and kappa-opioid receptor mRNA, while it increased the endogenous opioid peptide mRNA compared to controls. Conclusion: Opioid receptor blockade by naltrexone leads to improved LV function and decreases in rBNP-45 and angiotensin-2 plasma levels. In parallel, naltrexone resulted in opioid receptor mRNA downregulation and an elevated intrinsic tone of endogenous opioid peptides possibly reflecting a potentially cardiodepressant effect of the cardiac opioid system during volume overload

The presence of mu-, delta-, and kappa-opioid receptors in human heart tissue

Functional evidence suggests that the stimulation of peripheral and central opioid receptors (ORs) is able to modulate heart function. Moreover, selective stimulation of either cardiac or central ORs evokes preconditioning and, therefore, protects the heart against ischemic injury. However, anatomic evidence for OR subtypes in the human heart is scarce. Human heart tissue obtained during autopsy after sudden death was examined immunohistochemically for mu- (MOR), kappa- (KOR), and delta- (DOR) OR subtypes. MOR and DOR immunoreactivity was found mainly in myocardial cells, as well as on sparse individual nerve fibers. KOR immunoreactivity was identified predominantly in myocardial cells and on intrinsic cardiac adrenergic (ICA) cell-like structures. Double immunofluorescence confocal microscopy revealed that DOR colocalized with the neuronal marker PGP9.5, as well as with the sensory neuron marker calcitonin gene-related peptide (CGRP). CGRP-immunoreactive (IR) fibers were detected either in nerve bundles or as sparse individual fibers containing varicose-like structures. Our findings offer the first hint of an anatomic basis for the existence of OR subtypes in the human heart by demonstrating their presence in CGRP-IR sensory nerve fibers, small cells with an eccentric nucleus resembling ICA cells, and myocardial cells. Taken together, this suggests the role of opioids in both the neural transmission and regulation of myocardial cell function

Prostanoid Receptor Subtypes and Its Endogenous Ligands with Processing Enzymes within Various Types of Inflammatory Joint Diseases

A complex inflammatory process mediated by proinflammatory cytokines and prostaglandins commonly occurs in the synovial tissue of patients with joint trauma (JT), osteoarthritis (OA), and rheumatoid arthritis (RA). This study systematically investigated the distinct expression profile of prostaglandin E2 (PGE2), its processing enzymes (COX-2), and microsomal PGES-1 (mPGES-1) as well as the corresponding prostanoid receptor subtypes (EP1-4) in representative samples of synovial tissue from these patients (JT, OA, and RA). Quantitative TaqMan®-PCR and double immunofluorescence confocal microscopy of synovial tissue determined the abundance and exact immune cell types expressing these target molecules. Our results demonstrated that PGE2 and its processing enzymes COX-2 and mPGES-1 were highest in the synovial tissue of RA, followed by the synovial tissue of OA and JT patients. Corresponding prostanoid receptor, subtypes EP3 were highly expressed in the synovium of RA, followed by the synovial tissue of OA and JT patients. These proinflammatory target molecules were distinctly identified in JT patients mostly in synovial granulocytes, in OA patients predominantly in synovial macrophages and fibroblasts, whereas in RA patients mainly in synovial fibroblasts and plasma cells. Our findings show a distinct expression profile of EP receptor subtypes and PGE2 as well as the corresponding processing enzymes in human synovium that modulate the inflammatory process in JT, OA, and RA patients

Endothelin potentiates TRPV1 via ETA receptor-mediated activation of protein kinase C

© 2007 Plant et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens