Background:
Macrophage infiltration to inflammatory sites promotes wound repair and may be involved in pain hypersensitivity after surgical incision. We recently reported that the development of ...hyperalgesia during chronic inflammation is regulated by macrophage polarity, often referred to as proinflammatory (M1) or anti-inflammatory (M2) macrophages. Although opioids such as morphine are known to alter the inflammatory milieu of incisional wounds through interactions with immunocytes, the macrophage-mediated effects of morphine on the development of postincisional pain have not been well investigated. In this study, we examined how morphine alters pain hypersensitivity through phenotypic shifts in local macrophages during the course of incision-induced inflammation.
Results:
Local administration of morphine in the early phase, but not in the late phase alleviated mechanical hyperalgesia, and this effect was reversed by clodronate-induced peripheral depletion of local macrophages. At the morphine-injected incisional sites, the number of pro-inflammatory F4/80+iNOS+M1 macrophages was decreased during the course of pain development whereas increased infiltration of wound healing F4/80+CD206+M2 macrophages was observed during the early phase. Morphine increased the gene expression of endogenous opioid, proenkephalin, and decreased the pronociceptive cytokine, interleukin-1β. Heme oxygenase (HO)-1 promotes the differentiation of macrophages to the M2 phenotype. An inhibitor of HO-1, tin protoporphyrin reversed morphine-induced analgesic effects and the changes in macrophage phenotype. However, local expression levels of HO-1 were not altered by morphine. Conversely, cyclooxygenase (COX)-2, primarily produced from peripheral macrophages in acute inflammation states, was up-regulated in the early phase at morphine-injected sites. In addition, the analgesic effects and a phenotype switching of infiltrated macrophages by morphine was reversed by local administration of a COX inhibitor, indomethacin.
Conclusions:
Local administration of morphine alleviated the development of postincisional pain, possibly by altering macrophage polarity at the incisional sites. A morphine-induced shift in macrophage phenotype may be mediated by a COX-2-dependent mechanism. Therefore, μ-opioid receptor signaling in macrophages may be a potential therapeutic target during the early phase of postincisional pain development.
Ghrelin is a novel acylated peptide that functions in the regulation of growth hormone release and energy metabolism. It was isolated from rat stomach as an endogenous ligand for growth hormone ...secretagogue receptor. Ghrelin is also localized in the arcuate nucleus of rat hypothalamus. Intracerebroventricular (ICV) administration increases food intake and body weight. We examined the effect of ghrelin on gastric acid secretion in urethane-anesthetized rats and found that ICV administration of ghrelin increased gastric acid output in a dose-dependent manner. Vagotomy and administration of atropine abolished the gastric acid secretion induced by ghrelin. ICV administration of ghrelin also induced c-fos expression in the neurons of the nucleus of the solitary tract and the dorsomotor nucleus of the vagus, which are key sites in the central nervous system for regulation of gastric acid secretion. Our results suggest that ghrelin participates in the central regulation of gastric acid secretion by activating the vagus system.
Ghrelin is a 28-amino acid peptide originally isolated from rat stomach and is cleaved from a 117-amino acid precursor. The sequence of the mature peptide from rats and mice differs by two amino ...acids from that of human ghrelin. Alternative splicing of the ghrelin gene transcript can result in the translation of a second biologically active peptide, des-Gln14-ghrelin. Both peptides have a unique post-translational modification, octanoylation of Ser3, which is essential for the binding to receptors in hypothalamus and pituitary and stimulating the release of growth hormone from the pituitary. The growth hormone secretagogue receptor (GHS-R1a, Swiss-Prot code Q92847, LocusLink ID 2693), a rhodopsin-like seven transmembrane spanning G protein-coupled receptors belonging to Family A, was cloned in 1996 from the pituitary and hypothalamus and shown to be the target of growth hormone secretagogues (GHS), a class of synthetic peptide and nonpeptide compounds causing growth hormone release from the anterior pituitary. In 1999, ghrelin was identified as the endogenous cognate ligand for this receptor. The purpose of this review is to propose an official International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) nomenclature designating GHS-R1a as the ghrelin receptor to follow the convention of naming receptors after the endogenous agonist, abbreviated where necessary to GRLN.
To assess the effect of adiponectin on the circadian rhythm disturbances associated with metabolic syndrome, we generated a KK/Ta mouse line expressing the human adiponectin transgene in the liver. ...Locomotor activity of control C57BL/6 mice was highest during the beginning of the dark period and low during the light period. Under constant darkness, the length of locomotor activity rhythm of control mice was slightly shorter than 24 h. In KK/Ta mice the peak of locomotor activity was blunted and significant activity was observed during the light period. Furthermore, KK/Ta mice showed shorter average period length of free-running locomotor activity rhythm when compared with control mice. However, the transgenic expression of adiponectin in the liver significantly altered the circadian rhythm of locomotor activity and the length of free-running rhythm of KK/Ta mice towards those of C57BL/6 mice. In the liver and skeletal muscles from control mice, mRNA levels of Arntl and Cry1 were increased during the dark period, whereas those of Dbp, Cry2, Per1 and Per2 were elevated during the light period. KK/Ta mice exhibited phase advances in circadian rhythms of Arntl, Dbp, Cry2 and Per2 in both tissues. The phase shifts of the circadian clock gene expression in the liver were attenuated in adiponectin-transgenic mice. These results suggest that adiponectin is a peripheral regulator of the circadian clocks in the brain and peripheral organs, and may be a novel target for the treatment of obesity-associated disorders of circadian rhythms.
Summary
objective Ghrelin, a novel endogenous ligand for the GH secretagogue receptor, has been reported to have adipogenic actions and induce weight gain in addition to its GH‐releasing properties. ...Interestingly, recent data indicate that ghrelin is downregulated in human obesity, which is also known to be accompanied by reduced GH levels.
patients and methods To investigate the influence of weight loss on circulating levels of ghrelin we recruited eight obese women among patients attending a 6‐month weight‐loss course organized by The Danish Heart Association. We measured body composition including computerized tomography as well as fasting plasma ghrelin concentrations before and after weight loss.
results Plasma ghrelin concentrations increased by 12% following weight loss (P < 0·01), and the increase in ghrelin levels was positively correlated with the extent of weight loss (r = 0·68, P < 0·05). Exposure to exogenous GH intravenously did not influence fasting ghrelin levels either before or after weight loss. Our data further suggest the existence of hyperghrelinaemia in a single subject with long‐standing obesity but no signs of GH excess.
conclusions This study provides evidence of a reversible suppression of ghrelin associated with obesity. The feasibility of measuring ghrelin in the circulation provides a new tool for the investigation of the complex hormonal regulation of appetite and energy balance.
We found in a primary study that ingestion of medium-chain fatty acids (MCFAs) or medium-chain triacylglycerols (MCTs) increased the stomach contents of acyl ghrelin, and we further showed that the ...carbon-chain length of the acyl groups that modified the nascent ghrelin peptides corresponded to that of the ingested MCFAs or MCTs. These findings clearly demonstrated that the ingested MCFAs are directly used for the acyl-modification of ghrelin. Before the discovery of ghrelin-O-acyltransferase (GOAT), our in vivo study suggested that the putative GOAT preferred MCTs (composed of C6:0 to C10:0 FFAs) to either short- or long-chain triglycerides. In another study, we suggested that MCFAs or MCTs might represent a potential therapeutic modality for the clinical manipulation of energy metabolism through the modulation of ghrelin activity. After the discovery of GOAT, many studies have been done on the acylation of ghrelin using MCFAs, MCTs, or their derivatives; however, results and interpretations have been inconsistent, largely due to the differences in experimental conditions. This chapter describes detailed methods for the analysis of ghrelin acylation in vivo to facilitate future research in this field.
Most organisms display various periodicities. Periodicity has been observed in humans in association with sleep, body temperature and hormone secretion. The molecular mechanisms involved are being ...elucidated by the investigation of clock genes in mammals. The relationship between biological rhythms and disease is also being studied. For example, myocardial infarction occurs more frequently in the morning, and disruption of biological rhythm is associated with obesity and diabetes. Some drugs have different medicinal effects depending on the time of dosing. Drug therapy known as chronotherapy, that takes into account the diurnal rhythm found in a given target disease, is being administered in some cases. Moreover, physiological responses and metabolism differ with time. Therefore, understanding the mechanisms underlying biological rhythms could enable the safe and effective performance of physical activity, in addition to potential medical applications. This review article outlines current understandings of biological rhythmicity and explores the relationship between biological rhythms and exercise, training, and sports.
Purpose: Ghrelin, a novel growth hormone-releasing peptide,has been shown to cause a positive energy balance by stimulating food intake
and inducing adiposity. We sought to investigate the ...pathophysiology of ghrelin in cachexia associated with lung cancer.
Experimental design: Plasma ghrelin level was measured in 43 patients with lung cancer and 21 control subjects. Patients with lung cancer were
divided into two groups: patients with cachexia ( n = 21) and those without cachexia ( n = 22).
Results: Plasma ghrelin level did not significantly differ between all patients with lung cancer and controls (157 ± 10 versus 132 ± 8 fmol/ml, P = 0.1). However, plasma ghrelin level was significantly higher in patients with cachexia than in those without cachexia (180
± 17 versus 135 ± 10 fmol/ml, P = 0.011). Furthermore, plasma ghrelin level increased significantly in patients with decreased food intake after chemotherapy
(from 136 ± 11 fmol/ml to 170 ± 16 fmol/ml on day 8, 179 ± 20 fmol/ml on day 21 after start of chemotherapy), although plasma
ghrelin level did not significantly change in those without decreased food intake.
Conclusions: Baseline plasma ghrelin level was elevated in cachectic patients with lung cancer, and follow-up plasma ghrelin level increased
in patients with anorexia after chemotherapy. Considering the positive energy effects induced by ghrelin, increased ghrelin
may represent a compensatory mechanism under catabolic–anabolic imbalance in cachectic patients with lung cancer.
Ghrelin is a gastric peptide hormone in which serine 3 (threonine 3 in frogs) is modified primarily by an n-octanoic acid; this modification is essential for ghrelin's activity. The enzyme that ...transfers n-octanoic acid to the third serine residue of ghrelin peptide has been identified and named GOAT for ghrelin O-acyltransferase. GOAT is the only known enzyme that catalyzes the acyl modification of ghrelin and specifically modifies the third amino acid serine and does not modify other serine residues in ghrelin peptides. GOAT prefers n-hexanoyl-CoA over n-octanoyl-CoA as the acyl donor, although in the stomach n-octanoyl form is the main acyl-modified ghrelin and the concentration of n-hexanoyl form is very low. Moreover, a four-amino acid peptide derived from the N-terminal sequence of ghrelin can be modified by GOAT, indicating that these four amino acids constitute the core motif for substrate recognition by the enzyme.
Ghrelin is a novel hormone that possesses growth hormone (GH)-releasing, cardiovascular, and metabolic activities. Ghrelin is a unique acylated polypeptide, and the naked peptide, desacyl ghrelin, ...does not have the activity. This study examines plasma ghrelin concentrations in 41 patients with mild to severe renal diseases. Two kinds of radioimmunoassays were used: amino-terminal immunoreactivity represents ghrelin alone (N-IR), and carboxyl-terminal immunoreactivity corresponds to the sum of both ghrelin and desacyl ghrelin (C-IR). In all subjects, the plasma N-IR was much smaller than the C-IR, indicating that desacyl ghrelin predominates over ghrelin in the circulation. The plasma C-IR, but not N-IR, was significantly correlated with the serum creatinine level and was increased 2.8-fold in patients with end-stage renal disease compared with those in patients with normal renal function. The plasma GH concentration was significantly correlated with the plasma N-IR and the C-IR, as well as with the serum creatinine level. Bilateral nephrectomy in mice caused marked increase in the plasma C-IR without significant changes in the local C-IR and ghrelin mRNA level in the stomach, which is the main site of ghrelin production. These findings suggest that circulating ghrelin concentrations play a role in the regulation of blood GH concentrations and that the kidney is an important site for clearance and/or degradation of desacyl ghrelin. Furthermore, elevation of blood GH levels in renal failure seems to be caused by a mechanism other than alteration in the circulating ghrelin concentration.
PDF
