[Show abstract][Hide abstract]ABSTRACT: The cervical sympathetic nerves which innervate the medial basal hypothalamus-hypophyseal complex, primary and secondary lymph organs, and numerous glands, such as the pineal, thyroid, parathyroid and salivary glands form a relevant neuroimmunoendocrine structure that is involved in the regulation of systemic homeostasis. The superior cervical ganglia and the submandibular glands form a 'neuroendocrine axis' called the cervical sympathetic trunk submandibular gland (CST-SMG) axis. The identification of this axis usurps the traditional view of salivary glands as accessory digestive structures and reinforces the view that they are important sources of systemically active immunoregulatory and anti-inflammatory factors whose release is intimately controlled by the autonomic nervous system, and in particular the sympathetic branch. An end component of the CST-SMG axis is the synthesis, processing and release of submandibular rat-1 protein (SMR1), a prohormone, that generates several different peptides, one from near its N-terminus called sialorphin and another from its C-terminus called - submandibular gland peptide-T (SGP-T). SGP-T formed the template for tripeptide fragment (FEG) and its metabolically stable D-isomeric peptide feG, which are potent inhibitors of allergy and asthma (IgE-mediated allergic reactions) and several non-IgE-mediated inflammations. The translation from rat genetics and proteomics to humans has yielded structural and functional correlates that hopefully will lead to the development of new medications and therapeutic approaches for difficult to treat disorders. Although the CST-SMG axis has barely been explored in humans recognition of the importance of this axis could facilitate an understanding and improved management of periodontal disease, and other diseases with a more systemic and nervous system basis such as asthma, autoimmunity, graft-versus-host disease and even Parkinson's disease.
Full-text available · Article · Jun 2012 · Progress in allergy
[Show abstract][Hide abstract]ABSTRACT: Gastrointestinal (GI) motility is regulated in part by fatty acid ethanolamides (FAEs), including the endocannabinoid (EC) anandamide (AEA). The actions of FAEs are terminated by fatty acid amide hydrolase (FAAH). We investigated the actions of the novel FAAH inhibitor AM3506 on normal and enhanced GI motility.
We examined the effect of AM3506 on electrically-evoked contractility in vitro and GI transit and colonic faecal output in vivo, in normal and FAAH-deficient mice treated with saline or LPS (100 µg·kg(-1), i.p.), in the presence and absence of cannabinoid (CB) receptor antagonists. mRNA expression was measured by quantitative real time-PCR, EC levels by liquid chromatography-MS and FAAH activity by the conversion of [(3)H]-AEA to [(3)H]-ethanolamine in intestinal extracts. FAAH expression was examined by immunohistochemistry.
FAAH was dominantly expressed in the enteric nervous system; its mRNA levels were higher in the ileum than the colon. LPS enhanced ileal contractility in the absence of overt inflammation. AM3506 reversed the enhanced electrically-evoked contractions of the ileum through CB(1) and CB(2) receptors. LPS increased the rate of upper GI transit and faecal output. AM3506 normalized the enhanced GI transit through CB(1) and CB(2) receptors and faecal output through CB(1) receptors. LPS did not increase GI transit in FAAH-deficient mice.
Inhibiting FAAH normalizes various parameters of GI dysmotility in intestinal pathophysiology. Inhibition of FAAH represents a new approach to the treatment of disordered intestinal motility.
Full-text available · Article · Aug 2011 · British Journal of Pharmacology
[Show abstract][Hide abstract]ABSTRACT: Chronic pain is a common and debilitating symptom experienced in the context of numerous other physical and emotional symptoms by many patients with chronic kidney disease (CKD). Management of pain with opioids in CKD can be problematic given the prominence of adverse effects of opioids in CKD, which may exacerbate symptoms, such as nausea, anorexia, pruritus, and insomnia, all of which impact negatively on patients' health-related quality of life. Novel therapeutic approaches for pain and symptom management in CKD are required. Recent research in the area of cannabinoids (CBs) is legitimizing the use of cannabis-based medicine. In this review, we describe the symptom burden borne by patients with CKD and review some of the key basic science and clinical literature to evaluate the potential use of CBs for the management of overall symptom burden in CKD.
Full-text available · Article · Apr 2011 · Journal of pain and symptom management
[Show abstract][Hide abstract]ABSTRACT: The pancreatic polypeptide-fold (PP-fold) peptides neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) (500 pmol/kg) increased duodenal and colonic intraluminal pressure of urethane-anesthesized rats following intravenous (i.v.) bolus injections. Increases in mean arterial pressure (MAP) accompanied the excitatory effects of NPY and PYY on gastrointestinal motility in these rats during the same time period. Atropine attenuated PYY's excitatory effect on duodenal pressure of rats. Excitatory effects of NPY, PYY, and PP (i.v.) on rat colon were not mediated via the muscarinic receptors. In the presence of hexamethonium, a nicotinic antagonist, PP (i.v.) increased colonic pressure to a greater extent than when administered alone. This observation suggested that PP had an inhibitory effect on colonic motility, which was not apparent as a result of the larger excitatory component. The nicotinic antagonist did not modulate the effects of peripherally administered NPY or PYY on duodenal or colonic motility in anesthetized rats. The Y2 receptor ligand, NPY (13-36) (i.v.) (500 pmol/kg), increased duodenal and colonic pressure in rats to the same extent as the full NPY molecule. Therefore, the peripheral effect of PYY and NPY on duodenal and colonic motility in rats may be mediated via Y2 receptors. NPY and PYY (i.v.) initially increased MAP, which then return to baseline values. Unlike NPY and PYY (i.v.) which produced short-term hypertensive effects PP (i.v. decreased MAP. Atropine did not attenuate the hypertensive effects of PYY and NPY (i.v.); however, the hypotensive effect of PP (i.v.) was blocked by atropine. The effects of the PP-fold peptides on MAP were not altered in the presence of hexamethonium.(ABSTRACT TRUNCATED AT 250 WORDS)
Article · Feb 2011 · Canadian Journal of Physiology and Pharmacology
[Show abstract][Hide abstract]ABSTRACT: The limitations of steroidal and non steroidal anti-inflammatory drugs have prompted investigation into other biologically based therapeutics, and identification of immune selective anti-inflammatory agents of salivary origin. The traditional view of salivary glands as accessory digestive structures is changing as their importance as sources of systemically active immunoregulatory and anti-inflammatory factors is recognized. Salivary gland involvement in maintenance of whole body homeostasis is regulated by the nervous system and thus constitutes a "neuroendocrine axis". The potent anti-inflammatory activities, both in vivo and in vitro, of the tripeptide Phe-Glu-Gly (FEG) are reviewed. FEG is a carboxyl terminal peptide of the prohormone SMR1 identified in the rat submandibular salivary gland, The D-isomeric form (feG) mimics the activity of its L-isomer FEG. Macropharmacologically, feG attenuates the cardiovascular and inflammatory effects of endotoxemia and anaphylaxis, by inhibition of hypotension, leukocyte migration, vascular leak, and disruption of pulmonary function and intestinal motility. Mechanistically, feG affects activated inflammatory cells, especially neutrophils, by regulating integrins and inhibiting intracellular production of reactive oxygen species. Pharmacodynamically, feG is active at low doses (100 μg/kg) and has a long (9-12 hour) biological half life. As a therapeutic agent, feG shows promise in diseases characterized by over exuberant inflammatory responses such as systemic inflammatory response syndrome and other acute inflammatory diseases. Arthritis, sepsis, acute pancreatitis, asthma, acute respiratory inflammation, inflammatory bowel disease, and equine laminitis are potential targets for this promising therapeutic peptide. The term "Immune Selective Anti-Inflammatory Derivatives" (ImSAIDs) is proposed for salivary-derived peptides to distinguish this class of agents from corticosteroids and nonsteroidal anti-inflammatory drugs.
Full-text available · Article · Sep 2010 · Journal of Inflammation
[Show abstract][Hide abstract]ABSTRACT: Marijuana has been used for thousands of years to affect human health. Dissecting the peripheral effects from the central psychotropic effects has revealed a complex interplay between cannabinoids, endocannabinoids and their receptors. This review examines recent advances in understanding the expression, regulation and utilization of the CB2 receptor. Here we highlight the molecular aspects of the CB2 receptor, CB2 receptor signaling and new ligands for this receptor. We focus in the rest of the review on recent findings in the immune system, the gastrointestinal tract and liver, the brain and the cardiovascular system and airways as examples of areas where new developments in our understanding of the CB2 receptor have occurred. Early studies focused on expression of this receptor under baseline physiologic conditions; however, perturbations such as those that occur during inflammation, ischemia/reperfusion injury and cancer are revealing a critical role for the CB2 receptor in regulating these disease processes amongst others. As a result, the CB2 receptor is an appealing therapeutic target as well as a useful tool for shedding new light on physiological regulatory processes throughout the body.
[Show abstract][Hide abstract]ABSTRACT: We have previously shown that galantide ameliorates mild acute pancreatitis (AP), and the salivary tripeptide analogue, feG, ameliorates severe AP in mice. In this study, we compared the efficacy of combining galantide and feG with that of the individual agents in treating mild AP induced in mice with 7-hourly caerulein injections. Galantide was co-administered with each caerulein injection commencing with the first injection. feG was co-administered with the first injection of caerulein as a single intraperitoneal injection. Combination of the agents was also administered. Control animals received galantide, feG, or saline alone. Pancreata were harvested for histological examination and estimation of myeloperoxidase (MPO) activity. Plasma enzyme activities were measured. Galantide significantly reduced AP-induced hyperenzymemia by 41-49%. The combination of galantide and feG significantly reduced AP-induced hyperenzymemia by 39-40%, whereas feG alone was without effect. Plasma enzyme activity in the control groups was comparable with pre-treatment activity. Galantide, feG, and their combination significantly reduced MPO activity by 83, 44 and 74% respectively, and % abnormal acinar cells by 32, 29 and 36% respectively. This study demonstrates for the first time the beneficial effect of feG in mild caerulein-induced AP. Moreover the data indicate that the hyperenzymemia in mild caerulein-induced AP at 12h possibly reflect a larger secretory component as compared to enzyme release due to neutrophil-mediated acinar cell damage. The effects of the treatment with both peptides indicate a possible role for galantide in modulating neutrophil chemotaxis/activation and supports the hypothesis that galantide may influence neurogenic inflammation in AP.
[Show abstract][Hide abstract]ABSTRACT: Marijuana has been used for thousands of years to affect human health. Dissecting the peripheral effects from the central psychotropic effects has revealed a complex interplay between cannabinoids, endocannabinoids and their receptors. This review examines recent advances in understanding the expression, regulation and utilization of the CB(2) receptor. Here we highlight the molecular aspects of the CB(2) receptor, CB(2) receptor signaling and new ligands for this receptor. We focus in the rest of the review on recent findings in the immune system, the gastrointestinal tract and liver, the brain and the cardiovascular system and airways as examples of areas where new developments in our understanding of the CB(2) receptor have occurred. Early studies focused on expression of this receptor under baseline physiologic conditions; however, perturbations such as those that occur during inflammation, ischemia/reperfusion injury and cancer are revealing a critical role for the CB(2) receptor in regulating these disease processes amongst others. As a result, the CB(2) receptor is an appealing therapeutic target as well as a useful tool for shedding new light on physiological regulatory processes throughout the body.
[Show abstract][Hide abstract]ABSTRACT: Allergen-induced inflammation manifests as allergic asthma, dermatitis, rhinitis, conjunctivitis, food aller-gies, and life-threatening anaphylaxis. Allergic reactions consist of an acute phase hypersensitivity reaction and late phase inflammation. Current therapeutic strategies consist of immunotherapy to induce tolerance to an allergen or pharma-cotherapy to treat either the acute phase reaction or the chronic inflammation associated with allergic disease. For bron-chial asthma, the allergic disease with the greatest worldwide burden, three medications (2-adrenoceptor agonists, gluco-corticoids and leukotriene antagonists) are the mainstays of therapy, which when used alone or in combination control asthma symptoms in many asthmatics. A recent anti-IgE therapy has benefited some difficult to manage patients, however a significant proportion of asthma patients do not respond well to currently available drugs. There is a need for new effec-tive lost-cost therapies for asthma and other allergic diseases to complement existing therapies and improve long-term outcomes. There are several potential therapeutic targets including transcription factors, cytokines, chemokines and their receptors, proteases, and cell adhesion molecules. Within the next generation of anti-allergy drugs one or more will pro-bably be a peptide or a peptide mimetic.
Full-text available · Article · Dec 2008 · Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Cu rrent Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents)
[Show abstract][Hide abstract]ABSTRACT: Enhanced intestinal transit due to lipopolysaccharide (LPS) is reversed by cannabinoid (CB)2 receptor agonists in vivo, but the site and mechanism of action are unknown. We have tested the hypothesis that CB2 receptors are expressed in the enteric nervous system and are activated in pathophysiological conditions. Tissues from either saline- or LPS-treated (2 h; 65 microg/kg ip) rats were processed for RT-PCR, Western blotting, and immunohistochemistry or were mounted in organ baths where electrical field stimulation was applied in the presence or absence of CB receptor agonists. Whereas the CB2 receptor agonist JWH133 did not affect the electrically evoked twitch response of the ileum under basal conditions, in the LPS-treated tissues JWH133 was able to reduce the enhanced contractile response in a concentration-dependent manner. Rat ileum expressed CB2 receptor mRNA and protein under physiological conditions, and this expression was not affected by LPS treatment. In the myenteric plexus, CB2 receptors were expressed on the majority of neurons, although not on those expressing nitric oxide synthase. LPS did not alter the distribution of CB2 receptor expression in the myenteric plexus. In vivo LPS treatment significantly increased Fos expression in both enteric glia and neurons. This enhanced expression was significantly attenuated by JWH133, whose action was reversed by the CB2 receptor antagonist AM630. Taking these facts together, we conclude that activation of CB2 receptors in the enteric nervous system of the gastrointestinal tract dampens endotoxin-induced enhanced intestinal contractility.
Article · Aug 2008 · AJP Gastrointestinal and Liver Physiology
[Show abstract][Hide abstract]ABSTRACT: The management of pancreatic pain is a significant clinical problem so understanding of how sensory signals are generated in pancreatic tissue is fundamental. We aimed to characterize mechanosensitive and chemosensitive properties of pancreatic spinal and vagal afferents in vitro. Spinal and vagal afferent preparations from Sprague-Dawley rats were established incorporating the left splanchnic nerve or vagus nerves respectively. The common bile duct was cannulated for distension of the pancreatic duct with fluid. Nerve discharge evoked by blunt probing, duct distension or electrical stimulation was obtained from teased nerve bundles using standard extra-cellular recording. Discharge from 197 spinal afferent bundles was recorded, of which 57% displayed spontaneous activity. Blunt probing revealed 61 mechanosensitive receptive fields which were associated primarily with arteries/blood vessels (33/61) and the parenchyma (22/61). All mechanosensitive responses were slowly adapting, with 33% continuing to discharge after termination of the stimulus and 60% displaying a response threshold <10 g. Application of chemical mediators (bradykinin, histamine, 5-hydroxytryptamine, cholecystokinin octapeptide) evoked a response from 31/57 units, with 33% excitatory and 23% inhibitory. Spontaneous discharge was recorded from 72% of 135 vagal bundles. Mechanosensitive receptive fields were not identified in the pancreas but were evident in adjacent organs. No spinal or vagal afferent response to duct distension was obtained. In conclusion, pancreatic mechanosensitive spinal afferents are common, in contrast to pancreatic mechanosensitive vagal afferents indicating that pancreatic sensory innervation is predominantly spinal. Chemosensitive spinal afferent nerve endings are present in the pancreas and respond to a variety of inflammatory and physiological mediators.
Full-text available · Article · Jun 2008 · Neurogastroenterology and Motility
[Show abstract][Hide abstract]ABSTRACT: Acute pancreatitis (AP) is associated with significant morbidity and mortality; however, there is no specific treatment for this disease. A novel salivary tripeptide analog, feG, reduces inflammation in several different animal models of inflammation. The aims of this study were to determine whether feG reduced the severity of AP and modifies the expression of pancreatic ICAM-1 mRNA during AP in a mouse model. AP was induced in mice by hourly (x12) intraperitoneal injections of caerulein. A single dose of feG (100 microg/kg) was coadministered with caerulein either at time 0 h (prophylactic) or 3 h after AP induction (therapeutic). Plasma amylase and pancreatic MPO activities and pancreatic ICAM-1 mRNA expression (by RT-PCR) were measured. Pancreatic sections were histologically assessed for abnormal acinar cells and interstitial space. AP induction produced a sevenfold increase in plasma amylase, a tenfold increase in pancreatic MPO activity, and a threefold increase in interstitial space, and 90% of the acinar cells were abnormal. Prophylactic treatment with feG reduced the AP-induced plasma amylase activity by 45%, pancreatic MPO by 80%, the proportion of abnormal acinar cells by 30%, and interstitial space by 40%. Therapeutic treatment with feG significantly reduced the AP-induced abnormal acinar cells by 10% and the interstitial space by 20%. Pancreatic ICAM-1 mRNA expression was upregulated in AP and was reduced by 50% with prophylactic and therapeutic treatment with feG. We conclude that feG ameliorates experimental AP acting at least in part by modulating ICAM-1 expression in the pancreas.
Full-text available · Article · May 2008 · AJP Gastrointestinal and Liver Physiology