Inflammatory Hypersensitivity Research Articles

White Blood Count Components as Risk Predictors for Coronary Heart Disease: The Role of Eosinophils

To the Editor: We read with great interest the paper by Madjid and Fatemi1 about the components of the complete blood count as indicators of inflammation and risk predictors of coronary heart disease. Although all subtypes of the white blood count have been associated with an increased risk of coronary heart disease, the role of eosinophils has been underestimated. The authors1 correctly refer to genetic analysis of the inflammatory role of eosinophils, because a single nucleotide polymorphism at 12q24, in SH2B3, was found to have a significant association with myocardial infarction (MI). Eosinophils play an important role in inflammation, and their existence denotes hypersensitivity inflammation. Hypersensitivity inflammation can induce acute MI, and the Kounis hypersensitivity acute coronary syndrome is well described.2 In patients who had vasospastic angina pectoris, eosinophil counts were significantly increased and could predict the severity of the disease. After these patients underwent medical therapy and attained relief from chest symptoms, their eosinophil counts decreased significantly, to the same level as those of the control group.3 Clinical reports have shown that the absolute number of eosinophils and the eosinophil-to-leukocyte ratio are significantly elevated in patients who have coronary artery disease.4 Coronary vasospasm associated with eosinophilia responds poorly to conventional vasodilator therapy, and although the risk of recurrent coronary events is high, most patients respond to therapy that suppresses eosinophilia, such as corticosteroids.5 Eosinophils are pleiotropic multifunctional leukocytes involved in the initiation and propagation of inflammatory responses, and they express H4 histamine receptors on their surface. These receptors facilitate eosinophil chemotaxis toward mast cells, which are a source of inflammatory soluble mediators. These mediators can induce the coronary hypersensitivity associated with Kounis syndrome that manifests itself as vasospastic angina, acute MI, or both.2 Soluble mediators secreted by mast cells and eosinophils also modulate reciprocal interactions between these 2 cells in the so-called “allergic effector unit.” Major basic cationic protein released from eosinophils can activate mast cells.6 This activation elicits exocytosis and new eicosanoid and cytokine production, both of which are prominent responses after Fc∊RI-dependent activation of mast cells. Mediators similar to those found in Kounis syndrome are found in cases with nonallergic causes, which suggests that this is a more general problem. A common pathway between allergic and nonallergic coronary syndromes seems to exist.2 Eosinophil count has emerged as a novel biomarker of risk stratification in patients who have coronary artery disease. This reality is essential for elucidating the cause of inflammation.

흰쥐의 구강악안면 영역에서 포르말린 통증행위반응에 TRPV1 채널의 영향

The present study investigated the inflammatory hypersensitivity following activation of the transient receptor potential vanilloid receptor-1(TRPV1) in rats. Experiments were carried out on male Sprague-Dawley rats weighing 220-260g. Following an subcutaneous injection of 5% formalin in the orofacial area, nociceptive scratching behavior was recorded for 9 successive 5-min intervals in rats. The subcutaneous injection of of 5% formalin produced noxious scratching behavior. Injection of capsaicin, TRPV1 agonist, alone into the vibrissa pad did not produced nociceptive behavior. After subcutaneous injection of capsaicin(0, ) in the formalin-treated rats, nociceptive scratching behavior was recorded for 9 successive 5-min internals. Injection of capsaicin into the vibrissa pad significantly increased the number of scratches at 1 hours after injection. Noxious behavioral responses induced by subcutaneous capsaicin injection were significantly potentiated in formalin-treated rats. Pre or post-treatment with iodo-resinaferatoxin(IRTX), TRPV1 antagonist, significantly attenuated increased nociceptive behavior. These findings suggest that activation of the TRPV1 enhanced formalin-induced inflammatory pain in the orofacial area of rats.

White blood count and infarct size, myocardial salvage and clinical outcomes: the role of differentials

Evidence suggests that inflammation, both local and systemic, plays an important role in the pathogenesis of acute myocardial infarction [1]. There is also evidence that increased concentrations of inflammatory markers such as C-reactive protein interleukin-2 and tumor necrosis factor can identify patients at high risk of future ischemic events, suggesting that the intensity of the inflammatory response influences clinical outcome in acute coronary syndromes [2, 3]. Multiple studies have demonstrated also an association between elevated leucocyte count, which is a non-specific marker of inflammation, and the extent of coronary artery disease or increased short-term or long-term risk of death in patients with various manifestations of coronary artery disease [4, 5]. Other studies [6] have shown that total leucocyte count, but not C-reactive protein, predicts 1-year mortality in patients with acute coronary syndromes treated with percutaneous coronary intervention. Furthermore, recent studies have emphasized the usefulness of neutrophil to lymphocyte ratio in predicting short-and long-term mortality, thrombus formation, infarct related artery patency, TIMI flow grade after primary coronary angioplasty, impaired myocardial perfusion, ventricular arrhythmias and critical limb ischemia [7–9]. Indeed, in patients with non-ST-elevation myocardial infarction a ratio above 4.7 has been reported to be an independent predictor of short-term and long-term mortality [7] and ratio[3.3 was found to be an independent predictor of impaired coronary flow after primary percutaneous coronary intervention and of in-hospital major adverse cardiac events in patients with ST-segment elevation myocardial infarction [10]. In a recent issue of the Int J Cardiovasc Imaging [11] and additional very interesting paper was published which shows that in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction an elevated baseline white blood count is associated with less salvaged myocardium, larger infarct size and poorer clinical outcomes. All these papers and results really suggest a key role of inflammation in coronary artery disease. However, differential count was not available in these studies, and therefore, assessing the relative impact of white blood count subpopulations on myocardial infarction was not reported. Total white blood count comprises several cell types such as monocytes, lymphocytes and eosinophils all of which are implicated in the development, progression and instability of atherosclerotic plaque. None of the above studies have focused attention on the presence of eosinophils and this was probably based on an older study which has suggested that total white blood count is a better correlate of long-term than differentials [12]. Eosinophils, however, play an important role in inflammation and can identify the etiology of inflammation since they denote hypersensitivity inflammation [13–15]. Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. These cells are also bone marrow-derived granulocytic leukocytes which express H4 histamine receptors in their surface. These receptors facilitate eosinophil chemotaxis toward mast cells which are the major producers of an array of inflammatory soluble mediators. These inflammatory mediators can induce the coronary hypersensitivity associated Kounis syndrome manifesting as vasospastic angina and/or acute myocardial N. G. Kounis (&) Medical Sciences, Patras Highest Institute of Education and Technology, Patras, Achaia, Greece e-mail: ngkounis@otenet.gr

Localization of receptors for calcitonin-gene-related peptide to intraganglionic laminar endings of the mouse esophagus: peripheral interaction between vagal and spinal afferents?

The calcitonin-gene-related peptide (CGRP) receptor is a heterodimer of calcitonin-receptor-like receptor (CLR) and receptor-activity-modifying protein 1 (RAMP1). Despite the importance of CGRP in regulating gastrointestinal functions, nothing is known about the distribution and function of CLR/RAMP1 in the esophagus, where up to 90% of spinal afferent neurons contain CGRP. We detected CLR/RAMP1 in the mouse esophagus using immunofluorescence and confocal laser scanning microscopy and examined their relationship with neuronal elements of the myenteric plexus. Immunoreactivity for CLR and RAMP1 colocalized with VGLUT2-positive intraganglionic laminar endings (IGLEs), which were contacted by CGRP-positive varicose axons presumably of spinal afferent origin, typically at sites of CRL/RAMP1 immunoreactivity. This provides an anatomical basis for interaction between spinal afferent fibers and IGLEs. Immunoreactive CLR and RAMP1 also colocalized in myenteric neurons. Thus, CGRP-containing spinal afferents may interact with both vagal IGLEs and myenteric neurons in the mouse esophagus, possibly modulating motility reflexes and inflammatory hypersensitivity.

Antinociceptive effect of Phyllanthus fraternus extract in complete Freund's adjuvant induced chronic pain in mice

ObjectiveTo evaluate the effects of Phyllanthus fraternus (PF) extract on chronic inflammatory pain. MethodComplete Freund's adjuvant (CFA) induced inflammatory pain model was used to investigate the effects of (PF) extract on chronic inflammatory hypersensitivity in adult Swiss albino mice. Twenty-four hours after CFA injection, we used Von Frey filaments and acetone-evoked cooling to evaluate tactile and thermal hypersensitivity, respectively. The paw edema was measured with the help of a digital plethysmometer. ResultsSingle intraperitoneal injections of PF extract (200 & 400mg/kg) administered 30minutes before testing reduced CFA-induced mechanical hypersensitivity. Similarly, PF reduced acetone-evoked hypersensitivity up to 4hours after treatment. Compared with vehicle, PF produced a marked reduction in CFA-induced paw edema. Multiple treatments with PF extracts given chronically (twice a day from 1st to 5th day and from 9th to 10th day) significantly reduced mechanical hypersensitivity induced by CFA. This multi-dose strategy did not cause tolerance. ConclusionThe present study reveals the antinociceptive activity of PF in chronic inflammatory hyperalgesia and also indicates that it might be potentially effective in management of the persistent pain.

Artemin–GFRα3 interactions partially contribute to acute inflammatory hypersensitivity

The expression of artemin (ARTN), a glial cell line-derived neurotrophic factor (GDNF) family ligand, increases in pre-clinical models of nociception and recent evidence suggests this growth factor may play a causative role in inflammatory pain mechanisms. The aim of this study was to demonstrate functional inhibition of ARTN with monoclonal antibodies and to determine whether ARTN neutralisation could reverse inflammatory pain in mice. We show that monoclonal antibodies with high affinity to ARTN, completely inhibit ARTN-induced Ret and ERK activation in a human neuroblastoma cell line, and block capsaicin-induced CGRP secretion from primary rat DRG cultures. In addition, administration of anti-ARTN antibodies to mice provides a transient, partial reversal (41%) of FCA-induced mechanical hypersensitivity. Anti-ARTN antibodies had no effect on hypersensitivity in response to partial nerve ligation in mice. These data suggest that ARTN–GFRα3 interactions partially mediate early stage nociceptive signalling following an inflammatory insult.

Nuclear Calcium Signaling in Spinal Neurons Drives a Genomic Program Required for Persistent Inflammatory Pain

Persistent pain induced by noxious stimuli is characterized by the transition from normosensitivity to hypersensitivity. Underlying mechanisms are not well understood, although gene expression is considered important. Here, we show that persistent nociceptive-like activity triggers calcium transients in neuronal nuclei within the superficial spinal dorsal horn, and that nuclear calcium is necessary for the development of long-term inflammatory hypersensitivity. Using a nucleus-specific calcium signal perturbation strategy in vivo complemented by gene profiling, bioinformatics, and functional analyses, we discovered a pain-associated, nuclear calcium-regulated gene program in spinal excitatory neurons. This includes C1q, a modulator of synaptic spine morphogenesis, which we found to contribute to activity-dependent spine remodelling on spinal neurons in a manner functionally associated with inflammatory hypersensitivity. Thus, nuclear calcium integrates synapse-to-nucleus communication following noxious stimulation and controls a spinal genomic response that mediates the transition between acute and long-term nociceptive sensitization by modulating functional and structural plasticity.

Role of Voltage Gated Ca2+ Channels in Rat Visceral Hypersensitivity Change Induced by 2, 4, 6-Trinitrobenzene Sulfonic Acid

BackgroundVisceral pain is common symptom involved in many gastrointestinal disorders such as inflammatory bowel disease. The underlying molecular mechanisms remain elusive. We investigated the molecular mechanisms and the role for voltage gated calcium channel (VGCC) in the pathogenesis in a rat model of 2,4,6-trinitrobenzenesulfonic acid (TNBS) induced visceral inflammatory hypersensitivity.ResultsUsing Agilent cDNA arrays, we found 172 genes changed significantly in dorsal root ganglia (DRG) of TNBS treated rats. Among these changed genes, Cav1.2 and Cav2.3 were significantly up-regulated. Then the RT-PCR and Western blot further confirmed the up-regulation of Cav1.2 and Cav2.3. The whole cell patch clamp recording of acutely dissociated colonic specific DRG neurons showed that the peak IBa density was significantly increased in colonic neurons of TNBS treated rats compared with control rats (−127.82 ± 20.82 pA/pF Vs −91.67 ± 19.02 pA/pF, n = 9, *P < 0.05). To distinguish the different type of calcium currents with the corresponding selective channel blockers, we found that L-type (−38.56 ± 3.97 pA/pF Vs −25.75 ± 3.35 pA/pF, n = 9, * P < 0.05) and R-type (−13.31 ± 1.36 pA/pF Vs −8.60 ± 1.25 pA/pF, n = 9, * P < 0.05) calcium current density were significantly increased in colonic DRG neurons of TNBS treated rats compared with control rats. In addition, pharmacological blockade with L-type antagonist (nimodipine) and R-type antagonist (SNX-482) with intrathecal injection attenuates visceral pain in TNBS induced inflammatory visceral hypersensitivity.ConclusionCav1.2 and Cav2.3 in colonic primary sensory neurons play an important role in visceral inflammatory hyperalgesia, which maybe the potential therapeutic targets.

Transcription of the pain‐related TRPV1 gene requires Runx1 and C/EBPβ factors

Transient Receptor Potential Vanilloid type 1 channel (TRPV1) is an important endogenous transducer of noxious heat and chemical stimuli and is required during development of inflammatory hypersensitivity. The transcription factor Runx1 is known to play a relevant role in sensory neuron differentiation as it controls the expression of several sensory nociceptive receptors, including TRPV1. Here, we show that Runx1 up-regulates TRPV1 transcription activity by interacting directly with the proximal TRPV1 gene promoter sequence. Importantly, C/EBPβ a well-established heterodimer partner of Runx1 also binds to the TRPV1 promoter and cooperates with Runx1 to further stimulate TRPV1 transcription. Our results support a mechanism where Runx1-C/EBPβ-containing transcription regulatory complexes are recruited to the TRPV1 gene promoter to modulate TRPV1 expression in dorsal root ganglia neurons.

PCR based bronchoscopic detection of common respiratory pathogens in chronic cough: a case control study

BackgroundViral respiratory tract infection is the most frequent cause of acute cough and is reported at onset in about one third of patients with chronic cough. Persistent infection is therefore one possible explanation for the cough reflex hypersensitivity and pulmonary inflammation reported in chronic cough patients.MethodsBronchoscopic endobronchial biopsies and bronchoalveolar lavage cell counts were obtained from ten healthy volunteers and twenty treatment resistant chronic cough patients (10 selected for lavage lymphocytosis). A screen for known respiratory pathogens was performed on biopsy tissue. Chronic cough patients also underwent cough reflex sensitivity testing using citric acid.ResultsThere was no significant difference in incidence of infection between healthy volunteers and chronic cough patients (p = 0.115) or non-lymphocytic and lymphocytic groups (p = 0.404). BAL cell percentages were not significantly different between healthy volunteers and chronic cough patients without lymphocytosis. Lymphocytic patients however had a significantly raised percentage of lymphocytes (p < 0.01), neutrophils (p < 0.05), eosinophils (p < 0.05) and decreased macrophages (p < 0.001) verses healthy volunteers. There was no significant difference in the cough reflex sensitivity between non-lymphocytic and lymphocytic patients (p = 0.536).ConclusionsThis study indicates latent infection in the lung is unlikely to play an important role in chronic cough, but a role for undetected or undetectable pathogens in either the lung or a distal site could not be ruled out.Trials registrationCurrent Controlled Trials ISRCTN62337037 & ISRCTN40147207

Sa1487 Gene Expression Profiling and Endothelin in Acute Experimental Pancreatitis

AIM:To analyze gene expression profiles in an experimental pancreatitis and provide functional reversal of hypersensitivity with candidate gene endothelin-1 antagonists.METHODS:Dibutyltin dichloride(DBTC) is a chemical used as a polyvinyl carbonate stabilizer/catalyzer,biocide in agriculture,antifouling agent in paint and fabric.DBTC induces an acute pancreatitis flare through generation of reactive oxygen species.Lewis-inbred rats received a single i.v.injection with either DBTC or vehicle.Spinal cord and dorsal root ganglia(DRG) were taken at the peak of inflammation and processed for transcriptional profiling with a cDNA microarray biased for rat brain-specific genes.In a second study,groups of animals with DBTC-induced pancreatitis were treated with endothelin(ET) receptor antagonists [ET-A(BQ123) and ET-B BQ788)].Spontaneous pain related mechanical and thermal hypersensitivity were measured.Immunohistochemical analysis was performed using anti-ET-A and ET-B antibodies on sections from pancreatic tissues and DRG of the T10-12 spinal segments.RESULTS:Animals developed acute pancreatic inflammation persisting 7-10 d as confirmed by pathological studies(edema in parenchyma,loss of pancreatic architecture and islets,infiltration of inflammatory cells,neutrophil and mononuclear cells,degeneration,vacuolization and necrosis of acinar cells) and the painrelated behaviors(cutaneous secondary mechanical and thermal hypersensitivity).Gene expression profile was different in the spinal cord from animals with pancreatitis compared to the vehicle control group.Over 260 up-regulated and 60 down-regulated unique genes could be classified into 8 functional gene families:circulatory/acute phase/immunomodulatory;extracellular matrix;structural;channel/receptor/transporter;signaling transduction;transcription/translation-related;antioxidants/chaperones/heat shock;pancreatic and other enzymes.ET-1 was among the 52 candidate genes upregulated greater than 2-fold in animals with pancreatic inflammation and visceral pain-related behavior.Treatments with the ET-A(BQ123) and ET-B(BQ-788) antagonists revealed significant protection against inflammatory pain related mechanical and thermal hypersensitivity behaviors in animals with pancreatitis(P 0.05).Open field spontaneous behavioral activity(at baseline,day 6 and 30 min after drug treatments(BQ123,BQ788) showed overall stable activity levels indicating that the drugs produced no undesirable effects on normal exploratory behaviors,except for a trend toward reduction of the active time and increase in resting time at the highest dose(300 μmol/L).Immunocytochemical localization revealed that expression of ET-A and ET-B receptors increased in DRG from animals with pancreatitis.Endothelin receptor localization was combined in dual staining with neuronal marker NeuN,and glia marker,glial fibrillary acidic protein.ET-A was expressed in the cell bodies and occasional nuclei of DRG neurons in na ve animals.However,phenotypic expression of ET-A receptor was greatly increased in neurons of all sizes in animals with pancreatitis.Similarly,ET-B receptor was localized in neurons and in the satellite glia,as well as in the Schwann cell glial myelin sheaths surrounding the axons passing through the DRG.CONCLUSION:Endothelin-receptor antagonists protect against inflammatory pain responses without interfering with normal exploratory behaviors.Candidate genes can serve as future biomarkers for diagnosis and/or targeted gene therapy.

Comment:Sporotrichoid atopic prurigo. A common condition with an unusual clinical presentation

Prurigo is a very common dermatosis with no racial nor sex preference. It is frequently encountered in patients with atopic phenomenon. The causes of prurigo are mainly hypersensitivity reaction, inflammation and infection. Prurigo can also be classified simply as acute or chronic prurigo. The latter is more common type and one of its variant is actinic prurigo. Actinic prurigo is quite common in temperate regions. There are chronic recurrent prurigo nodules on sun-exposed areas of the body such as nape and sides of the neck, backs of the hands, extensor forearms and upper chest, and is usually resistant to treatment. Sporotrichoid atopic prurigo is a rare variant where itchy prurigo nodules are seen along the lymphatic or vascular drainage area, and usually seen in lower limbs. Sporotrichoid atopic prurigo is commonly seen in atopic patients who do hard works and are prone to minor trauma. This includes military persons, people who work in paddy fields and manual labor. The case presented by Beatriz Di Martino Ortiz et al is an unusual type of sporotrichoid atopic prurigo affecting the left axilla. Its cause seems to be inflammation caused by infection. So it is rapidly resolved by systemic antibiotics.

Disruption of δ-opioid receptor phosphorylation at Threonine 161 attenuates morphine tolerance in rats with CFA-induced inflammatory hypersensitivity

Our previous study identified Threonine 161 (Thr-161), located in the second intracellular loop of the δ-opioid receptor (DOR), as the only consensus phosphorylation site for cyclin-dependent kinase 5 (Cdk5). The aim of this study was to assess the function of DOR phosphorylation by Cdk5 in complete Freund's adjuvant (CFA)-induced inflammatory pain and morphine tolerance. Dorsal root ganglion (DRG) neurons of rats with CFA-induced inflammatory pain were acutely dissociated and the biotinylation method was used to explore the membrane localization of phosphorylated DOR at Thr-161 (pThr-161-DOR), and paw withdrawal latency was measured after intrathecal delivery of drugs or Tat-peptide, using a radiant heat stimulator in rats with CFA-induced inflammatory pain. Both the total amount and the surface localization of pThr-161-DOR were significantly enhanced in the ipsilateral DRG following CFA injection. Intrathecal delivery of the engineered Tat fusion-interefering peptide corresponding to the second intracellular loop of DOR (Tat-DOR-2L) increased inflammatory hypersensitivity, and inhibited DOR- but not µ-opioid receptor-mediated spinal analgesia in CFA-treated rats. However, intrathecal delivery of Tat-DOR-2L postponed morphine antinociceptive tolerance in rats with CFA-induced inflammatory pain. Phosphorylation of DOR at Thr-161 by Cdk5 attenuates hypersensitivity and potentiates morphine tolerance in rats with CFA-induced inflammatory pain, while disruption of the phosphorylation of DOR at Thr-161 attenuates morphine tolerance.

The place escape/avoidance paradigm: A novel method to assess nociceptive processing

This paper summarizes a behavioral paradigm that was developed as a novel method to dissociate the multidimensional pain experience in rodents. The place escape/avoidance paradigm (PEAP) is based on the assumption that if animals escape and/or avoid a noxious stimulus, then the stimulus is aversive to the animal. Data is presented showing that when animals are placed in a specific environmental condition, they will perform purposeful behavior to escape and/or avoid the noxious stimulus. Additional data is presented to demonstrate the validity of the behavioral paradigm and how the paradigm has been used to test the hypothesis that the affective/motivational dimension of pain can be dissociated and studied independent of sensory pain processing. The behavioral paradigm highlights the emerging trend in the area of pain research and management towards developing more realistic behavioral paradigms to assess nociceptive processing in rodent models of chronic pain.

The Plant-Derived Alkylamide, Hydroxy-Alpha-Sanshool, Induces Analgesia through Inhibition of Voltage-Gated Sodium Channels

Many native cultures use extracts from Xanthozylum plants to topically treat toothache and joint pain. One active component of these extracts is the alkylamide, hydroxy-α-sanshool, which induces tingling and numbing paresthesia when applied to the skin or tongue. To understand the physiological mechanisms underlying paresthesias, we sought to identify the molecular targets of sanshool in the somatosensory system. We first measured the analgesic properties of sanshool using mouse models of somatosensory behavior. Topical application of sanshool on the hind paw of naive mice did not alter their sensitivity to noxious thermal or mechanical stimuli. However, in a model of neurogenic inflammation, sanshool acutely suppressed inflammatory hypersensitivity to mechanical force whereas it did not suppress hypersensitivity to heat. These data suggest that sanshool inhibits activity of a subset of sensory neurons that transduce mechanical, but not thermal, stimuli. In cultured dorsal root ganglion (DRG) neurons from mice, sanshool inhibited action potential (AP) firing in a subset of medium-to-large diameter neurons, which are thought to mediate mechanotransduction. In contrast, sanshool did not inhibit AP firing in small-diameter sensory neurons, which predominantly transduce noxious heat. In addition to size, sensory neurons are distinct in their expression of sensory neuron-specific voltage-gated sodium channels. Thus the differential effect of sanshool on sensory neurons may be due to selective activity of sanshool on different sodium channels. To test this idea, we compared the effects of sanshool on two sodium channel subtypes that are expressed in sensory neurons, Nav1.7 and 1.8. Sanshool reduced the magnitude of Nav1.7 and Nav1.8 currents but caused a hyperpolarizing shift in the steady-state inactivation curve of Nav1.7 only. Thus intrinsic molecular differences between sensory neurons, such as expression of different sodium channel subtypes, may underlie specificity of sanshool action.

Comparison of the antinociceptive effects of ibuprofen arginate and ibuprofen in rat models of inflammatory and neuropathic pain

Aims Ibuprofen arginate is a highly soluble salt formed by combining racemic ibuprofen with the amino acid l-arginine. This formulation is absorbed faster, and it is safe and effective in treating many forms of mild to moderate pain. We compared the analgesic effect of ibuprofen arginate and conventional ibuprofen in rat models of pain. Main methods Mechanical and cold allodynia were assessed in the chronic constriction injury (CCI) model of neuropathic pain, and mechanical allodynia was also examined in capsaicin-injected rats (a model of central sensitization). Inflammatory hypersensitivity was assessed with the formalin test. Ibuprofen- l-arginine, ibuprofen, l-arginine or saline was administered orally on a daily basis after CCI or capsaicin injection, and the von Frey and cold plate tests were performed on days 1, 3 and 7 after CCI or capsaicin administration. In the formalin-induced inflammatory pain test, the drugs were administered 30 min before formalin injection. Key findings Ibuprofen only exerts an antinociceptive effect in the formalin model whereas ibuprofen- l-arginine exerts antinociceptive effects on both mechanical and cold allodynia induced by CCI, mechanical allodynia induced by capsaicin injection, and in phase 2 of the formalin test, exhibiting superior antinociceptive activity to ibuprofen in all these tests. l-Arginine only exerted antinociceptive effects on cold allodynia in CCI. Significance These results demonstrate that ibuprofen arginate has stronger antinociceptive effects than ibuprofen in all the models used, suggesting it might improve the therapeutic management of neuropathic and inflammatory pain.

TRPV1 and TRPA1 Function and Modulation Are Target Tissue Dependent

The nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF) families of growth factors regulate the sensitivity of sensory neurons. The ion channels transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential channel, subfamily A, member 1 (TRPA1), are necessary for development of inflammatory hypersensitivity and are functionally potentiated by growth factors. We have shown previously that inflamed skin exhibits rapid increases in artemin mRNA with slower, smaller increases in NGF mRNA. Here, using mice, we show that, in inflamed colon, mRNA for both growth factors increased with a pattern distinct from that seen in skin. Differences were also seen in the pattern of TRPV1 and TRPA1 mRNA expression in DRG innervating inflamed skin and colon. Growth factors potentiated capsaicin (a specific TRPV1 agonist) and mustard oil (a specific TRPA1 agonist) behavioral responses in vivo, raising the question as to how these growth factors affect individual afferents. Because individual tissues are innervated by afferents with unique properties, we investigated modulation of TRPV1 and TRPA1 in identified afferents projecting to muscle, skin, and colon. Muscle and colon afferents are twice as likely as skin afferents to express functional TRPV1 and TRPA1. TRPV1 and TRPA1 responses were potentiated by growth factors in all afferent types, but compared with skin afferents, muscle afferents were twice as likely to exhibit NGF-induced potentiation and one-half as likely to exhibit artemin-induced potentiation of TRPV1. Furthermore, skin afferents showed no GDNF-induced potentiation of TRPA1, but 43% of muscle and 38% of colon afferents exhibited GDNF-induced potentiation. These results show that interpretation of afferent homeostatic mechanisms must incorporate properties that are specific to the target tissue.

The study on the mechanism of voltage gated calcium channels on 2, 4, 6-trinitrobenzene sulfonic acid induced inflammatory visceral hypersensitivity

Objective To screen the difference of gene expression in dorsal root ganglia (DRG)of inflammatory visceral hypersensitivity rats and to explore the role of voltage gated calcium channel (VGCC) in inflammatory visceral hypersensitivity. Methods Total 180 male Sprague-Dawley rats were in this study,the weight varied from 200 gram to 300 gram. 2,4,6-trinitrobenzenesulfonic acid (TNBS) model group was maken by 2. 0% TNBS slowly injection,the dosage was 100mg per kilogram. The normal control group was only injected with same volume of 0. 9% sodium chloride solution. After the model had been maken for four days,gene expression profiles of L6-S2 DRGs were tested by rat cDNA microarray chips. And the result was verified by RT-PCR and Western blot. The changes of intracellular Ca2+ and the voltage gated calcium currents were recorded by patch-clamp.The special Ca2+ channel blockers were given by intrathecal injection,and then the changes of visceral sensitivity were observed. The visceral sensitivity was measured by abdominal withdrawal reflex (AWR). Results There were significant changes of 172 genes expression in L6-S2 DRGs of TNBS model rats,which included Ca2+ channel,membrane receptor and intracellular second messenger. Of those,L-type Ca2+ channel (Cav1. 2) and R-type Ca2+ channel (Cav2. 3) were significantly up-regulated. The results of gene microarray chips were further confirmed by RT-PCR and Western blot.The intracellular Ca2+ testing indicated that there was no statistical significant of resting intracellular Ca2+ in colonic special sensory neuron between TNBS group and normal control group (P＞0. 05);while the evoked transients [Ca2+] significantly increased compared with normal control group (P＜0. 05). The whole cell patch clamp recording showed that the L-type and R-type calcium current were significantly increased in colonic primary sensory neurons of TNBS group compared with normal control group (P＜0. 05). The inflammatory visceral hypersensitivity was significantly reduced by intrathecal injection of nimodipine and SNX-482 (P＜0. 05). Conclusion The up-regulation of Cav1. 2and Cav2. 3 play an important role in inflammatory visceral hyperalgesia,which may be the possible potential therapeutic targets for visceral inflammatory hyperalgesia. Key words: Ganglia,spinal; Potassium channels,voltage-gated; Calcium channel; Visceral; Trinitrobenzenesulfonic acid; Sensitivity and specificity

Role of preprotachykinin A (TAC1) gene-derived peptides and the neurokinin 1 (NK1) receptor in acute nocifensive behaviours and hyperalgesia

Event Abstract Back to Event Role of preprotachykinin A (TAC1) gene-derived peptides and the neurokinin 1 (NK1) receptor in acute nocifensive behaviours and hyperalgesia Z. Hajna1*, É. Borbély1, J. P. Quinn2, A. Zimmer3, E. Pintér1, J. Szolcsányi1 and Z. Helyes1 1 University of Pécs, Department of Pharmacology and Pharmacotherapy, Hungary 2 Liverpool University, School of Biomedical Sciences, United Kingdom 3 University of Bonn, Institute of Molecular Psychiatry, Germany Substance P (SP) and neurokinin A (NKA) encoded by the preprotachykinin A (TAC1) gene are involved in neurogenic inflammation and pain via neurokinin 1 and 2 (NK1 and NK2) receptors, respectively, localized in the sensory cortex, spinal cord and primary sensory neurones. Therefore, we investigated the role of SP, NKA and the NK1 receptor in acute somatic and visceral nociception and inflammatory hypersensitivity using gene-deleted mice (TAC1-/- and NK1-/-). Formalin-evoked paw liftings and lickings in the early phase (0-5 min) induced by direct activation of sensory nerves was not altered by deleting either the TAC1 or the NK1 receptor genes. This nocifensive behaviour in the later phase (20-45 min) mediated by inflammatory mechanisms was significantly reduced in the TAC1-/- group. Abdominal contractions evoked by i.p. acetic acid were markedly decreased in TAC1-/- and NK1-/- mice. Attenuation of i.pl. resiniferatoxin-induced thermal allodynia mediated by peripheral mechanisms was greater in TAC1-/- than in NK1-/- mice, while mechanical hyperalgesia involving central sensitization was only decreased in the NK1-/- group. It can be concluded that SP and NKA are responsible for acute visceral and somatic chemonociception, but NK1 receptors mediate their effect only in the visceral region. Inflammatory thermal allodynia develops by these TAC1-encoded tachykinins, but only partially through NK1 receptors. Meanwhile, mechanical hyperalgesia is mediated predominantly by NK1 receptors. Keywords: Behaviour and cognition, Neuroscience Conference: 13th Conference of the Hungarian Neuroscience Society (MITT), Budapest, Hungary, 20 Jan - 22 Jan, 2011. Presentation Type: Abstract Topic: Behaviour and cognition Citation: Hajna Z, Borbély É, Quinn JP, Zimmer A, Pintér E, Szolcsányi J and Helyes Z (2011). Role of preprotachykinin A (TAC1) gene-derived peptides and the neurokinin 1 (NK1) receptor in acute nocifensive behaviours and hyperalgesia. Front. Neurosci. Conference Abstract: 13th Conference of the Hungarian Neuroscience Society (MITT). doi: 10.3389/conf.fnins.2011.84.00131 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 03 Mar 2011; Published Online: 23 Mar 2011. * Correspondence: Dr. Z. Hajna, University of Pécs, Department of Pharmacology and Pharmacotherapy, Pécs, Hungary, zsofia.hajna@aok.pte.hu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Z. Hajna É. Borbély J. P Quinn A. Zimmer E. Pintér J. Szolcsányi Z. Helyes Google Z. Hajna É. Borbély J. P Quinn A. Zimmer E. Pintér J. Szolcsányi Z. Helyes Google Scholar Z. Hajna É. Borbély J. P Quinn A. Zimmer E. Pintér J. Szolcsányi Z. Helyes PubMed Z. Hajna É. Borbély J. P Quinn A. Zimmer E. Pintér J. Szolcsányi Z. Helyes Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Possible Consequences of Blocking Transient Receptor Potential Vanilloid 1

The cloning of the first sensory Transient Receptor Potential (TRP) channel, TRPVanilloid 1 (TRPV1) in 1997, initiated a new era of pain research and coincided with the Decade of Pain Control and Research promulgated by the United States Congress. When cloned, TRPV1 channel was shown to be predominantly expressed in nociceptors (C- and Aδ-fibers) and are activated by physical and chemical stimuli. Channel function can be amplified by transcriptional upregulation and posttranslational modification by proinflammatory agents. Indeed, TRPV1 gene disruption confirms that it is involved in transmitting inflammatory thermal hypersensitivity, but not acute thermal or mechanical pain sensitivity. Based on its distribution and functions, TRPV1 is considered as an ideal target for developing small molecule antagonists. Now, there is a growing body of evidence that TRPV1 is expressed in non-sensory neurons and non-neuronal cells. This raises the possibility of unwanted effects that may result from targeting TRPV1. A major consequence of TRPV1 blockade that has come to light in clinical trials following administration of antagonists is hyperthermia. This observation has threatened the abandonment of TRPV1 antagonists, although they are proven to be useful in certain modalities of pain. In this review, we will discuss the expression and functions of TRPV1 in various organ systems and highlight the consequences that might be associated with blocking the receptor.