aconitine and Inflammation

Since westernized diet-induced insulin resistance is a risk factor in Alzheimer's disease (AD) development, and lipopolysaccharide (LPS) coexists with amyloid β (Aβ)1-42 in these patients, our AD novel model was developed to resemble sporadic AD by injecting LPS into high fat/fructose diet (HFFD)-fed rats. The neuroprotective potential of palonosetron and/or methyllycaconitine, 5-HT3 receptor and α7 nAChR blockers, respectively, was evaluated after 8 days of daily administration in HFFD/LPS rats. All regimens improved histopathological findings and enhanced spatial memory (Morris Water Maze); however, palonosetron alone or with methyllycaconitine promoted animal performance during novel object recognition tests. In the hippocampus, all regimens reduced the expression of glial fibrillary acidic protein and skewed microglia M1 to M2 phenotype, indicated by the decreased M1 markers and the enhanced M2 related parameters. Additionally, palonosetron and its combination regimen downregulated the expression of ASC/TMS1, as well as levels of inflammasome downstream molecules and abated cleaved caspase-1, interleukin (IL)-1β, IL-18 and caspase-11. Furthermore, ACh and 5-HT were augmented after being hampered by the insult. Our study speculates that blocking 5-HT3 receptor using palonosetron overrides methyllycaconitine to combat AD-induced neuroinflammation and inflammasome cascade, as well as to restore microglial function in a HFFD/LPS novel model for sporadic AD.

Topics: Aconitine; Alzheimer Disease; Amyloid beta-Peptides; Animals; CARD Signaling Adaptor Proteins; Cognition; Diet, Western; Disease Models, Animal; Hippocampus; Humans; Inflammasomes; Inflammation; Insulin Resistance; Interleukin-18; Lipopolysaccharides; Microglia; Palonosetron; Peptide Fragments; Pyroptosis; Rats; Receptors, Serotonin, 5-HT3; Risk Factors; Spatial Memory

Rheumatoid arthritis (RA) is a kind of systemic autoimmune disease, and patients with RA usually suffer serious pain, resulting in low quality of life. The development of drug delivery systems (DDSs) provides a valid approach for RA therapy via inhibiting the secretion of inflammatory cytokines from macrophages. As a prevailing drug nanocarrier with distinctive superiority, polymeric nanoparticles (NPs) have attracted much attention in recent years. However, low biocompatibility and limited exploitation of drug with high efficiency are still the main challenges in RA treatment. To overcome the limitations, we prepared a biocompatible copolymer methoxy-poly(ethylene glycol)-poly(lactide-co-glycolide) (mPEG-PLGA). Moreover, benzoylaconitine (BAC) with superior anti-inflammatory effect was selected as model drug. It was isolated from Aconitum kusnezoffii Reichb and encapsulated into mPEG-PLGA NPs (NP/BAC) to increase the bioavailablity of BAC. The NPs exhibited high cytocompatibility for activated macrophages and well compatibility with red blood cells. Furthermore, the anti-inflammatory property of NP/BAC was testified by substantially inhibiting secretion of pro-inflammatory cytokines. The TNF-α and IL-1β cytokines of NP/BAC group reduced 70 % and 66 % compared with that of activated macrophages. Especially, NP/BAC reduced the overexpression of NF-κB p65 to inhibit NF-κB signaling pathway, which was a critical regulator of inflammatory responses. NP/BAC also showed efficient in vivo anti-inflammatory effect with high ear (69.8 %) and paw (87.1 %) swelling suppressing rate. These results revealed the anti-inflammatory mechanism of NP/BAC and proved it was a suitable DDS to suppress inflammation, providing a promising strategy for RA therapy and research of Aconitum kusnezoffii Reichb.

Topics: Aconitine; Animals; Anti-Inflammatory Agents; Cytokines; Drug Delivery Systems; Edema; Female; Inflammation; Macrophages; Nanoparticles; NF-kappa B; Rats

Inflammatory storm is an important pathological mechanism of multiple organ dysfunction, and it is associated with most deaths in septic patients, deserving to be studied. Recent findings have confirmed that the Medullary Visceral Zone (MVZ) regulates inflammation and immunity through the cholinergic anti-inflammatory pathway (CAP), but how sepsis affects the MVZ and leads to uncontrolled inflammation remain unclear. The current study reported that sepsis induced MVZ to inhibit CAP which underlies the inflammation storm. Our studies have shown that the rat models of sepsis prepared by cecal ligation and puncture had a higher inflammatory level, higher mortality, and higher Murine Sepsis Score. In septic rats, some indicators of heart rate variability (HRV) such as SDNN, HF band, RMSSD, SD1, and SD2 significantly reduced. In MVZ of septic rats, many cholinergic and catecholaminergic neurons showed apoptotic, with low expressions of tyrosine hydroxylase and choline acetyltransferase. The

Topics: Aconitine; Animals; Apoptosis; CD4 Antigens; Choline O-Acetyltransferase; Cytokines; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Fluorescent Antibody Technique; Heart Rate; In Situ Nick-End Labeling; Inflammation; Interleukin-2 Receptor alpha Subunit; Kaplan-Meier Estimate; Male; Neurons; Rats; Sepsis; Th17 Cells; Tyrosine 3-Monooxygenase

BACKGROUND Bulleyaconitine A (BLA) has been widely used as analgesic against chronic inflammatory pain in China. However, its potential therapeutic role in asthma remains unclear. The purpose of this study was to investigate the effect of BLA on airway inflammation in mice with allergic asthma. MATERIAL AND METHODS Specific-pathogen-free (SPF) female Balb/c mice were randomly divided into the following 6 groups: (1) Control group (NC), (2) Asthma group (AS), (3) BLA-L group, (4) BLA-M group, (5) BLA-H group, and (6) Dexamethasone group. An asthma mouse model was established by administration of ovalbumin (OVA) and mice were sacrificed within 24 h after the last challenge. Enzyme-linked immunosorbent assay (ELISA) method was used to determine the relative expression levels of IgE and IgG in mouse serum. In addition, bronchoalveolar lavage fluid (BALF) was collected and IL-4, TNF-α, and MCP-1 levels were determined by ELISA. Furthermore, eosinophils, lymphocytes, and macrophages in BALF were classified and analyzed, and inflammatory cell infiltration in the airways of mice was determined by hematoxylin-eosin (HE) staining. The expression of NF-κB1 and PKC-δ in mouse lung tissue was determined by Western blot analysis. RESULTS The levels of serum IgE and IgG in BLA- or Dex- treated mice were significantly reduced compared to those in the asthma (AS) group (P<0.01), whereas the levels of cytokines IL-4, TNF-α, and MCP-1 were significantly decreased (P<0.01). HE-staining showed that BLA significantly reduced inflammatory cell infiltration and mucus secretion in lung tissue. Moreover, BLA inhibited the expression of NF-κB1 and PKC-d via the NF-κB signaling pathway in the lung. CONCLUSIONS Our data show that BLA activates PKC-δ/NF-κB to reduce airway inflammation in allergic asthma mice.

Topics: Aconitine; Animals; Anti-Asthmatic Agents; Asthma; Bronchoalveolar Lavage Fluid; Chemokine CCL2; China; Cytokines; Disease Models, Animal; Eosinophils; Female; Inflammation; Interleukin-4; Lung; Mice; Mice, Inbred BALB C; NF-kappa B; Ovalbumin; Protein Kinase C-delta; Tumor Necrosis Factor-alpha

Evidence suggests that α7 nicotinic acetylcholine receptor (α7 nAChR) in the central nervous system has a critical role in the regulation of microglial function and neuroinflammation associated with the pathophysiology of major depressive disorder. The objectives of the present study were to determine the effects of PNU 120596, an α7 nAChR positive allosteric modulator (PAM), on depressive-like behavior and expression of ionized calcium binding adaptor molecule 1 (Iba-1), a microglial marker, in male C57BL/6J mice following lipopolysaccharide (LPS) administration, an animal model for depressive-like behavior. Forced swim test (FST), tail suspension test (TST), and sucrose preference test were used to determine the effects of PNU 120596 on depressive-like behavior, measured by increased immobility time or decreased sucrose preference. We also examined the effects of PNU 120596 on Iba-1 expression by using Western blot analysis and immunofluorescence staining in the hippocampus and prefrontal cortex, the brain regions implicated in major depressive disorder. Administration of LPS (1 mg/kg, i.p.) significantly increased immobility time during FST and TST and decreased sucrose preference. The PNU 120596 (1 or 4 mg/kg, i.p.) dose-dependently prevented LPS-induced depressive-like behavior during FST, TST, and sucrose preference test. The PNU 120596 (1 or 4 mg/kg) alone did not show any significant alteration on immobility time and sucrose preference. Pretreatment of methyllycaconitine (3 mg/kg, i.p.), an α7 nAChR antagonist, significantly prevented the antidepressant-like effects of PNU (4 mg/kg). Similarly, the PNU 120596 (4 mg/kg, i.p.) significantly reduced LPS-induced increased expression of Iba-1 in the hippocampus or prefrontal cortex. Overall, these results suggest that PNU 120596 reduces LPS-induced depressive-like behavior and microglial activation in the hippocampus and prefrontal cortex in mice. Therefore, α7 nAChR PAMs could be developed as potential therapeutic utility for the treatment of major depressive disorder in humans.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Antidepressive Agents; Calcium-Binding Proteins; Cholinergic Agents; Depressive Disorder; Disease Models, Animal; Hippocampus; Inflammation; Isoxazoles; Lipopolysaccharides; Male; Mice, Inbred C57BL; Microfilament Proteins; Microglia; Motor Activity; Phenylurea Compounds; Prefrontal Cortex

Many studies have found that abnormalities in the proportion and differentiation of CD4

Topics: Aconitine; Acute Disease; Animals; CD4-Positive T-Lymphocytes; Cell Differentiation; Cholinergic Agents; Coxsackievirus Infections; Flow Cytometry; Inflammation; Lymphocyte Activation; Male; Mice; Mice, Inbred BALB C; Myocarditis; Myocardium; Nicotine; Nicotinic Antagonists; Spleen; Th1 Cells; Th17 Cells

Zymosan, a natural compound, provokes acute peritonitis and multiple organ dysfunction that affects the kidney, beside other organs via exaggerated inflammatory response. The aim of the present study is to test the role of cholinergic anti-inflammatory pathway (CAP) in alleviating acute kidney injury (AKI) induced by zymosan in BALB/c mice, using galantamine, a cholinesterase inhibitor, known to act via α7 nicotinic acetylcholine receptor (α7 nAChR) to stimulate CAP. Galantamine verified its anti-inflammatory effect by elevating acetylcholine (ACh) level, while abating the interleukin-6/ janus kinase 2 (Y1007/1008)/ signal transducer and activator of transcription 3 (Y705) (IL-6/ pY(1007/1008)-JAK2/ pY705-STAT3) inflammatory axis, with a consequent inhibition in suppressor of cytokine signaling 3 (SOCS3). This effect entails also the nuclear factor-kappa B (p65)/ high mobility group box protein-1/ (NF-κB (p65)/ HMGB-1) signaling pathway. Furthermore, the reno-curattive effect of galantamine was associated by a reduction in plasma creatinine (Cr), cystatin (Cys)-C, IL-18, and renal neutrophil gelatinase-associated lipocalin (NGAL), as well as an improved histopathological structure. Blocking the α7 nAChR by methyllycaconitine abolished the beneficial effect of galantamine to document the involvement of this receptor and the CAP in the amelioration of AKI induced by zymosan.

Topics: Acetylcholine; Aconitine; Acute Kidney Injury; alpha7 Nicotinic Acetylcholine Receptor; Animals; Cholinesterase Inhibitors; Galantamine; Inflammation; Mice; Mice, Inbred BALB C; Signal Transduction; Zymosan

The hippocampus is a brain region that is rich in nicotinic acetylcholine receptors (nAChRs), especially the α7 subtype. The hippocampus is severely affected in disorders that have a neuroinflammatory component, such as Alzheimer's disease, Parkinson's disease, and schizophrenia. Previous studies demonstrated both in vivo and in vitro that nicotine inhibits immunological responses, including those that are triggered by the inflammatory agent lipopolysaccharide (LPS), the endotoxin of Gram-negative bacteria. The present study investigated whether chronically administered nicotine interferes with the nuclear binding of nuclear factor-κB (NF-κB) and the expression of LPS-induced inflammatory response genes. The results indicated that chronic nicotine administration (0.1mg/kg, s.c., 14days) inhibited the LPS-induced nuclear binding of NF-κB and mRNA expression levels of Tnf, Il1b, Nos2, and Tlr4. The presence of both the selective α7 nAChR antagonist methyllycaconitine (MLA; 5.0mg/kg i.p., 14days) and the nonselective nAChR antagonist mecamylamine (Meca; 1.0mg/kg, s.c., 14days) reversed the inhibitory effects of nicotine. These results suggest that the chronic activation of α7- and α

Topics: Aconitine; Animals; Hippocampus; Inflammation; Lipopolysaccharides; Male; Mecamylamine; NF-kappa B; Nicotine; Nicotinic Agonists; Rats, Wistar; Receptors, Nicotinic; Signal Transduction; Toll-Like Receptor 4

Activation of antiinflammatory cholinergic (vagal) pathways can reduce inflammation, and in vitro studies support a pivotal role of α7 nicotinic acetylcholine receptors (α7-nAChR), macrophages, and T cells in these events. The aim of this study was to assess α7-nAChR agonists as an antiinflammatory treatment for Freund's complete adjuvant (CFA)-induced monoarthritis.. Arthritis was induced by intraarticular injection of CFA unilaterally into the knee joints of mice. Animals were treated with α7-nAChR agonists (AR-R17779 or A844606), with or without antagonists (COG133 or methyllycaconitine), and joint inflammation and pain were assessed. Experiments were repeated in c-Kit(W-sh) mast cell-deficient mice, and the effects of an α7-nAChR agonist on mast cell proliferation, migration, and activation by lipopolysaccharide (LPS) were tested.. Treatment with α7-nAChR agonists significantly exacerbated CFA-induced arthritis and pain, as gauged by all indices of assessment, the specificity of which was confirmed by coadministration of an nAChR antagonist that attenuated the increase in disease severity. Toluidine blue-positive mast cells were increased in the joint capsule of CFA plus AR-R17779-treated mice, and AR-R17779 enhanced LPS-induced TNF proliferation and migration of a human mast cell line. The AR-R17779-driven increase in severity of CFA-induced arthritis was significantly reduced in mast cell-deficient mice.. Using CFA to elicit a local inflammatory response, we found that pharmacologic activation of α7-nAChR exacerbated joint inflammation and pain, in part via mast cells, which illustrates the organ- and disease-specific nature of regulatory neuroimmune mechanisms. Thus, α7-nAChR activation may not be uniformly antiinflammatory in all types of inflammatory joint disease.

Topics: Aconitine; Adjuvants, Immunologic; alpha7 Nicotinic Acetylcholine Receptor; Animals; Apolipoproteins E; Arthritis, Experimental; Bridged-Ring Compounds; Cell Movement; Cell Proliferation; Disease Models, Animal; Disease Progression; Freund's Adjuvant; Inflammation; Injections, Intra-Articular; Lipopolysaccharides; Male; Mast Cells; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Nicotinic Antagonists; Peptide Fragments; Pyrroles; Spiro Compounds; Xanthones

Cholinergic antiinflammatory (CAI) pathway functions importantly in inflammation via α7 nicotinic acetylcholine receptors (α7nAChR). The present work tested circadian rhythm in peripheral CAI activity and validities of CAI activity and glucocorticoids in chronotherapy for lipopolysaccharide (LPS)-induced shock.. Vesicular acetylcholine transporter (VAChT) expressed in liver and kidney was examined every 3 h in C57BL/6 mice. Proinflammatory cytokines in serum and survival time in shock were monitored after LPS injection every 3 h. Mifepristone, antagonist of glucocorticoid receptors, and methyllycaconitine (MLA), antagonist of α7nAChR, were administrated before LPS to block antiinflammatory function of endogenous glucocorticoids and acetylcholine.. Both levels of tumor necrosis factor α, interleukin 1β, and interleukin 6 and mortality exhibited diurnal variations with prominent peaks when LPS was given at 15:00, and the minimum mortality occurred at 00:00. Expression of VAChT increased during resting period. MLA increased serum proinflammatory cytokines slightly, but not affected survival rate. Both differences in cytokines and in survival times between LPS injection at 15:00 and 00:00 were eliminated by mifepristone, but not by MLA.. Peripheral CAI pathway exerts more powerful antiinflammatory effect during resting period. Glucocorticoids appear to be efficient in chronotherapy for septic shock.

Topics: Acetylcholine; Aconitine; Animals; Circadian Rhythm; Corticosterone; Cytokines; Disease Models, Animal; Hormone Antagonists; Inflammation; Kidney; Lipopolysaccharides; Liver; Mice; Mice, Inbred C57BL; Mifepristone; Nicotinic Antagonists; Vesicular Acetylcholine Transport Proteins

Cryptococcal meningitis is the most common fungal infection of the central nervous system (CNS) in HIV/AIDS. HIV-1 virotoxins (e.g., gp41) are able to induce disorders of the blood-brain barrier (BBB), which mainly consists of BMEC. Our recent study suggests that α7 nAChR is an essential regulator of inflammation, which contributes to regulation of NF-κB signaling, neuroinflammation and BBB disorders caused by microbial (e.g., HIV-1 gp120) and non-microbial [e.g., methamphetamine (METH)] factors. However, the underlying mechanisms for multiple comorbidities are unclear.. In this report, an aggravating role of α7 nAChR in host defense against CNS disorders caused by these comorbidities was demonstrated by chemical [inhibitor: methyllycaconitine (MLA)] and genetic (α7(-/-) mice) blockages of α7 nAChR.. As shown in our in vivo studies, BBB injury was significantly reduced in α7(-/-) mice infected with C. neoformans. Stimulation by the gp41 ectodomain peptide (gp41-I90) and METH was abolished in the α7(-/-) animals. C. neoformans and gp41-I90 could activate NF-κB. Gp41-I90- and METH-induced monocyte transmigration and senescence were significantly inhibited by MLA and CAPE (caffeic acid phenethyl ester, an NF-κB inhibitor).. Collectively, our data suggest that α7 nAChR plays a detrimental role in the host defense against C. neoformans- and HIV-1 associated comorbidity factors-induced BBB injury and CNS disorders.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Blood-Brain Barrier; Central Nervous System Stimulants; Coinfection; Cryptococcus neoformans; HIV Envelope Protein gp41; HIV Infections; HIV-1; Inflammation; Meningitis, Cryptococcal; Methamphetamine; Mice; Mice, Knockout; NF-kappa B; Nicotinic Antagonists

Amount evidence indicates that α7 nicotinic acetylcholine receptor (nAChRα7) activation reduces production of inflammatory mediators. This work aimed to verify the influence of endogenous nAChRα7 activation on the regulation of full-blown muscular inflammation in mdx mouse with Duchenne muscular dystrophy. We used mdx mice with 3 weeks-old at the height myonecrosis, and C57 nAChRα7(+/+) wild-type and nAChRα7(-/-) knockout mice with muscular injury induced with 60µL 0.5% bupivacaine (bp) in the gastrocnemius muscle. Pharmacological treatment included selective nAChRα7 agonist PNU282987 (0.3mg/kg and 1.0mg/kg) and the antagonist methyllycaconitine (MLA at 1.0mg/kg) injected intraperitoneally for 7 days. Selective nAChRα7 activation of mdx mice with PNU282987 reduced circulating levels of lactate dehydrogenase (LDH, a marker of cell death by necrosis) and the area of perivascular inflammatory infiltrate, and production of inflammatory mediators TNFα and metalloprotease MMP-9 activity. Conversely, PNU282987 treatment increased MMP-2 activity, an indication of muscular tissue remodeling associated with regeneration, in both mdx mice and WTα7 mice with bp-induced muscular lesion. Treatment with PNU282987 had no effect on α7KO, and MLA abolished the nAChRα7 agonist-induced anti-inflammatory effect in both mdx and WT. In conclusion, nAChRα7 activation inhibits muscular inflammation and activates tissue remodeling by increasing muscular regeneration. These effects were not accompanied with fibrosis and/or deposition of non-functional collagen. The nAChRα7 activation may be considered as a potential target for pharmacological strategies to reduce inflammation and activate mechanisms of muscular regeneration.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Benzamides; Bridged Bicyclo Compounds; Bupivacaine; Cell Death; Disease Models, Animal; Dose-Response Relationship, Drug; Inflammation; Male; Mice, Inbred C57BL; Mice, Inbred mdx; Mice, Knockout; Muscle, Skeletal; Muscular Dystrophy, Animal; Muscular Dystrophy, Duchenne; Necrosis; Nicotinic Agonists; Nicotinic Antagonists; Regeneration

Ulcerative colitis involves complicated etiology and presents diverse symptoms including intestine inflammation, bowel pain and diarrhea. Anti-inflammatory drugs are the mainstay in patient care, accompanied with antidiarrhea and analgesic agents used as symptomatic treatment. A classic traditional Chinese medicine formula, Fructus Mume pill (FMP), showed remarkable therapeutic efficacy in treating ulcerative colitis. However, since it contains many herbs and countless chemicals, the underlying mechanism is not clear. In this study, we selected three alkaloids from FMP, namely, berberine, hypaconitine and skimmianine to study the individual drug effect and compare these results with the BHS combination on: 1) The recovery of ulcerative colitis rats induced by trinitrobenzene-sulfonic acid. 2) Mice with xylene-induced acute exudative edema and acetic acid-induced writhing. 3) Gastrointestinal transit inhibition, and 4) the response of HT29 cells after treatment with lipopolysaccharide. We found that the compound hypaconitine showed a potent analgesic effect, while skimmianine acted as an antidiarrhea agent and the component berberine was the key agent exerting anti-inflammatory effect. However, since berberine killed the commensal bacteria and induced lipopolysaccharide release, it could at the same time aggravate colon inflammation. The three-alkaloid combination BHS produced complementary and synergistic effects in colon inflammation recovery, relieving acetic acid-induced bowel pain and xylene-induced acute exudative edema. BHS also decreased lipopolysaccharide production and enhanced the therapeutic efficacy. It is hoped that this study will lay the foundation to further dissect and understand the FMP formula to improve the treatment with simplified and well defined drug combinations for this dreadful disease.

Topics: Acetic Acid; Aconitine; Alkaloids; Analgesics; Animals; Antidiarrheals; Behavior, Animal; Berberine; Colitis, Ulcerative; Colon; Drug Evaluation, Preclinical; Drug Synergism; Edema; Epithelial Cells; Gastrointestinal Transit; HT29 Cells; Humans; Inflammation; Male; Mice; NF-kappa B; Prunus; Quinolines; Rats; Toll-Like Receptor 4; Trinitrobenzenesulfonic Acid; Xylenes

CDP-choline (citicholine; cytidine-5'-diphosphate choline) is an endogenously produced nucleotide which, when injected intracerebroventricularly, exerts an antinociceptive effect in acute pain models mediated by central cholinergic mechanisms and alpha7 nicotinic acetylcholine receptors (alpha7nAChR). Previous reports also suggest that the peripheral cholinergic system has an antiinflammatory role mediated by alpha7nAChRs on macrophages.. We used male Sprague-Dawley rats to assess the antihypersensitivity and antiinflammatory effect of CDP-choline after intraplantar injection of carrageenan (100 microL, 2%). Mechanical paw withdrawal thresholds and paw thickness were measured by Randall-Selitto testing and microcallipers, respectively. All drugs were administered intraplantarly in a volume 50 microL.. CDP-choline (1, 2.5, 5 micromol; intraplantar) increased the mechanical paw withdrawal threshold and decreased paw edema in a dose- and time-dependent manner in the carrageenan-injected hindpaw. CDP-choline administration to the noninflamed contralateral hindpaw did not alter ipsilateral inflammation. Methyllycaconitine (100 nmol), a selective alpha7nAChR antagonist, completely blocked the effects of CDP-choline when administered to the inflamed hindpaw. However, the administration of methyllycaconitine to the contralateral hindpaw did not block the effects of CDP-choline in the ipsilateral paw. The administration of CDP-choline (5 micromol) 10 min after carrageenan administration to the ipsilateral hindpaw did not reduce swelling and edema but did significantly reduce hypersensitivity. Treatment with CDP-choline decreased tumor necrosis factor-alpha production in the rat paw tissue after carrageenan.. The results of this study suggest that intraplantar CDP-choline has antihypersensitivity and antiinflammatory effects mediated via alpha7nAChRs in the carrageenan-induced inflammatory pain model.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Analgesics; Animals; Anti-Inflammatory Agents; Carrageenan; Cytidine Diphosphate Choline; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Inflammation; Injections; Male; Nicotinic Agonists; Nicotinic Antagonists; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic; Time Factors; Tumor Necrosis Factor-alpha

The role of specific nicotinic receptor (nAChR) subtypes in antinociception has not been fully elucidated because of the lack, until recently, of selective tool compounds. (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiopene-2-carboxamide) (compound B) is reported to be an agonist selective for the alpha(7)nAChR and in the present study was found to be efficacious in inflammatory pain models in 2 species. Compound B reversed complete Freund adjuvant-induced reductions in paw withdrawal thresholds in rat and mouse in a dose-related manner, producing maximum reversals of 65% +/- 4% at 10 mg/kg and 87% +/- 15% at 20 mg/kg. When rats and mice were predosed with the centrally penetrant, broad-spectrum nicotinic receptor antagonist mecamylamine, the efficacy of the agonist was significantly inhibited, producing reversals of only 11% +/- 5% at 10 mg/kg and 5% +/- 13% at 20 mg/kg, confirming activity via nicotinic receptors. Rats were also predosed systemically with the selective low-brain penetrant alpha(7)-antagonist methyllycaconitine, which had no effect on agonist activity (90% +/- 18% at 10 mg/kg), suggesting a central involvement. This hypothesis was further established with methyllycaconitine completely inhibited the agonist effect when dosed intrathecally (1% +/- 7%).. These studies provide good rationale for the utility of selective, central nervous system penetrant agonists at the alpha(7)-nicotinic receptor for the treatment of inflammatory pain.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Behavior, Animal; Benzofurans; Dose-Response Relationship, Drug; Female; Freund's Adjuvant; Hyperalgesia; Inflammation; Injections, Intraperitoneal; Male; Mecamylamine; Mice; Mice, Inbred C57BL; Models, Animal; Nicotinic Antagonists; Pain; Pain Measurement; Quinuclidines; Rats; Receptors, Nicotinic; Weight-Bearing

We used the hot plate test and the formalin test to evaluate the antinociception of choline after i.c.v. or i.v. administration. The analgesic mechanism of choline was also studied. The response latency of mice was significantly prolonged in the hot plate test after choline (90-120 mug/animals) i.c.v. administration in a dose-dependent manner. Pretreatment with methyllycaconitine citrate (MLA), alpha-bungarotoxin, or atropine blocked the antinociception of choline in the hot plate test. In contrast, mecamylamine and naloxone had no effect. No antinociceptive action of choline was found in the hot plate test, but it did have an effect in the late phase of the formalin test after i.v. administration. The effect of choline on anti-inflammatory pain was blocked by MLA, but not by mecamylamine, naloxone and atropine, which is indicative of the involvement of alpha7 receptors in peripheral sites. When choline (2 mg/kg) was coadministered with aspirin (9.4 mg/kg), the licking/biting times in the late phase significantly decreased, although no effects were shown when these doses of drugs were used alone. Similarly, coadministration of choline (2 mg/kg) with morphine (0.165 mg/kg) significantly increased the antinociception of morphine in the late phase, but had no effect in the early phase. These results demonstrate that activation of alpha7 nicotinic receptors by choline elicits antinociceptive effects both in an acute thermal pain model and in an inflammatory pain model. Choline holds promise for development as a non-addictive analgesic drug and in reducing the regular dose of aspirin or morphine in inflammatory pain.

Topics: Aconitine; Acute Disease; alpha7 Nicotinic Acetylcholine Receptor; Analgesics; Animals; Anti-Inflammatory Agents; Aspirin; Atropine; Bungarotoxins; Central Nervous System; Choline; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Female; Inflammation; Mice; Morphine; Muscarinic Antagonists; Nicotinic Antagonists; Nociceptors; Pain; Pain Measurement; Reaction Time; Receptors, Nicotinic

The anti-nociceptive effect of processed aconiti tuber (TJ-3021), one of the traditional oriental herbal medicines (Kampo), was investigated by utilizing various methods including repeated cold stress and adjuvant articular inflammation in rats and mice. Analgesic potency was compared with that of mesaconitine, a potent component of aconitine alkaloids, and other analgesic agents. It was found that mesaconitine was more potent than morphine, and a processed aconiti tuber [(TJ-3021), Tsumura-shuchi-bushi-matsu] showed some analgesic effect, although it was weaker than those of dichlofenac, aminopyrine and indomethacine.

Topics: Acetates; Acetic Acid; Aconitine; Analgesics; Animals; Arthritis, Experimental; Cold Temperature; Disease Models, Animal; Drugs, Chinese Herbal; Inflammation; Male; Mice; Mice, Inbred ICR; Pain; Pain Threshold; Rats; Rats, Sprague-Dawley

Aconitines are the total alkaloids isolated from the main root of Aconitum carmichaeli. They have marked suppressive effect on the swelling of rat's hind paw induced by injections of fresh egg protein, carrageenin, histamine and 5-HT, on the mouse's ear oedema induced by bimethylphenyl, on the exudate and proliferation of granulation tissue of granuloma pouch induced by croton oil, on the leukocyte migration and on the contents of PGE in the exudate of the swelling hind paw induced by injecting carrageenin. Aconitines have been found useful in inhibiting significantly such immune inflammations as reversible passive Arthus reaction, rat's delayed skin hypersensitivity and adjuvant arthritis. They have also a noticeable analgesic effect.

Topics: Aconitine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Arthus Reaction; Female; Hypersensitivity, Delayed; Inflammation; Male; Mice; Rats