Oxytocin is a well-known neurohypophysial hormone that plays an important role in behavioral anxiety and nociception. Two major forms of long-term potentiation, presynaptic LTP (pre-LTP) and ...postsynaptic LTP (post-LTP), have been characterized in the anterior cingulate cortex (ACC). Both pre-LTP and post-LTP contribute to chronic-pain-related anxiety and behavioral sensitization. The roles of oxytocin in the ACC have not been studied. Here, we find that microinjections of oxytocin into the ACC attenuate nociceptive responses and anxiety-like behavioral responses in animals with neuropathic pain. Application of oxytocin selectively blocks the maintenance of pre-LTP but not post-LTP. In addition, oxytocin enhances inhibitory transmission and excites ACC interneurons. Similar results are obtained by using selective optical stimulation of oxytocin-containing projecting terminals in the ACC in animals with neuropathic pain. Our results demonstrate that oxytocin acts on central synapses and reduces chronic-pain-induced anxiety by reducing pre-LTP.
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•Oxytocin microinjected into ACC attenuates injury-related pain and anxiety responses•Oxytocin blocks the maintenance of pre-LTP, but not post-LTP•Oxytocin depolarizes the interneurons and decreases the ratio of E/I transmission•Activation of PVN-ACC pathway blocks pre-LTP and has analgesic and anxiolytic effects
Li et al. report that microinjection of oxytocin into the ACC attenuates nerve-injury-induced nociceptive and anxiety behavioral responses. They show that oxytocin blocks the maintenance of pre-LTP and potentiates inhibitory transmission. Optical activation of endogenous oxytocin release in the ACC blocks pre-LTP and produces analgesic and anxiolytic effects.
•Low dose single and mixtures of toxic metals had adverse effect on mice.•Metal mixtures exhibited higher toxicities compared to individual metals.•Mixtures of low dose Pb+Hg+Cd induced neuronal ...degeneration in brain of mice.•Exposure to Pb+Hg+As+Cd showed renal tubular necrosis in kidney.
Humans are exposed to a cocktail of heavy metal toxicants in the environment. Though heavy metals are deleterious, there is a paucity of information on toxicity of low dose mixtures. In this study, lead (Pb) (0.01mg/L), mercury (Hg) (0.001mg/L), cadmium (Cd) (0.005mg/L) and arsenic (As) (0.01mg/L) were administered individually and as mixtures to 10 groups of 40 three-week old mice (20 males and 20 females), for 120 days. The study established that low dose exposures induced toxicity to the brain, liver, and kidney of mice. Metal mixtures showed higher toxicities compared to individual metals, as exposure to low dose Pb+Hg+Cd reduced brain weight and induced structural lesions, such as neuronal degeneration in 30-days. Pb+Hg+Cd and Pb+Hg+As+Cd exposure induced hepatocellular injury to mice evidenced by decreased antioxidant activities with marginal increases in MDA. These were accentuated by increases in ALT, AST and ALP. Interactions in metal mixtures were basically synergistic in nature and exposure to Pb+Hg+As+Cd induced renal tubular necrosis in kidneys of mice. This study underlines the importance of elucidating the toxicity of low dose metal mixtures so as to protect public health.
•Low dose metal mixtures interacted with toxic and essential metals.•Interaction within metal mixtures were largely synergistic.•Low dose exposures influenced homeostasis of toxic and essential ...metals.•Essential metals in liver were influenced most by low dose metal mixtures.•Elevation in toxic metals were linked to reductions in essential metals.
The deleterious effects of long term exposure to individual toxic metals in low doses are well documented. There is however, a paucity of information on interaction of low dose toxic metal mixtures with toxic and essential metals. This study reports on interactions between low dose mixtures of lead (Pb), mercury (Hg), arsenic (As) and cadmium (Cd) and toxic and essential metals. For 120d, six groups of forty mice each were exposed to metal mixtures, however, the control group was given distilled water. Exposure to Pb+Cd increased brain Pb by 479% in 30d, whiles Pb+Hg+As+Cd reduced liver Hg by 46.5%, but increased kidney As by 130% in 30d. Brain Cu, increased by 221% on Pb+Hg+As+Cd exposure, however, liver Ca reduced by 36.1% on Pb+Hg exposure in 60-d. Interactions within metal mixtures were largely synergistic. Principal component analysis (PCA) showed that low dose metal exposures influenced greatly levels of Hg (in brain and liver) and As (brain). The influence exerted on essential metals was highest in liver (PC1) followed by kidney (PC2) and brain (PC3). Exposure to low dose metal mixtures affected homeostasis of toxic and essential metals in tissues of mice.
This study was aimed at investigating the effect of ethanol on oral bioavailability of kaempferol in rats, namely, at disclosing their possible interaction. Kaempferol (100 or 250 mg kg
bm) was ...administered to the rats by oral gavage with or without ethanol (600 mg kg
bm) co-administration. Intravenous administration (10 and 25 mg kg
bm) of kaempferol was used to determine the bioavailability. The concentration of kaempferol in plasma was estimated by ultra high performance liquid chromatography. During coadministration, a significant increase of the area under the plasma concentration-time curve as well as the peak concentration were observed, along with a dramatic decrease in total body clearance. Consequently, the bioavailability of kaempferol in oral control groups was 3.1 % (100 mg kg
bm) and 2.1 % (250 mg kg
bm). The first was increased by 4.3 % and the other by 2.8 % during ethanol co-administration. Increased permeability of cell membrane and ethanolkaempferol interactions on CYP450 enzymes may enhance the oral bioavailability of kaempferol in rats.
Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer’s disease. Chronic pain is experienced by the vast majority of patients living with Parkinson’s disease. The ...degeneration of dopaminergic neuron acts as the essential mechanism of Parkinson’s disease in the midbrain dopaminergic pathway. The impairment of dopaminergic neurons leads to dysfunctions of the nociceptive system. Key cortical areas, such as the anterior cingulate cortex (ACC) and insular cortex (IC) that receive the dopaminergic projections are involved in pain transmission. Dopamine changes synaptic transmission via several pathway, for example the D2-adenly cyclase (AC)-cyclic AMP (cAMP)-protein kinase A (PKA) pathway and D1-G protein-coupled receptor kinase 2 (GRK2)-fragile X mental retardation protein (FMRP) pathway. The management of Parkinson’s disease-related pain implicates maintenance of stable level of dopaminergic drugs and analgesics, however a more selective drug targeting at key molecules in Parkinson’s disease-related pain remains to be investigated.
Pain triggers emotional changes in humans and animals, including fear and anxiety. Conversely, fear and anxiety may enhance suffering of patients with pain. However, in animal models of acute pain, ...it has been reported that fear may inhibit pain by activating endogenous inhibitory systems. In this study, we wanted to examine if behavioral withdrawal responses may be affected during fear retrieval, a condition where fear-associated tone is applied. We found that thermal pain thresholds were significantly increased during fear retrieval. Our results indicate that animals are suffering fear like-events, while their behavioral responses are inhibited. These results indicate that it will be important to evaluate both emotional and behavioral withdrawal responses for future development of new pain medicine.
Cortical long-term potentiation (LTP) serves as a cellular model for chronic pain. As an important subtype of adenylyl cyclases (ACs), adenylyl cyclase subtype 1 (AC1) is critical for the induction ...of cortical LTP in the anterior cingulate cortex (ACC). Genetic deletion of AC1 or pharmacological inhibition of AC1 blocked behavioral allodynia in animal models of neuropathic and inflammatory pain. Our previous experiments have identified a lead candidate AC1 inhibitor, NB001, which is highly selective for AC1 over other AC isoforms, and found that NB001 is effective in inhibiting behavioral allodynia in animal models of chronic neuropathic and inflammatory pain. However, previous experiments were carried out in adult male animals. Considering the potential gender difference as an important issue in researches of pain and analgesia, we investigated the effect of NB001 in female chronic pain animal models. We found that NB001, when administered orally, has an analgesic effect in female animal models of neuropathic and inflammatory pain without any observable side effect. Genetic deletion of AC1 also reduced allodynia responses in models of neuropathic pain and chronic inflammation pain in adult female mice. In brain slices of adult female mice, bath application of NB001(20 μM) blocked the induction of LTP in ACC. Our results indicate that calcium-stimulated AC1 is required for injury-related cortical LTP and behavioral allodynia in both sexes of adult animals, and NB001 can be used as a potential therapeutic drug for treating neuropathic and inflammatory pain in man and woman.
Two new Bi3+-Hericium erinaceus polysaccharide (BiHEP) complexes were prepared using Bi3+ and two purified polysaccharides from H. erinaceus (HEPs), respectively. The complexes were characterized by ...elemental analysis, FT-IR, CD, SEM, AFM, XRD, and TG. The anti-Helicobacter pylori (Hp) activities in vitro by agar dilution assay of the complexes were evaluated. The molecular weights of HEPs were 197 and 20 kDa, respectively. All the analyses confirmed the formation of new BiHEP complexes with lower content of Bi3+ compared with colloidal bismuth subcitrate (CBS), the most utilized bismuth preparation clinically. Furthermore, HEPs themselves have definite inhibition effects on Hp, and BiHEP complexes have lower content of Bi exhibited strong inhibition effects on Hp (MIC=20 μg/mL), similar to that of CBS with higher content of Bi. The study provides a basis for further development of multiple treatments of Hp infection or new medicines.
Abstract
Parkinson’s disease (PD) is a multi-system neurodegenerative disorder. Patients with PD often suffer chronic pain. In the present study, we investigated motor, sensory and emotional changes ...in three different PD mice models. We found that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treatment caused significant changes in all measurements. Mechanical hypersensitivity of PD model induced by MPTP peaked at 3 days and persisted for at least 14 days. Using Fos transgenic mice, we found that neurons in the anterior cingulate cortex (ACC) were activated after MPTP treatment. Inhibiting ACC by bilateral microinjection of muscimol significantly reduced mechanical hypersensitivity and anxiety-like responses. By contrast, MPTP induced motor deficit was not affected, indicating ACC activity is mostly responsible for sensory and emotional changes. We also investigated excitatory synaptic transmission and plasticity using brain slices of MPTP treated animals. While L-LTP was blocked or significantly reduced. E-LTP was not significantly affected in slices of MPTP treated animals. LTD induced by repetitive stimulation was not affected. Furthermore, we found that paired-pulse facilitation and spontaneous release of glutamate were also altered in MPTP treated animals, suggesting presynaptic enhancement of excitatory transmission in PD. Our results suggest that ACC synaptic transmission is enhanced in the animal model of PD, and cortical excitation may play important roles in PD related pain and anxiety.
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