Experimental studies on the mechanisms and treatments of chronic pain

Chronic pain is a major concern for physical and mental health of a large patient population today while casting a significant economical burden on society. Work presented in this thesis deal with aspects of mechanisms and treatments of chronic pain using experimental models. A common characteristic for many chronic pain conditions, particularly those after nerve injury, is hypersensitivity to cold stimulation. In the first part of the thesis, I presented a new method using a Peltier thermode to examine the responses of rats to quantitative thermal stimulation (heating and cooling). Using this method with temperature as end points, I showed that we can reliably detect cold hypersensitivity in spinally injured rats as well as study quantitatively the effects of analgesics again cold pain. Sinomenine is a morphinan derivative alkaloid originally isolated from the root of the climbing plant Sinomenium Acutum that is native to Japan and China. The root of Sinomenium Acutum has long been used in East Asia as a remedy for disease conditions similar to rheumatism and sinomenine is currently used in China as an anti-rheumatic agent. In the second part of the thesis, we characterized the analgesic effect of sinomenine in a variety of experimental pain models. We showed that while sinomenine has modest effects on acute pain in normal rats, it produces marked analgesic effects in a wide-spectrum of models, including neuropathic pain in rats and mice after injury to the peripheral and central nervous system, acute inflammatory pain by carrageenan in mice as well as arthritic pain in mice using the collagen antibody-induced arthritis model (CAIA). We further showed that under chronic administration, sinomenine maintained its analgesic effect in neuropathic and arthritic pain models without producing tolerance or dependence. Our results thus suggested that sinomenine may be considered as a novel analgesic in treating neuropathic and arthritic pain. One of the main clinical features of rheumatoid arthritis (RA) is sex difference in its prevalence and symptoms, including pain. The underlying mechanisms of sex differences in RA are still largely unknown. In the last part of the thesis, we studied sex differences in the development arthritis and pain-like behaviors in mice using the CAIA model. We observed a significant sex difference (females > males) in the development of joint inflammation and localized mechanical allodynia in the paws after CAIA in CBA strain of mice. Similarly, female CAIA mice also developed more persistent spread mechanical allodynia in their neck and flank areas. Following CAIA, the greater mechanical hypersensitivity in females was correlated to a higher expression of ionized calcium-binding adapter molecule 1, but lower expressions of activating transcription factor 3 and galanin, in dorsal root ganglion (DRG) compared with males. We conclude that sex differences in the CAIA model in CBA mice are similar to the clinical condition and sex dependent phenotypic changes in the DRG may be keys for the sex differences in RA and pain

Polyether/Polythioether Synthesis via Ring-Opening Polymerization of Epoxides and Episulfides Catalyzed by Alkali Metal Carboxylates

Alkali metal carboxylates were evaluated as simple and green catalysts for the ring-opening polymerization (ROP) of various epoxides (e.g., alkyl-substituted epoxides and glycidyl ethers) and episulfides (alkyl-substituted episulfides and thioglycidyl ethers). The thus-produced functional polyethers (end-functionalized polyethers, block copolyethers, polyether- polyester block copolymers, topologically unique polyethers, and isotactic-enriched polyethers) and polythioethers featured well-defined structures and controlled molecular weights (Mn,SEC = 1.0-32 kg mol-1). The most effective catalyst was identified as cesium pivalate, and the variation of carboxylate moieties and alkali metal cations enabled the tuning of acid/base character-istics and thus allowed one to control polymerization behavior and expand the scope of functional monomers and initiators. Kinetic analysis confirmed the controlled/living nature of the polymerization process, while mechanistic studies revealed that carboxylate moieties did not directly initiate the ring-opening of epoxide monomers via nucleophilic attack but rather activated the alcohol initiators/chain ends via H-bonding and thus rendered the corresponding OH groups sufficiently nucleophilic to attack the alkali metal cation-activated epoxides

Multidimensional Control of Repeating Unit/Sequence/Topology for One-Step Synthesis of Block Polymers from Monomer Mixtures

Synchronously and thoroughly adjusting the chemical structure difference between two blocks of the diblock copolymer is very useful for designing materials but difficult to achieve via self-switchable alternating copolymerization. Here, we report self-switchable alternating copolymerization from a mixture of two different cyclic anhydrides, epoxides, and oxetanes, where a simple alkali metal carboxylate catalyst switches between ring-opening alternating copolymerization (ROCOP) of cyclic anhydrides/epoxides and ROCOP of cyclic anhydrides/oxetanes, resulting in the formation of a perfect block tetrapolymer. By investigating the reactivity ratio of these comonomers, a reactivity gradient was established, enabling the precise synthesis of block copolymers with synchronous adjustment of each unit's chemical structure/sequence/topology. Consequently, a diblock tetrapolymer with two glass transition temperatures (T-g) can be easily produced by adjusting the difference in chemical structures between the two blocks

Synthesis of hyperbranched polyesters via the ring-opening alternating copolymerisation of epoxides with a cyclic anhydride having a carboxyl group

Hyperbranched polyesters (HBPEs) are well-known interesting materials used in many fields. However, the known synthetic approaches for HBPEs lack versatility. Herein, we report a novel synthetic approach for an HBPE via ring-opening alternating copolymerisation (ROAC) using epoxides and trimellitic anhydride (TA) as the latent difunctional and trifunctional monomers, respectively. Caesium pivalate-catalysed ROACs of TA and excess epoxides were performed in the presence of an alcohol initiator at 80 degrees C in bulk. The obtained products, together with their linear counterparts (i.e., poly(phthalic anhydride-alt-epoxide) s), were characterised by NMR, viscometry, and light scattering. The results supported the successful synthesis of hyperbranched poly(TA-alt-epoxide)s. The versatility of the present HBPE synthesis was demonstrated by applying a range of alcohol initiators, such as typical diol and functional alcohols (e.g., poly (ethylene glycol) as a mono-alcohol or diol, and azido-/alkene-functionalised alcohols as another mono-alcohol), leading to HBPE-based block copolymers and functional HBPEs. Various epoxides, such as mono- and disubstituted alkylene oxides, glycidyl ether, and glycidyl amine, were found to be applicable in the present polymerisation system, which successfully produced HBPEs with different properties depending on the resulting backbone structure of the polymer

The complete mitochondrial DNA genome of a cone snail, Conus betulinus (Neogastropoda: Conidae), from the South China sea

The complete mitochondrial genome of the tubular cone snail Conus betulinus is presented in this study. The C. betulinus mitochondrial genome was 16,240 bp with 13 protein-coding genes (PCGs), 22 transfer RNA (tRNA) genes, 2 ribosomal RNA (rRNA) genes, and a non-coding AT-rich region (D-loop). The overall base composition was estimated to be 25.67% for A, 38.26% for T, 21.38% for G, and 14.69% for C, with a high A + T content of 63.93%. Phylogenetic analyses based on 13 PCGs showed the close relationship of vermivorous C. betulinus with the common ancestor of molluscivorous Conus textile and Conus gloriamaris, providing a basis for further studies on the phylogenetics of cone snails according to their dietary type

Research on anti-seepage grouting in completely weathered granite based on superfine materials

Objective To solve the problems of "draught without slurry", poor groutability and slurry stability in the grouting process of completely weathered granite, a new composite grouting material is proposed in this paper to improve the anti-seepage and mechanical properties of completely weathered granite. Methods Through a series of laboratory experiments, it investigates the effects of different water-solid ratios, superfine bentonite, and superfine Portland cement content on the engineering properties of grouting materials. The formation mechanism of the slurry were studied, and the optimal formula of the cement slurry was determined. The experiment revealed the action mechanism of the two superfine materials on the fluidity, stability, and stone body strength of the grout. Finally, the castability and effectiveness of the grouting material were verified by a field test. Results The results show that the composite slurry with a water-solid ratio of 1.2, a content of superfine bentonite and superfine Portland cement of 10%, and a content of ordinary Portland cement of 80% has good fluidity, stability, and resistance. The funnel viscosity was 35.5 s, the water separation rate was 2.4%, and the compressive strengths at 7 d and 28 d were both greater than 5 MPa. The compressive strength and the content of superfine bentonite in the composite material play a leading role in the properties of the slurry. The content of superfine bentonite and the morphology and distribution of its hydrated colloids determine the stability of the slurry, while an appropriate amount of superfine Portland cement increases the content of fine particles, making it easier for the cement to fill the gaps between the particles and improving the injectability of the slurry and the strength of the stone body. Conclusion The composite grouting material has excellent performance in the field test and good grouting performance. The wall formed after grouting meets the design requirements in terms of the anti-seepage effect and reinforcement performance

The complete chloroplast genome sequence of Alpinia oxyphylla Miq. and comparison analysis within the Zingiberaceae family.

Alpinia oxyphylla Miq. (A. oxyphylla) is an important edible and traditional herbal medicine. In this study, the complete chloroplast genome of A. oxyphylla was sequenced, analysed, and compared to five species in the Zingiberaceae family. The size of the A. oxyphylla chloroplast genome was 161351 bp, which consisted of a large single-copy (LSC, 87248 bp) and small single-copy (SSC, 16175 bp) region separated by a pair of inverted repeats (IRa and IRb, 28964 bp each). The genome encoded 132 unique genes, including 87 protein-coding genes, 37 tRNAs and four rRNAs. The GC content of the genome was 36.17%. A total of 53 simple sequence repeats (SSRs) and 80 long repeats were identified in the A. oxyphylla chloroplast genome. The chloroplast genome of A. oxyphylla shared the highest sequence similarity of >90% with the chloroplast genome of A. zerumbet, and six chloroplast genomes in the Zingiberaceae family were compared by using CGView Comparison Tool (CCT). According to the phylogenetic tree, the Zingiberaceae family is divided into two categories, which coincide with the classification of the characteristics of sun-like and shade-like in plants. Our results reveal the phototrophic component of NADH-dehydrogenase (ndhB and ndhC), photosystem II (psbZ) and ATP synthase (atpE, atpF) exhibit adaptive evolution under different environments, and the strength of light is an important trigger for the adaptations at the chloroplast level