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Our previous study showed that electroacupuncture (EA) significantly attenuated inflammatory hyperalgesia. It has also been reported that EA analgesia in uninjured animals is mediated by mu and delta opioid receptors at 2-15 Hz and by kappa opioid receptor at 100 Hz. Because persistent pain changes neural response to external stimulation, we hypothesized that (1) the mechanisms of EA anti-hyperalgesia may be different under conditions of persistent pain and that (2) combining EA with a sub-effective dose of morphine could enhance EA anti-hyperalgesia. Hyperalgesia, decreased paw withdrawal latency (PWL) to a noxious thermal stimulus, was induced by subcutaneously injecting complete Freund's adjuvant (CFA) into the hind paws of rats. Selective antagonists against mu (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-ThrNH2, CTOP), delta (naltrinodole, NTI) and kappa (nor-binaltorphimine, BNI) opioid receptors were administered intrathecally 10 min before each of two EA treatments at acupoint Huantiao (GB30), one immediately post and the other 2 h post-CFA. Morphine was given (i.p.) 40 min before the second EA treatment. PWL was measured before and 2.5 and 5 h post-CFA. Both 10 and 100 Hz EA-produced anti-hyperalgesia were blocked spinally by mu- and delta- but not kappa-receptor antagonists. EA combined with a sub-threshold dose of morphine (2.5 mg/kg) enhanced anti-hyperalgesia additively (10 Hz EA) or synergistically (100 Hz EA) compared to that produced by each component alone. These results suggest selective involvement of mu and delta, but not kappa, receptors in EA-produced anti-hyperalgesia in rats. A combined EA and opioid drug protocol may provide an improved treatment strategy for inflammatory pain.

Our previous study showed that electroacupuncture (EA), an adjuvant to conventional medicine, significantly attenuated hyperalgesia and inflammation. The present study is an evaluation of the potential synergism of EA and a subeffective dosage of indomethacin (INDO) in a rat model. Inflammation and hyperalgesia, manifesting as edema and decreased paw withdrawal latency (PWL) to a noxious stimulus, were induced by injecting complete Freund's adjuvant (CFA) subcutaneously into the plantar surface of one hind paw of the rat. EA treatments were given at acupoint GB30 immediately and 2 h post-CFA. INDO at 2 mg/kg was given (intraperitoneally) 40 min before the second EA. PWL and edema were measured prior to CFA and 2.5 and 5 h post-CFA. Ten and 100 Hz EA significantly inhibited CFA-induced hind paw hyperalgesia. Both low- and high-frequency EA combined with INDO enhanced antihyperalgesia compared to each component alone, and 10 Hz but not 100 Hz EA significantly reduced CFA-induced hind paw edema. A combination of low-frequency EA and INDO did not show synergistic inhibitory effects on edema. The results demonstrate that EA combined with INDO synergistically inhibits hyperalgesia and suggest an improved treatment strategy for inflammatory pain.

Glucocorticoids (GC) play important roles in response to stressful stimuli, including pain. This study examined the effects of bilateral adrenalectomy (ADX) and dexamethasone (DEX) replacement on the hyperalgesia and spinal preprodynorphin (PPD) mRNA expression induced by injecting complete Freund's adjuvant (CFA) into rats' hind paws. The results demonstrated that CFA induced more intense hyperalgesia and up-expression of spinal PPD mRNA in ADX rats than in control rats, while both of these intensified reactions could be significantly suppressed by subcutaneous pretreatment with DEX. This leads to the conclusion that both exogenous (pharmacological) and endogenous (physiological) GC suppresses the behavioral hyperalgesia and the up-regulation of spinal PPD mRNA induced by sustained peripheral inflammation. The results also suggest that spinal PPD mRNA suppression may partially underlie the inhibition of behavioral hyperalgesia.

The experience of pain is highly variable among individuals, which may be due in part to the effects of genetic factors on the central transmission and modulation of noxious inputs. This study examined behavioral responses and the expression of preprodynorphin (PPD) mRNA at the spinal level during complete Freund's adjuvant-induced inflammation of the unilateral hind paw in male Fischer 344 (F344), Sprague-Dawley (SD), and Lewis (LEW) rats. Experiments showed that F344 rats exhibited stronger hind paw hyperalgesia and greater spinal PPD mRNA induction than SD or LEW rats. These results indicate that genetic factors that determine the spinal PPD mRNA and dynorphin production underlie strain-dependent differences in pain perception.

Immunocytochemical technique was used to compare the contents of neurokinin A (NKA), calcitonin gene-related peptide (CGRP), and dynorphin A (1-8) (DynA) on two sides of the lumbar dorsal horn of rats in which the unilateral thoracic dorsalateral funiculus (DLF) was transected while formalin (0.2 ml, 0.5%) was injected equally into two hindpaws. The results showed that all the NKA-like, CGRP-like, and DynA (1-8)-like immunoreactivities were significantly lower in the superficial laminae of the dorsal horn on the side ipsilateral to the lesioned DLF than that on the side with intact DLF. This implies that peripheral noxious inputs activate the supraspinal descending inhibitory systems which in turn modulate the transmission of noxious message at the spinal level by changing the release of related neuropeptides.

Nociceptive c-fos expressions in the dorsal horn following intraplantar injection of two kinds of algogenic agents combined with different doses of nitric oxide (NO) synthase inhibitor (N(omega)-nitro-L-arginine methyl ester (L-NAME)) or of NO donor (L-arginine) were used to explore if NO was involved in the activation of peripheral nociceptors. The results showed that: 1) combined injections of L-NAME with formalin into the plantar aspect of one hindpaw of normal rats elicited a dose-dependent suppression of c-fos expression as compared to that induced by formalin alone; 2) combined injections of L-arginine with formalin elicited considerable enhancement of c-fos expression when the dosages of L-arginine were less than 20 micromol, while it elicited marked suppression of c-fos expression when the dosages were in the range from 50 to 100 micromol; and 3) combined injection of L-NAME with NMDA, a selective agonist for NMDA receptors, into the hindpaw could also inhibit the NMDA-induced c-fos expression in the spinal dorsal horn. These results suggest that endogenously generated concentrations of nitric oxide may enhance the initiation of nociceptive inputs of peripheral nociceptors following local injection of formalin or NMDA.

The low-affinity neurotrophin receptor (p75) binds all members of the neurotrophin family. In the rat, during the first week postpartum, dense p75-immunoreactivity (IR) is present throughout all components of the trigeminal brainstem complex (TBC), largely associated with primary sensory afferents. Within subnucleus caudalis (SpC) of the TBC, intense p75-IR is present in all laminae at birth. During the second and third postnatal weeks, p75-IR in SpC gradually fades within the deeper laminae, becoming generally restricted in the adult to laminae I and II. Similar declines in p75-IR intensity occur in the subnucleus oralis (SpO); in the SpO in the adult, p75-IR is confined to the dorsalmost portion of SpO. In subnucleus interpolaris, an emerging, vibrissa-related pattern of p75-IR is detectable on PD0 (first 24 hr postpartum), which becomes fully differentiated during PD4–PD7. However, this pattern gradually disappears during the third postnatal week. Ventrally in the nucleus principalis (PrV), a pattern of p75-IR that mirrors the topographical arrangement of the vibrissae is detectable by PD0–PD1, is fully differentiated by the end of the first postnatal week, and persists into adulthood. Perinatal unilateral sectioning of the infraorbital nerve on PD0–PD1, but not as late as PD4, disrupts p75-IR patterning in the adult PrV. Although p75 appears to be associated with primary afferent pattern formation, to determine whether it is essential, we examined mutant mice unable to form functional p75. In the TBC of these knockout mice, examined as adults, patterns of cytochrome oxidase staining (which parallel those of p75-IR) appeared to be normal. In summary, during early development, p75 is widely expressed in the TBC during periods of active synaptogenesis and pattern formation, whereas in the adult, its expression is restricted to association with populations of primary sensory afferents. However, the absence of functional p75 in genetically altered mice does not appear to prevent primary afferent pattern formation. Anat Rec 254:549–565, 1999. © 1999 Wiley-Liss, Inc.

Double-labeling techniques were used to demonstrate the nociceptive activation of NMDA receptor-contained neurons in spinal dorsal horn by using c-Fos immunoreactivity as an indicator of this activation in a rat model of inflammation. About 25% and 55% of the c-Fos-immunoreactive neurons that were found in laminae I-II and lamina V showed NMDA receptor immunoreactivity, while about 4% and 11% of NMDA-receptor immunoreactive neurons in these two regions showed c-Fos immunoreactivity, respectively. The implication of the results was discussed.

Modern surface mines, either mono-system or multi-systems, need a large fleet of equipment consisting of excavators, loaders, haulers and auxiliary machines. Presently, the complexity of the system, the interference between sub-systems and the lag in management skills has been a bottle neck for improving productivity of the system. Based on the fact that the traditional tools for safety analysis have been insufficient to evaluate systematically and dynamically the safety risks, this paper tries to create a virtual reality tool consisting of human, machine and mines, using Pro/E and the 3D MAX software in order to evaluate visually the operations of typical mining equipment, such as the bucket wheel excavator (BWE), the shovel, the truck and the dragline. Within this virtual world, the behavior of the system, such as interaction, interference and potential risk can be replayed and reviewed visually. The objective of the study is to identify the critical safety issues of the system and to provide a convenient and powerful tool for safety training and safety management.

Summary Objective Osteoarthritis (OA) is a complex and painful disease of the whole joint. At present there are no satisfying agents for treating OA. To promote OA research and improved treatment, this review summarizes current preclinical evidence on the development of OA. Methods Preclinical OA research was searched and key findings are summarized and commented. Results Mechanisms of OA-associated pain have been studied in rodent knee OA models produced by intra-knee injection of the chondrocyte glycolytic inhibitor mono-iodoacetate (MIA), surgery, or spontaneous development in some species. These models are clinically relevant in terms of histological damage and functional changes, and are used to study mechanisms underlying mechanical, thermal, ambulatory, body weight supporting-evoked, and ongoing OA pain. Recent peripheral, spinal, and supraspinal biochemical and electrophysiological studies in these models suggest that peripheral pro-inflammatory mediators and neuropeptides sensitize knee nociceptors. Spinal cytokines and neuropeptides promote OA pain, and peripheral and spinal cannabinoids inhibit OA pain respectively through cannabinoid-1 (CB1) and CB1/CB2 receptors. TRPV1 and metalloproteinases contribute and supraspinal descending facilitation of 5-hydroxytryptamine (5-HT)/5-HT 3 receptors may also contribute to OA pain. Conditioned place preference tests demonstrate that OA pain induces aversive behaviors, suggesting the involvement of brain. During OA, brain functional connectivity is enhanced, but at present it is unclear how this change is related to OA pain. Conclusion Animal studies demonstrate that peripheral and central sensitization contributes to OA pain, involving inflammatory cytokines, neuropeptides, and a variety of chemical mediators. Interestingly, brainstem descending facilitation of 5-HT/5-HT3 receptors plays a role OA pain.

Pain has sensory-discriminative and emotional-affective dimensions. Recent studies show that the affective component can be assessed with a conditioned place avoidance (CPA) test. We hypothesized that systemic morphine before a post-conditioning test would more potently attenuate the affective aspect compared to the sensory component and that [d-Ala2-N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO), a μ-selective opioid receptor agonist, injected into the central nucleus of the amygdala (CeA) would reduce established CPA. A rat model of inflammatory pain, produced by a complete Freund adjuvant (CFA) injection into the hind paw, was combined with a CPA test. Three experiments were performed on adult male Sprague-Dawley rats. Systemic morphine (0.5 or 1.0mg/kg) in Experiment 1, intrathecal (i.t.) morphine (2.5 μg/rat) in Experiment 2, and intra-CeA DAMGO (7.7-15.4 ng/0.4 μl) in Experiment 3 were given to CFA-injected rats (n=6-8/group) prior to a post-conditioning test. Saline-injected rats were used as control. Time spent in a pain-paired compartment was recorded twice, before conditioning and after a post-conditioning test. Paw withdrawal latency (PWL) to a noxious thermal stimulus was measured before experiment at day-1 and after the post-conditioning test; hyperalgesia was defined as a decrease in PWL. The data showed that CFA-injected rats had significantly negative CPA compared to those of saline-injected rats (P

In this article, we firstly analyzed the development direction and trends of the information application of coal mine enterprise, and introduced the status of using 3DGIS into the mine information development. Secondly, we gave the principle of the coal mine comprehensive information system development, and put forward a framework of coal mine comprehensive information system platform based on this principle. This platform generates the 3D topography, mine tunnel stereoscopic drawing and excavated stereoscopic drawing based on the data of the geological survey and engineering, and shows the production information, real-time dynamic monitoring information by 3D on the mine excavated stereoscopic drawing, and the overall real perspective of the mine, including the ground and underground, will be spread out. Finally, we tried a pilot to develop and apply an information system platform based on this platform framework.

Background: Bortezomib-induced peripheral neuropathy (BIPN) is a common and severe dose-limiting side effect in multiple myeloma (MM) patients. Treatment with narcotics, antidepressants, and anticonvulsants are of limited value in reducing symptoms, and they have the potential for significant side effects. Acupuncture has been reported to be effective in treating neuropathic pain. There has been limited reporting on the effect of acupuncture in treating BIPN. Objective: The aim of this study was to report on the effect of acupuncture in treating BIPN. Design and Patients: This study was a retrospective case series of five MM patients experiencing painful BIPN. Intervention: The patients were treated with the same acupuncture protocol on a weekly basis, adjusted to twice a week or once every 2 weeks based on response. Treatment included insertion of disposable sterile acupuncture needles, which were retained for 25 minutes, at the following bilateral ear points: shen men, point zero, and two auric...

The herbal analgesic gel Tong-Luo-San-Jie (TLSJ) and its modifications are used in traditional Chinese medicine to manage cancer pain. However, its mechanisms are still unknown.To investigate the effects and mechanisms of TLSJ gel on bone cancer pain in a rat model.A bone cancer pain rat model was established by inoculating Walker 256 rat carcinoma cells directly into the right tibial medullary cavity of Sprague-Dawley rats (150-170 g); Phosphate buffered saline (PBS) tibial inoculation was used as control. Cancer-bearing rats were treated twice a day with external TLSJ gel (0.5 g/cm(2)/day) or inert gel control for 21 day (n=10/group). Behavioral tests such as mechanical threshold and paw withdrawal latency (PWL) were carried out. Osteoclastic activities were determined and carboxyterminal pyridinoline cross-linked type I collagen telopeptides (ICTP) and bone-specific alkaline phosphatase (BAP) concentrations were detected with ELISA after treatment. Adverse effects were monitored, and biochemical and histological tests were performed in naïve rats treated with local TLSJ gel for six weeks.TLSJ treatment significantly restored bone cancer-induced decrease of PWL and mechanical threshold compared to inert gel. It also decreased the level of blood serum ICTP and BAP and inhibited osteoclast activities. No adverse effects or abnormal biochemical and histological changes were detected after TLSJ treatment.The present study shows that TLSJ significantly inhibits bone cancer-induced thermal and mechanical sensitization. It suggests that the gel may be useful in managing cancer pain and that it may act by inhibiting osteoclastic activity.

Background Although acupuncture analgesia is well documented, its mechanisms have not been thoroughly clarified. We previously showed that electroacupuncture (EA) activates supraspinal serotonin- and norepinephrine-containing neurones that project to the spinal cord. This study investigates the involvement of spinal alpha(2)-adrenoceptors (α2-ARs) and 5-hydroxytryptamine (serotonin) receptors (5-HTRs) in EA effects on an inflammatory pain rat model. Methods Inflammatory hyperalgesia was induced by injecting complete Freund's adjuvant (CFA, 0.08 ml) into the plantar surface of one hind paw and assessed by paw withdrawal latency (PWL) to a noxious thermal stimulus. The selective α2a-AR antagonist BRL-44408, α2b-AR antagonist imiloxan hydrochloride, 5-HT2B receptor (5-HT2BR) antagonist SB204741, 5-HT3R antagonist LY278584, or 5-HT1AR antagonists NAN-190 hydrobromide, or WAY-100635 were intrathecally administered 20 min before EA or sham EA, which was given 2 h post-CFA at acupoint GB30. Results EA significantly increased PWL compared with sham [7.20 (0.46) vs 5.20 (0.43) s]. Pretreatment with α2a-AR [5.35 (0.45) s] or 5-HT1AR [5.22 (0.38) s] antagonists blocked EA-produced anti-hyperalgesia; α2b-AR, 5-HT2BR, and 5-HT3R antagonist pretreatment did not. Sham plus these antagonists did not significantly change PWL compared with sham plus vehicle, indicating that the antagonists had little effect on PWL. Immunohistochemical staining demonstrated that α2a-ARs are on primary afferents and 5-HT1ARs are localized in N-methyl-d-aspartic acid (NMDA) subunit NR1-containing neurones in the spinal dorsal horn. Conclusions The data show that α2a-ARs and 5-HT1ARs are involved in the EA inhibition of inflammatory pain and that the NMDA receptors are involved in EA action.

Pain is a major symptom of bone cancer. Bone cancer pain significantly affects quality of life, but its underlying mechanisms have not been defined. Because skeletal metastases are particularly common in patients with prostate cancer, a model that mimics bone cancer pain has been established by injecting AT-3.1 prostate cancer cells into the tibia of the male Copenhagen rat. The model shows progressive hyperalgesia and allodynia that are associated with the gradual destruction of the tibia and can be used to study the mechanisms, such as glial activation, of these disorders.

It is known that interleukin-17 (IL-17) is associated with autoimmune disorders and that peripheral IL-17 plays a role in arthritis and neuropathic pain. The present study investigated the possibility of spinal cell expression of IL-17 during inflammatory pain and possible IL-17 involvement in such pain. Hyperalgesia was induced by injecting complete Freund adjuvant (CFA, 0.08mL, 40μg Mycobacterium tuberculosis) into one hind paw of the rat. Paw withdrawal latency (PWL) was tested before (-48h) and 2 and 24h after CFA injection to assess hyperalgesia. IL-17 antibody (0.2-2μg/rat) was given intrathecally (i.t.) 24h before CFA to block the action of basal IL-17 and 2h before each of 2 PWL tests to block CFA-induced IL-17. I.t. recombinant IL-17 (10-400ng per rat) was administered to naive rats to determine its effects on PWL and phosphorylated NR1 (p-NR1). p-NR1 modulates N-methyl-d-aspartate receptor (NMDAR) activity to facilitate pain. Spinal cords were removed for IL-17 immunostaining, double immunostaining of IL-17/cell markers and IL-17 receptor A (IL-17RA)/NR1, for Western blot testing of IL-17, p-NR1, IL-17RA, and GFAP, for in situ IL-17RA hybridization, and for real time polymerase chain reaction of IL-17RA. The data reveal that IL-17 is up-regulated in activated and nonactivated astrocytes; that IL-17RA is localized in NR1-immunoreactive neurons and up-regulated; and that IL-17 antibody at 2μg/rat significantly increased PWL (P

Research supports the effectiveness of acupuncture for conditions such as chronic low back and knee pain. In a five-patient pilot study the modality also improved the symptoms of chemotherapy-induced neuropathic pain. Using an established rat model of paclitaxel-induced peripheral neuropathy, we evaluated the effect of electroacupuncture (EA) on paclitaxel-induced hyperalgesia and allodynia that has not been studied in an animal model. We hypothesize that EA would relieve the paclitaxel-induced mechanical allodynia and hyperalgesia, which was assessed 30 min after EA using von Frey filaments. Beginning on day 13, the response frequency to von Frey filaments (4-15 g) was significantly increased in paclitaxel-injected rats compared to those injected with vehicle. EA at 10 Hz significantly (P

Pain is one of the common symptoms of cancer which seriously affects the quality of life of the patients. Cancer pain is mainly treated with the three-step method, biological therapy or nerve block therapy based on antitumor therapy. However, up to 50 percent of patients with cancer-related pain do not receive adequate pain relief, affecting their physical and psychological well-being, and leading to a lower quality of life for the patient after conventional treatment. Clinical observation suggests that traditional Chinese medicine may alleviate cancer-related pain either by oral administration, topical administration, acupuncture or other means with continuing non-addictive and non-drug-resistant qualities. However, scientific evaluation of the efficacy of herbs in the treatment of pain is insufficient; the underlying mechanisms are unclear and, safety and toxicity remain a concern.

Peripheral neuropathy is a common and severe dose-limiting side effect of the chemotherapy agent, bortezomib, in multiple myeloma patients. Treatment with narcotics, antidepressants, and anticonvulsants has limited response and potential significant side effects. Acupuncture has been reported to be effective in treating diabetic neuropathy and chemo-induced peripheral neuropathy. There has not been report on the effect of acupuncture in treating bortezomib-induced peripheral neuropathy specifically. Here, we report a successful case of using acupuncture to relieve bortezomib-induced peripheral neuropathy symptoms.

Osteoarthritis currently has no cure. Acupuncture can benefit patients with knee osteoarthritis by providing pain relief, improving joint function and serving as an effective complement to standard care. However, the underlying mechanisms of its effects are still not completely understood. The present study, an investigation of the effectiveness and mechanisms of electroacupuncture (EA) in attenuating osteoarthritis pain in a rat model, is focused on the involvement of 5-hydroxytryptamine 2A/C (5-HT2A/C) receptors, which play an important role in pain modulation at the spinal level. Osteoarthritis was induced under isoflurane anesthesia by a single intraarticular injection of monosodium iodoacetate (3 mg/50 μL/rat) into one hind leg of each rat. EA was given at acupoints GB 30 and ST 36 on days 1–4 after the injection. Vehicle or ketanserin, a 5-HT2A/C receptor antagonist, was given intraperitoneally (1 mg kg−1) or intrathecally (5 μg or 10 μg/10 μL), 30 min before each EA treatment. Assessment of weight-bearing difference between injected and uninjected hind legs was done on days 0, 1–4 and 7. Fos /serotonin and serotonin/Fluorogold double labeling were performed to determine EA activation of serotonergic neurons in the nucleus raphe magnus (NRM) that project to spinal cord. The results showed that EA significantly decreases weight-bearing difference compared to sham EA. Ketanserin pretreatment blocked the analgesic effect of EA but did not influence weight bearing in sham EA control rats. EA also activated serotonergic NRM neurons that project to the spinal cord. These data show that EA inhibits osteoarthritis-induced pain by enhancing spinal 5-HT2A/2C receptor activity.

Animal models of inflammatory pain have been widely used to study the mechanisms of tissue injuryinduced persistent pain. A variety of inflammatory agents or irritants, including complete Freund’s adjuvant, carrageenan, zymosan, mustard oil, formalin, capsaicin, bee venom, acidic saline, lipopolysaccharide, inflammatory cytokines, and sodium urate crystals, have been used to produce tissue injury and hyperalgesia in such structures as cutaneous/subcutaneous tissues, joints, and muscles. Additionally, models of pain hypersensitivity have also been established with injuries produced by burning, freezing, and ultra irradiation. Although these models do not simulate every aspect of chronic pain, they do model key features of human inflammatory pain. Studies in animals give insight into certain aspects of human pain conditions and lead to improved pain management for patients. Pain perception is more complex in humans than in animals since human pain perception encompasses psychosocial, cultural, developmental, and environmental variables. However, human and animal pain perceptions show parallels, and animal models partially mimic the persistent pain encountered in the clinic. In the last two decades animal models of inflammatory pain have been widely used to study the mechanisms of tissue injury-induced persistent pain. Although none of the existing models can simulate all symptoms of inflammatory pain, studies in animals give insight into certain aspects of human pain conditions and lead to better pain management for patients. In the following paragraphs, commonly used inflammatory pain animal models will be summarized. Interested readers may consult more comprehensive reviews for further details (1, 2).

Chinese herbal medicine, mainly in herbal formulations, is a major modality of traditional Chinese medicine (TCM) and has been used for thousands of years in China and other Asian countries to treat a variety of inflammatory diseases [1]. In recent years, the medicinal use of herbs, including Chinese herbs, has received increasing public interest in Western countries [2]. In 2002 alone, there was 19% of American adults using herbs for their health issues [3]. Although Chinese herbs have been used widely, their safety evaluation is not well conducted, especially in herbal formulations. Herbal formulations, typically of 10 or more herbs, are commonly prescribed by Chinese herbalists, and numerous such formulas are well documented in ancient and modern Chinese literature [4–6]. Although the use of individual Chinese herbs also is prolifically documented [7–9], it is believed that a combination of herbs of various functions can augment the effectiveness of a treatment. According to the theory of Chinese herbalism, the interactions among the herbs may produce synergistic effects and neutralize potential toxicity or side effects of the individual constituents [1,10–12]. The Chinese formula Huo Luo Xiao Ling Dan (HLXLD) (fantastically effective pill to invigorate the collaterals), actually a group of formulations with the core herbs Boswellia carterii Birdw. (Ruxiang), Commiphora myrrha Engl. (Moyao), Angelica sinensis (Oliv.) Diels (Danggui) and Salvia miltiorrhiza Bge. (Danshen), is an effective and popular formula used in current clinical practice in treating various inflammation or pain disorders, and has been modified to suit the various clinical conditions or patient's constitution [13–22]. The main actions of this formula and its modifications are promotion of circulation, alleviation of pain and reduction of swelling [6,10]. In our previous studies, one of HLXLD formulas containing eleven herbs (Table 1) was used in arthritis and other inflammatory disorders, and the whole formula was proved having significant effects against inflammatory hyperalgesia and edema [23,24], and arthritis [25,26]. Table 1 The components of HLXLD and acute toxicity data in literature of its constituents In the present study, we evaluated this formula by both literature review and experiments in rats. Specifically, the aims of the present study were to review the safety data of HLXLD related in literature, evaluate its acute toxicity, assess the effect on motor function, evaluate potential adverse effects and toxicity in inflammatory rats, arthritis rats and naive rats under repeat-dose treatments, and investigate its chronic toxicity in naive rats.

It has been shown that interleukin-1beta (IL-1beta) facilitates nociception during neuropathic and inflammatory pain, but its involvement in bone cancer pain and its mechanisms have not previously been established. This study is an investigation of IL-1beta spinal expression and the N-methyl-D-aspartate (NMDA) receptor (NMDAR) NR1 subunit phosphorylation during cancer pain, co-localization of IL-1 receptor type I (IL-1RI) and NMDAR in the spinal cord, and the effects of IL-1 receptor antagonist (IL-1ra) on NMDAR1 (NR1) phosphorylation and hyperalgesia in a rat model of bone cancer pain. Cancer was induced by injecting AT-3.1 prostate cancer cells into the tibia of the male Copenhagen rat. Phosphorylation of NR1, an essential subunit of the NMDAR, is known to modulate NMDAR activity and facilitate pain. Mechanical hyperalgesia, established by a decrease in paw withdrawal pressure threshold (PWPT), was measured at baseline and 2 h after IL-1ra treatment. IL-1ra was given (i.t.) daily for 7 days between days 13 and 19 after the cancer cell inoculation. Spinal cords were removed for Western blot to measure IL-1beta and NR1 phosphorylation and for double immunostaining of IL-1RI and NR1. The data showed that 1) spinal IL-1beta was up-regulated and NR1 phosphorylation was increased, 2) IL-1ra at 0.1 mg/rat significantly (P

Background: Studies show that electroacupuncture (EA) has beneficial effects in patients with inflammatory diseases. This study investigated the mechanisms of EA anti-inflammation, using a rat model of complete Freund's adjuvant (CFA)-induced hind paw inflammation and hyperalgesia. Design: Four experiments were conducted on male Sprague-Dawley rats (n = 6-7/per group). Inflammation was induced by injecting CFA into the plantar surface of one hind paw. Experiment 1 examined whether EA increases plasma adrenocorticotropic hormone (ACTH) levels. Experiments 2 and 3 studied the effects of the ACTH and corticotropin-releasing hormone (CRH) receptor antagonists, ACTH(11-24) and astressin, on the EA anti-edema. Experiment 4 determined whether EA activates CRH neurons in the paraventricular nucleus of the hypothalammus. EA treatment, 10 Hz at 3 mA and 0.1 ms pulse width, was given twice for 20 min each, once immediately post and again 2 hr post-CFA. Plasma ACTH levels, paw thickness, and paw withdrawal latency to a noxious thermal stimulus were measured 2 h and 5 h after the CFA. Results: EA significantly increased ACTH levels 5 h (2 folds) after CFA compared to sham EA control, but EA alone in naive rats and CFA alone did not induce significant increases in ACTH. ACTH(11-24) and astressin blocked EA anti-edema but not EA anti-hyperalgesia. EA induced phosphorylation of NR1, an essential subunit of the N-methyl-D-aspartic acid (NMDA) receptor, in CRH-containing neurons of the paraventricular nucleus. Conclusion: The data demonstrate that EA activates CRH neurons to significantly increase plasma ACTH levels and suppress edema through CRH and ACTH receptors in a rat model of inflammation. © 2008 Li et al; licensee BioMed Central Ltd., link_to_subscribed_fulltext

Although electroacupuncture (EA) is widely used to treat pain, its mechanisms have not been completely understood. The present study investigated the descending inhibitory system involvement in EA action. Inflammatory pain was induced by injecting complete Freund's adjuvant subcutaneously into one hind paw of rats with dorsolateral funiculus lesions and sham-operated rats. EA treatment, 10 Hz at 3 mA, was given twice for 20 min each, once immediately post- and again 2 h post-Freund's adjuvant at GB 30, at the junction of the lateral 1/3 and medial 2/3 of the distance between the greater trochanter and sacral hiatus. For sham EA control, acupuncture needles were inserted bilaterally into GB 30 without electrical or manual stimulation. Paw withdrawal latency to a noxious thermal stimulus was measured at baseline and 20 min after EA treatment. Compared to sham EA, EA significantly (P

Background: Electroacupuncture (EA) has been reported to produce anti-edema and anti-hyperalgesia effects on inflammatory disease. However, the mechanisms are not clear. The present study investigated the biochemical mechanisms of EA anti-inflammation in a rat model. Methods: Three experiments were conducted on male Sprague-Dawley rats (n = 7-8/per group). Inflammation was induced by injecting complete Freund's adjuvant (CFA) subcutaneously into the plantar surface of one hind paw. Experiment 1 measured plasma corticosterone (CORT) levels to see if EA regulates CORT secretion. Experiment 2 studied the effects of the adrenal gland on the therapeutic actions of EA using adrenalectomy (ADX) rats. Experiment 3 determined whether a prototypical glucocorticoid receptor antagonist, RU486, affects EA anti-edema. EA treatment, 10 Hz at 3 mA and 0.1 ms pulse width, was given twice, for 20 min each, once immediately after CFA administration and again 2 h post-CFA. Plasma CORT levels, paw thickness, indicative of the intensity of inflammation, and paw withdrawal latency (PWL) were measured 2 h and 5 h after the CFA injection. Results: EA significantly increased plasmacorticosterone levels 2 h (5 folds) and 5 h (10 folds) after CFA administration compared to sham EA control, but EA alone in naive rats and CFA alone did not induce significant increases in corticosterone. Adrenalectomy blocked EA-produced anti-edema, but not EA anti-hyperalgesia. RU486 (15 μl, 15 μg/μl), a prototypical glucocorticoid receptor antagonist, also prevented EA anti-edema. Conclusion: The data demonstrate that EA activates the adrenals to increase plasma corticosterone levels and suppress edema and suggest that EA effects differ in healthy subjects and in those with pathologies. © 2007 Li et al; licensee BioMed Central Ltd., link_to_subscribed_fulltext

It is known that interleukin-1beta facilitates pain, but the mechanisms of this are not understood. This study investigated the role of interleukin-1beta in the expression of Fos, a marker of neuronal activation, and hyperalgesia caused by injecting complete Freund's adjuvant into one hind paw of the rat. Interleukin-receptor antagonist (interleukin-1ra, 0.005 mg/rat) was given intrathecally twice, 24 h before complete Freund's adjuvant and immediately before complete Freund's adjuvant injection, to block interleukin-1beta action. Fos expression was measured 2 h after complete Freund's adjuvant injection. Paw withdrawal latency was used to assess hyperalgesia. The findings were that interleukin-1ra inhibited inflammation-induced Fos expression and hyperalgesia, which suggests that endogenous interleukin-1beta facilitates transmission of noxious messages at the spinal level by processes involving an enhanced Fos expression.

Chinese herbal medicine has been used for thousands of years in China and other Asian countries to treat a variety of inflammatory diseases. The classic Chinese herbal formula, Huo Luo Xiao Ling Dan (活络效灵丹, HLXL) is commonly used in traditional Chinese herbal medicine for the treatment of joint pain and other symptoms of arthritis. The present study is an investigation of the effects of a modified HLXL extract on persistent hyperalgesia and edema in rats with peripheral inflammation. Inflammation was induced by injecting complete Freund's adjuvant (CFA) into one hind paw. Four dosages of the extract were compared to a vehicle control. Each was administered intragastrally (i.g.) daily for seven days beginning one day before CFA. Hyperalgesia was assessed using a paw withdrawal latency (PWL) test and edema was determined by measuring paw thickness at pre-CFA and 2 hours, 24 hours, and 5 days post-CFA. Immunohistochemistry was performed 2 hours post-CFA to determine spinal Fos protein expression. Adverse effects of the extract were monitored by observing the animals closely for unusual behavioral changes. Compared to the control, HLXL at the two lower dosages (0.575 g/kg and 1.15 g/kg) were effective in the later stage (day 5) of inflammatory hyperalgesia and edema, while the two higher dosages (2.3 g/kg and 4.6 g/kg) alleviated early stage hind paw inflammation and hyperalgesia and facilitated recovery from paw edema and hyperalgesia during the late stage. HLXL at 2.30 g/kg significantly suppressed Fos expression in laminae I–II, III–IV and V–VI ipsilaterally and in III-IV contralaterally. No significant signs of toxicity or adverse effects were observed. The data suggest that HLXL dosage-dependently attenuates CFA-induced inflammation and hyperalgesia, at least in part by inhibiting noxious transmission at the dorsal horn of the spinal cord.

The study was designed to determine whether the protein kinase C (PKC) is involved in nociceptive c-Fos expression and the concomitant signaling processes of endogenous opioid-like substances (OLS) that modulate c-Fos expression in the spinal dorsal horn following formalin injection into the unilateral hindpaw in rats by using immunocytochemical techniques. In the first part of experiments in which rats were pretreated with intrathecal (i.t.) chelerythrine (Chel), an inhibitor of PKC, the nociceptive c-Fos-like immunoreactive (Fos-LI) neurons in the lumbar dorsal horn ipsilateral to the formalin injection were significantly suppressed with a reduction rate of 60.3% (p < .001) as compared to that in the control group with i.t. saline. In the second part of experiments in which rats were pretreated with i.t. naloxone (Nal), the nociceptive Fos-LI neurons were significantly increased by 53.2% (p < .01) as compared to that in the control group; however, when rats were pretreated with combined i.t. Nal + Chel, the nociceptive Fos-LI neurons exhibited a percentage reduction similar to that in group with i.t. Chel alone, although the real number of Fos-LI neurons in group with i.t. Nal + Chel still significantly surpassed that in group with i.t. Chen only. These results suggest that: (1) PKC may play an important role in the induction of nociceptive c-Fos expression; (2) nociceptive c-Fos expression is subject to the modulation of endogenous OLS that suppress the nociceptive responses of the dorsal horn neurons; and (3) PKC may not be involved in the signaling processes by which the endogenous OLS modulate the nociceptive c-Fos expression in the spinal level.

It has been demonstrated that electroacupuncture (EA) significantly suppresses behavioral hyperalgesia in a rat model of persistent inflammatory pain and that neurokinin-1 (NK-1)/substance P (SP) receptors play important roles in nociception and hyperalgesia at the spinal cord level. The present study investigated spinal NK-1 receptor involvement in EA-produced suppression of hyperalgesia in a rat model of persistent inflammatory pain. The results showed that hind paw inflammation induced a significant increase of NK-1 receptor expression in the spinal dorsal horn and that this effect was significantly suppressed by EA. This suggests that EA-induced suppression of hyperalgesia is involved, at least partly, in the suppression of the spinal NK-1 receptors induced by sustained peripheral nociceptive input.

Studies suggest that astrocytes and microglia in the spinal cord are involved in the development of persistent pain induced by tissue inflammation and nerve injury. However, the role of glial cells in bone cancer pain is not well understood. The present study evaluated the spinal glial activation in a novel rat model of bone cancer pain produced by injecting AT-3.1 prostate cancer cells into the unilateral tibia of male Copenhagen rats. The structural damage to the tibia was monitored by radiological analysis. The thermal hyperalgesia, mechanical hyperalgesia and allodynia, and spontaneous flinch were measured. The results showed that: (1) inoculation of prostate cancer cells, but not the vehicle Hank's solution, induced progressive bone destruction at the proximal epiphysis of the tibia from day 7-20 post inoculation; (2) the inoculation also induced progressive thermal hyperalgesia, mechanical hyperalgesia, mechanical allodynia, and spontaneous flinches; (3) astrocytes and microglia were significantly activated in the spinal cord ipsilateral to the cancer leg, characterized by enhanced immunostaining of both glial fibrillary acidic protein (GFAP, astrocyte marker) and OX-42 (microglial marker); (4) IL-1beta was up-regulated in the ipsilateral spinal cord, evidenced by an increase of IL-1beta immunostained astrocytes. These results demonstrate that injection of AT-3.1 prostate cancer cells into the tibia produces progressive hyperalgesia and allodynia associated with the progression of tibia destruction, indicating the successful establishment of a novel male rat model of bone cancer pain. Further, bone cancer activates spinal glial cells, which may release IL-1beta and other cytokines and contribute to hyperalgesia.

Ruxiang (Gummi olibanum), the dried gum resin of Boswellia carterii (BC), has been used in traditional Chinese medicine to alleviate pain and inflammation for thousands of years. In this random, blinded study, the anti-arthritic effects of a BC extract were observed and compared to vehicle control in a Lewis rat adjuvant arthritis model (n=8/group). Arthritis was induced by injecting CFA subcutaneously into the base of the tail, and the extract was administered orally (i.g.) for 10 consecutive days beginning on day 16 after the injection. Arthritic scores, paw edema, and the local tissue pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1beta) were assessed. Toxicity and adverse effects of the extract were evaluated. At 0.90 g/kg per day, BC significantly decreased arthritic scores between days 20 and 25 (p

Our previous study showed that electroacupuncture (EA), an adjuvant to conventional medicine, significantly attenuated hyperalgesia in a rat model of inflammatory pain. In the present study, we evaluated the potential additive and/or synergism of EA and a sub-effective dose of dizocilpine maleate (MK-801), a non-competitive N -methyl- d -aspartate (NMDA) receptor antagonist, on hyperalgesia in the same rat model of inflammatory pain. Hyperalgesia, manifesting as decreased paw withdrawal latency (PWL) to a noxious stimulus, was induced by injecting complete Freund's adjuvant (CFA) into the plantar surface of one hind paw of each rat. EA treatments were given at acupoint GB30 immediately after and 2 h after CFA. MK-801 at 0.001 mg/rat was given (i.t.) 10 min before each of the two EA treatments. PWL was measured prior to and 2.5 and 5 h post-CFA. Ten and 100 Hz EA significantly inhibited CFA-induced hind paw hyperalgesia. Both 10 and 100 Hz EA combined with the sub-effective dose of 0.001 mg/rat MK-801 showed prolonged anti-hyperalgesia with no side effects. These results demonstrate that EA combined with a sub-effective dose of this NMDA receptor antagonist enhances anti-hyperalgesia, and this combination may provide an effective strategy for pain management.

The present study was aimed to examine if protein kinase C (PKC) activation is necessarily involved in both the c-fos protein expression in the nocuously-activated c-fos protein-like immunoreactive (Fos-LI) neurons and the concomitant opioid receptor-mediated modulation in the dorsal horn circuitry of the spinal cord. Formalin was injected into a hindpaw of rats 5 min after the rats were pretreated with intrathecal (i.t.) administration of chelerythrine (Chel), an inhibitor of PKC, naloxone (Nal), combined administration of these two (Chel + Nal), or vehicle (n=5 in each group),respectively. By using immunocytochemical techniques, the formalin-induced Fos-LI neurons in the lumbar dorsal horn were calculated 1 h after formalin injection. The results showed that: (1) i.t. Chel significantly reduced the number of Fos-LI neurons in the dorsal horn of the spinal cord on the side ipsilateral to the formalin injection, showing a decrease by 60.3% (P0.001) as compared to that observed in the i.t.vehicle group; (2) i.t. Nal significantly increased the number of Fos-LI neurons in the ipsilateral dorsal horn, with an increase of 46.0% (P0.01) as compared to that in the i.t.vehicle group, the highest percentage increase being found in the deeper laminae of the dorsal horn; and (3) i.t. Chel + Nal also exhibited a significant decrease in Fos-LI neurons in the ipsilateral dorsal horn as compared to i.t. Nal group, showing a reduction of 53.2%, a value similar to that in the i.t. Chel group. These results suggest that: (1) PKC plays a role in the c-fos protein expression only in nearly one half of the Fos-LI neurons in the dorsal horn; and (2) PKC is possibly not involved in the concomitant modulation on the nociception mediated by micro- (and also partly delta-) opioid receptors in the spinal cord.

The aging process is associated with various morphological and biochemical changes in the nervous system that may affect the processing of noxious inputs. This study showed greater hyperalgesia and up-regulation of spinal dynorphin (DYN) expression in aging than in young adult rats during CFA-induced peripheral inflammation. These data indicate that nociception is regulated differently in aging individuals, a fact that should be considered when selecting treatment strategies for aging populations with persistent pain.

We previously reported the anti-hyperalgesia of electroacupuncture (EA) on persistent inflammatory pain in an unrestrained, unsedated, and conscious rat model. Using this model, induced by injecting complete Freund's adjuvant (CFA) into one hind paw, we systematically evaluated the anti-hyperalgesia of EA stimulation parameters (frequency, intensity, treatment duration, and pulse width). We assessed hyperalgesia by paw withdrawal latency (PWL) to a noxious thermal stimulus and found that 10- and 100-Hz EA frequencies at a current intensity of 3 mA produced the greatest anti-hyperalgesia, when compared to other parameters. Both frequencies significantly increased PWL in the early phases of hyperalgesia (2.5 and 24 h; p < 0.05), and 10 Hz EA also significantly increased PWL in later phases (5 to 7 days; p < 0.05). A sufficient but tolerable intensity of 3 mA was more effective than lower intensities (1-2 mA). A 20-min treatment produced better anti-hyperalgesia than longer and shorter (10 and 30 min) treatments. Acupoint specificity study demonstrated that GB30 produced significant EA anti-hyperalgesia, while Waiguan (TE5) and sham points, an abdominal point and a point at the opposite aspect of GB30, did not. The spinal Fos protein expression study demonstrated that the optimal EA selectively suppressed Fos expression in superficial laminae (I/II) and activated it in deeper laminae (III/IV) of the spinal dorsal horn. The results suggest that the EA anti-hyperalgesia is parameter-dependent and point-specific, and they provide important information for designing further clinical acupuncture research on persistent inflammatory pain.

Changes of substance P (SP)-, calcitonin gene-related peptide (CGRP)-, somatostatin (SS)-, Met-enkephalin (Met-Enk)- and neurotensin (NT)- immunoreactive materials on two sides of the lumbar dorsal horn were inspected microscopically and quantified with a computer-assisted image processing system in rats with intact or totally transected spinal cord 2 h after injection of 0.2 ml of 0.5% formalin into the right hindpaw subcutaneously. The results showed that the SP-like immunoreactivity (SP-LI), CGRP-LI, SS-LI, Met-Enk-LI, and NT-LI were significantly higher in fibers and terminals in superficial laminae of the dorsal horn ipsilateral to the formalin injection in both of the experimental groups. It is supposed that the increased contents of these peptides reflect an increased biosynthesis, transport, and release of these peptides in primary afferents and spinal intrinsic neurons in response to the long-lasting inflow of noxious messages, and that these changes seem to be produced even in the condition when the supraspinal effects have been excluded.

Immunocytochemical staining for serotonin (5-HT), tyrosine hydroxylase (TH) and galanin (GAL) was combined with horseradish peroxidase (HRP) retrograde tract-tracing technique to analyze the localizations of 5-HT-, catecholamine (CA)- and GAL-containing neurons in the brainstem which project to the nucleus parafascicularis (PF) in rats. It is demonstrated that most of the retrogradely HRP-labeled neurons (70%) in bilateral periaqueductal gray (PAG) and raphe nuclei are positively immunostained by antiserum to 5-HT, and that most of the retrogradely HRP-labeled neurons (over 80%) in bilateral locus coeruleus (LC) are positively immunostained by antisera to both TH and GAL. The possible functions of these PF-petal serotonergic, catecholaminergic (actually noradrenergic) and galaninergic projections are discussed.

the immunohistochemical staining technology to detect the expression of IL-6, TNF, MCP-1, TG Fin the brain tissue of affected side. Results: Electro-acupuncture treatment on DU20, affected side ST36, contrast the points DU20, EX-HN3 and DU26, could significantly lower the inflammatory response signals’ expression levels in the brain tissue of affected side in the rat model, including IL-6, TNF, MCP-1, TGF, could show the second peak of IL-6, TGFin advance. Conclusion: Electro-acupuncture treatment on DU20, affected side ST36, contrast the points DU20, EX-HN3 and DU26, had better influences in regulating the body’s inflammatory stress response to injury, reducing the inflammatory response and inflammatory, activating repair function, combined use of points on the head and body may be better in reducing inflammatory injury than using the head acupuncture points only. Contact: WANG YU, wy8166@126.com