Therapeutic ultrasound suppresses neuropathic pain and upregulation of substance P and neurokinin-1 receptor in rats after peripheral nerve injury.

We studied the mechanisms and impact of therapeutic ultrasound (TU) for pain caused by nerve injury. TU began on post-operative day 5 (POD5) and then continued daily for the next 22 d. Sensitivity to thermal and mechanical stimuli and levels of neurokinin-1 receptor, substance P, tumor necrosis factor-α and interleukin-6 in the sciatic nerve were examined. On POD7, chronic constriction injury rats undergoing TU at an intensity of 1 W/cm(2), but not 0.25 or 0.5 W/cm(2), had increases in both the mechanical withdrawal threshold and the thermal withdrawal latency compared with the chronic constriction injury group. Moreover, chronic constriction injury rats exhibited upregulation of neurokinin-1 receptor, substance P, tumor necrosis factor-α and interleukin-6 in the sciatic nerve on PODs 14 and 28, whereas TU inhibited their increased expression. We suggest that the efficacy of TU is dependent on its ability to limit the upregulation of neurokinin-1 receptor, substance P, tumor necrosis factor-α and interleukin-6 around the injured sciatic nerve.

Nisoxetine produces local but not systemic analgesia against cutaneous nociceptive stimuli in the rat.

The aim of this study was to evaluate the local anesthetic effect of nisoxetine as infiltrative cutaneous analgesic. After rats were injected subcutaneously with nisoxetine, dose-response curves were constructed. The cutaneous anesthetic effect of nisoxetine or MK-801 (dizocilpine) was compared with lidocaine, a traditional local anesthetic. We found that nisoxetine and MK-801 acted like lidocaine and elicited dose-related cutaneous (local) anesthesia. The relative potency was nisoxetine>MK-801>lidocaine (P<0.01) as infiltrative anesthesia of skin. On an equianesthetic doses (20% effective dose [ED20], ED50, and ED80), nisoxetine produced longer action of cutaneous anesthesia than that of lidocaine or MK-801 (P<0.01). Coadministration of nisoxetine or lidocaine with MK-801 showed an additive cutaneous anesthesia. Neither local injection of a large dose of nisoxetine, MK-801 nor lidocaine in the thigh area produced cutaneous anesthesia (data not shown). In conclusion, nisoxetine had a local anesthetic effect as infiltrative cutaneous analgesia with durations of actions longer than that of lidocaine or MK-801. That N-methyl-d-aspartate receptors may not contribute to the cutaneous (local) anesthetic effect of nisoxetine or lidocaine.

Comparison of hydration, tyrosinase resistance, and antioxidant activation in three kinds of pearl powders.

In recent years, people have bred freshwater pearls as a substitute for natural pearls that occur in seawater, and they have also developed water-soluble pearl powder (P-w) and ultra-micro (P-mu) and ultra-nano pearl powder (P-n) products. However, neither the scientific value of pearl powder, nor the differences in efficiencies of different pearl powder products is still unknown. In this study, the effectiveness of three kinds of pearl powder products in various applications was compared. Tests for transepidermal water loss (TEWL) and evaluations of the skin surface hydration of test subjects showed that pearl powder has a satisfactory moisturizing effect on skin and that P-mu has a distinctly stronger moisturizing effect than P-w. The three pearl powder products can also significantly reduce the activation of tyrosinase and free radicals. In tests for reducing power and 1,1-diphenyl-2-picrylhydrazyl (DPPH) for scavenging free radicals, P-n and P-mu showed better performance than P-w. These results provide a reliable scientific basis for the use of pearl powder in beauty treatment, resistance to aging, and clinical medical treatment.

The systemic toxicity of equipotent proxymetacaine, oxybuprocaine, and bupivacaine during continuous intravenous infusion in rats.

BACKGROUND: Although proxymetacaine and oxybuprocaine produce topical ocular and spinal anesthesia, they have never been tested as cutaneous anesthetics. We compared cutaneous analgesia of proxymetacaine and oxybuprocaine with bupivacaine and tested their central nervous system and cardiovascular toxicity. METHODS: After blockade of cutaneous trunci muscle reflex with subcutaneous injections, we evaluated the local anesthetic effect of proxymetacaine and oxybuprocaine on cutaneous analgesia in rats. After i.v. infusions of equipotent doses of oxybuprocaine, proxymetacaine, and bupivacaine, we observed the onset time of seizure, apnea, and impending death and monitored mean arterial blood pressure and heart rate. RESULTS: Proxymetacaine and oxybuprocaine acted like bupivacaine and produced dose-related cutaneous analgesia. On a 50% effective dose basis, the ranks of potencies were proxymetacaine > oxybuprocaine > bupivacaine (P < 0.01). Under equipotent doses, the infusion times of proxymetacaine or oxybuprocaine required to cause seizure, apnea, and impending death were longer than that of bupivacaine (P < 0.05). The decrease in mean arterial blood pressure and heart rate was slower with oxybuprocaine and proxymetacaine compared with bupivacaine (P < 0.05 for the differences) at equipotent doses. CONCLUSIONS: Oxybuprocaine and proxymetacaine were more potent at producing cutaneous anesthesia but were less potent than bupivacaine at producing central nervous system and cardiovascular toxicity.

Exercise pretraining attenuates endotoxin-induced hemodynamic alteration in type I diabetic rats.

Higher expression of heat shock protein 72 (HSP72) reduces the mortality rate and organ damage in septic shock and prevents cardiac mitochondrial dysfunction due to lipopolysaccharide (LPS). Our hypothesis is that exercise preconditioning may increase the expression of HSP72 in heart and the nucleus tractus solitarii (NTS) of the brain to alleviate the cardiovascular dysfunction in type I diabetic rats receiving endotoxin. Wistar rats were randomly assigned to the following groups: sedentary normal, sedentary type I diabetic rats, and type I diabetic rats with exercise training. The trained rats ran on a treadmill 5 d.week-1, 30-60 min.d-1, at an intensity of 1.0 mile.h-1 (1 mile = 1.6 km) over a 3 week period. Twenty-four hours after the last training session, we compared the temporal profiles of mean arterial pressure, heart rate, cardiac output, stroke volume, and serum tumor necrosis factor alpha level in rats receiving an injection of LPS. In addition, HSP72 expression in heart and NTS from each group was determined. We found that HSP72 expression in the heart and NTS was significantly increased in diabetic rats with exercise training. After administration of LPS, the survival time was significantly longer in diabetic rats with exercise training. Additionaly, serum tumor necrosis factor alpha levels decreased as compared with those rats not receiving exercise training. Exercise training also diminished cardiovascular dysfunction in diabetic rats during endotoxemia. These data suggest that exercise may increase the expression of HSP72 in the heart and NTS to protect against the high mortality rate and attenuate cardiovascular dysfunction in diabetic rats during endotoxemia.

Inhibition of nuclear factor-kappa B prevents staphylococcal enterotoxin A-induced fever.

It has been shown that staphylococcal enterotoxin A (SEA) acts through human peripheral blood mononuclear cells (PBMC) to stimulate synthesis or release of pyrogenic cytokines. Nuclear factor-kappa B (NF-kappaB) is thought to play an important role in inflammatory responses through the regulation of genes encoding pro-inflammatory cytokines. The purpose of the present study was to determine whether the NF-kappaB mechanisms in human PBMC are involved in SEA-induced fever. Western blot evaluation revealed SEA was able to induce nuclear translocation of NF-kappaB from cytosol to nucleus in PBMC, which could be abolished by a NF-kappaB inhibitor such as pyrrolidine dithiocarbamate (PDTC), sodium pyrithione (Pyri), N-acetyl-L-cysteine (NAC), or curcumin (Cur). Electrophoretic mobility shift assay also showed that the NF-kappaB DNA-binding activity was increased in the SEA-treated PBMC. Again, the SEA-induced increased NF-kappaB binding activity was significantly attenuated by either PDTC, Pyri, NAC or Cur. The pyrogenic responses to supernatant fluids obtained from human PBMC stimulated with SEA were associated with increased levels of interleukin 1-beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) in the supernatant fluids. Both the fever and the increased levels of IL-1beta, IL-6, and TNF-alpha in supernatant fluids obtained from the SEA-stimulated PBMC were decreased by incubating SEA-PBMC with either PDTC, Pyri, NAC, or Cur. Furthermore, the fever induced by systemic or central administration of SEA in rabbits were attenuated by pre-treatment with an systemic or central dose of either PDTC, Pyri, NAC, or Cur. The data indicate that inhibition of NF-kappaB prevents SEA-induced fever.

Platonin, a cyanine photosensitizing dye, inhibits pyrogen release and results in antipyresis.

Intravenous injection of the supernatant fluids from human peripheral blood mononuclear cells (PBMC) incubated with lipopolysaccharide (LPS) caused fever in rabbits. The fever was in parallel with the levels of either interleukin-1 beta (IL-1 beta), IL-6, or tumor necrosis factor-alpha (TNF-alpha) in supernatant fluids. When incubating the platonin with the LPS-human PBMC, both the levels of IL-1 beta, IL-6, or TNF-alpha in supernatant fluids and the pyrogenicity of supernatant fluids were significantly suppressed. The febrile response to supernatant fluids from the LPS-stimulated PBMC was attenuated almost completely by adding anti-IL-1 beta, but not anti-IL-6 or anti-TNF-alpha, monoclonal antibody to supernatant fluids. In addition, both the fever and the increased levels of either IL-1 beta, IL-6, or TNF-alpha in rabbit serum following an intravenous administration of LPS were significantly attenuated by pretreatment with an intravenous dose of platonin. Furthermore, the fever induced by intravenous injection of IL-1 beta was reduced by pretreatment of rabbits with intravenous injection of platonin. The data indicate that platonin inhibits production of pyrogenic cytokines (in particular, IL-1 beta) from PBMC and results in antipyresis.

Blocking NF-kappaB activation may be an effective strategy in the fever therapy.

Lipopolysaccharide (LPS) stimulates peripheral mononuclear cells (PBMC) to synthesize or release pyrogenic cytokines, including interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha). Nuclear factor-kappa B (NF-kappaB) influences inflammatory responses through the regulation of genes encoding cytokines. In the present study, experiments were carried out to determine whether an inhibition of NF-kappaB mechanisms causes an inhibition of pyrogenic cytokine synthesis or release from PBMC and results in antipyresis. Intravenous administration of the supernatant fluids obtained from the human PBMC incubated with LPS caused feverlike hyperthermia in rabbits. The febrile responses were in parallel with the levels of IL-1beta, IL-6, and TNF-alpha in supernatant fluids. Both the fever and the increased levels of these cytokines in supernatant fluids were decreased by incubating LPS-PBMC with NF-kappaB inhibitors, including pyrrolidine dithiocarbamate, sodium pyrithione, N-acetyl-cysteine, and curcumin. Moreover, an intravenous administration of LPS (0.5-2 microg/kg) produced dose-dependent fever in the rabbits. The fevers were in parallel with the levels of IL-1beta, IL-6, and TNF-alpha in rabbit serum. A pretreatment of rabbits with an intravenous injection of pyrrolidine dithiocarbamate, sodium pryithione, N-acetyl-cysteine, or curcumin 1 h before the intravenous administration of LPS significantly attenuated the LPS-induced fever and/or increased levels of these cytokines in the serum of rabbits. Furthermore, pretreatment with an intravenous dose of anti-IL-1beta, anti-IL-6, or anti-TNF-alpha monoclonal antibody significantly attenuated the fever induced by the intravenous injection of LPS in rabbits. The antipyretic effects exerted by anti-L-1beta monoclonal antibody were greater than those exerted by anti-L-6 or anti-NF-alpha monoclonal antibody. The data indicate that NF-kappaB activation correlates with an LPS-induced synthesis or a release of cytokines (in particular, IL-1beta) from PBMC and triggers fever. Blocking NF-kappaB mechanisms in the PBMC with NF-kappaB inhibitors may be an effective strategy in the fever therapy.