Antinociceptive Effects of Botulinum Toxin Type A on Trigeminal Neuropathic Pain.

Previous studies have demonstrated that botulinum toxin type A (BoNT-A) attenuates orofacial nociception. However, there has been no evidence of the participation of the voltage-gated sodium channels (Navs) in the antinociceptive mechanisms of BoNT-A. This study investigated the cellular mechanisms underlying the antinociceptive effects of BoNT-A in a male Sprague-Dawley rat model of trigeminal neuropathic pain produced by malpositioned dental implants. The left mandibular second molar was extracted under anesthesia, followed by a miniature dental implant placement to induce injury to the inferior alveolar nerve. Mechanical allodynia was monitored after subcutaneous injection of BoNT-A at 3, 7, or 12 d after malpositioned dental implant surgery. Subcutaneous injections of 1 or 3 U/kg of BoNT-A on postoperative day 3 significantly attenuated mechanical allodynia, although 0.3 U/kg of BoNT-A did not affect the air-puff threshold. A single injection of 3 U/kg of BoNT-A produced prolonged antiallodynic effects over the entire experimental period. Treatment with BoNT-A on postoperative days 7 and 12, when pain had already been established, also produced prolonged antiallodynic effects. Double treatments with 1 U/kg of BoNT-A produced prolonged, more antiallodynic effects as compared with single treatments. Subcutaneous administration of 3 U/kg of BoNT-A significantly inhibited the upregulation of Nav isoform 1.7 (Nav1.7) expression in the trigeminal ganglion in the nerve-injured animals. These results suggest that antinociceptive effects of BoNT-A are mediated by an inhibition of upregulated Nav1.7 expression in the trigeminal ganglion. BoNT-A is therefore a potential new therapeutic agent for chronic pain control, including neuropathic pain.

Malonyl coenzyme A affects insulin-stimulated glucose transport in myotubes.

There seems to be an association between increased concentrations of malonyl coenzyme A (malonyl CoA) in skeletal muscle and diabetes and/or insulin resistance. The purpose of the current study was to test the hypothesis that treatments designed to manipulate malonyl CoA concentrations would affect insulin-stimulated glucose transport in cultured C2C12 myotubes. We assessed glucose transport after polyamine-mediated delivery of malonyl CoA to myotubes, after incubation with dichloroacetate (which reportedly increases malonyl CoA levels), or after exposure of myotubes to 2-bromopalmitate, a carnitine palmitoyl transferase I inhibitor. All three of these treatments prevented stimulation of glucose transport by insulin. We also assayed glucose transport after 30 min of inhibition of acetyl coenzyme A carboxylase (ACC), the enzyme which catalyzes the production of malonyl CoA. Three unrelated ACC inhibitors (diclofop, clethodim, and Pfizer CP-640186) all enhanced insulin-stimulated glucose transport. However, none of the treatments designed to manipulate malonyl CoA concentrations altered markers of proximal insulin signaling through Akt. The findings support the hypothesis that acute changes in malonyl CoA concentrations affect insulin action in muscle cells but suggest that the effects do not involve alterations in proximal insulin signaling.

Peripheral glutamate receptors participate in interleukin-1beta-induced mechanical allodynia in the orofacial area of rats.

The present study was performed to examine peripheral cytokine-induced mechanical allodynia in the orofacial area and to investigate whether peripheral excitatory amino acids participate in the cytokine-induced mechanical allodynia. Experiments were carried out on male Sprague-Dawley rats. After interleukin-1beta (IL-1beta) was applied subcutaneously to the orofacial area, we examined withdrawal responses produced by air puffs applied to the IL-1beta injection site. The threshold of air puffs that produced withdrawal behavioral responses decreased significantly in a dose-dependent manner after injection of IL-1beta. Pretreatment with an IL-1 receptor antagonist abolished the decrease in the threshold of air puffs. Pretreatment with dl-2-amino-5-phosphonvaleric acid, an N-methyl-d-aspartic acid (NMDA) receptor antagonist, did not affect IL-1beta-induced mechanical allodynia. However, pretreatment with 6,7-dinitroquinoxaline-2,3-dione, a non-NMDA receptor antagonist, abolished the decrease in the threshold of air puffs. These results suggest that peripheral cytokine can produce mechanical allodynia in the orofacial area and that excitatory amino acids can modulate IL-1beta-induced mechanical allodynia via non-NMDA receptors.

Central cyclooxygenase-2 participates in interleukin-1 beta-induced hyperalgesia in the orofacial formalin test of freely moving rats.

The present study was performed to investigate effects of central cyclooxygenase (COX) on interleukin (IL)-1beta-induced hyperalgesia in the orofacial area. Experiments were carried out on 72 male Sprague-Dawley rats weighing 220-280 g. Surgical procedures were performed under pentobarbital sodium. We examined noxious behavioral scratching responses induced by 50 microl of 5% formalin injected subcutaneously into the vibrissa pad without any restraints. The orofacial formalin responses exhibited two distinct phases with early responses (0-10 min) and continuous prolonged responses (11-45 min). Intracisternal injection of 100 pg IL-1beta significantly increased noxious behavioral responses. Pretreatment with indomethacin, a non-selective COX inhibitor, or NS-398, a selective COX-2 inhibitor, blocked IL-1beta-induced hyperalgesic responses. However, pretreatment with SC-560, a selective COX-1 inhibitor, did not change hyperalgesic response to IL-1beta. These data suggest that central IL-1beta modulates the transmission of nociceptive information in the orofacial area and that central COX-2 plays an important role in IL-1beta-induced hyperalgesia.

Microinjection of arginine vasopressin into the central nucleus of amygdala suppressed nociceptive jaw opening reflex in freely moving rats.

This study was performed to examine the antinociceptive effect after microinjection of arginine vasopressin (AVP) into the central nucleus of amygdala. We recorded the jaw opening reflex in freely moving rats. After injection of 0.2 or 0.4 nM AVP into the central nucleus of amygdala, digastric electromyogram (dEMG) was suppressed to 55 +/- 5% or 88 +/- 3 of the control. Artificial cerebrospinal fluid had no effects on the basal dEMG activity. V(1) vasopressin receptor antagonist blocked the suppressive effect produced by microinjection of 0.4 nM AVP from 53 +/- 3 to 81 +/- 3% of the control. However, V(2) vasopressin receptor antagonist did not affect changes in dEMG. We observed dEMG activity after intracerebroventricular injection of naloxone, methysergide, or phentolamine. All drugs did not affect the basal dEMG activity at our dose. Naloxone blocked the suppressive effect of 0.4 nM AVP from 42 +/- 4 to 79 +/- 5% of the control. Methysergide also inhibited the suppression of dEMG from 44 +/- 3 to 83 +/- 6% of the control. However, phentolamine, an alpha-adrenergic receptor antagonist, did not affect the suppression of dEMG. These results indicate AVP in the central nucleus of amygdala has potent analgesic effects in the orofacial area. The antinociception of central AVP seems to be mediated by opioid and serotonergic pathways.

Skeletal muscle respiratory uncoupling prevents diet-induced obesity and insulin resistance in mice.

To determine whether uncoupling respiration from oxidative phosphorylation in skeletal muscle is a suitable treatment for obesity and type 2 diabetes, we generated transgenic mice expressing the mitochondrial uncoupling protein (Ucp) in skeletal muscle. Skeletal muscle oxygen consumption was 98% higher in Ucp-L mice (with low expression) and 246% higher in Ucp-H mice (with high expression) than in wild-type mice. Ucp mice fed a chow diet had the same food intake as wild-type mice, but weighed less and had lower levels of glucose and triglycerides and better glucose tolerance than did control mice. Ucp-L mice were resistant to obesity induced by two different high-fat diets. Ucp-L mice fed a high-fat diet had less adiposity, lower levels of glucose, insulin and cholesterol, and an increased metabolic rate at rest and with exercise. They were also more responsive to insulin, and had enhanced glucose transport in skeletal muscle in the setting of increased muscle triglyceride content. These data suggest that manipulating respiratory uncoupling in muscle is a viable treatment for obesity and its metabolic sequelae.

Nutrition in the Republic of Korea.

Until the 1970s, the Korean economy was dominantly agriculture, but nowadays, less than 10 % of the population lives in a rural area, and it is expected that within a generation the proportion of the population engaged in agriculture will be less than 5 %. The living standard is rising as the national economy benefits from the increased sale of industrial products. The dietary patterns are being changed. The diet has changed from one based predominantly on starch based food such as cereals or roots and vegetables to one in which animal products take great prominence with consequent increases in animal fat and protein. The move from simple unrefined foods to more refined and complex manufactured foods has become commonplace. As a result, the general nutritional situation has been improved. Such improvement, however, has brought about an increase in overnutrition in more affluent sections of the population, whereas dietary inadequacy among the lower socio-economic groups and vulnerable classes still persists. Overall, Korea suffers from both undernutrition and overnutrition. The national school feeding program started in 1953 after the Korean War with the support of UNICEF, CARE, and USAID as a relief food program and is now expanding successfully to a self-supporting nationwide scale. The applied nutrition project in rural areas introduced in 1967 with the support of UNICEF, FAO, WHO, and the Korean government continues successfully to the present day. A national dietary survey has been carried out once a year since 1969, and once every 3 years from 1998. Korean recommended dietary allowances were established in 1962 and have been revised every 5 years. The government intends to establish national dietary guidelines for health promotion and prevention of chronic degenerative diseases. Nutrition education and research are also very important national undertakings.